Frameless stereotaxy in subthalamic deep brain stimulation: 3-year clinical outcome.

Abstract:
BACKGROUND
In most centers, the surgery of deep brain stimulation (DBS) is performed using a stereotactic frame. Compared with frame-based technique, frameless stereotaxy reduces the duration of surgical procedure and patient's discomfort, with lead placing accuracy equivalent after the learning curve. Although several studies have investigated the targeting accuracy of this technique, only a few studies reported clinical outcomes, with data of short-term follow-up.

OBJECTIVE
To assess clinical efficacy and safety of frameless bilateral subthalamic nucleus (STN) DBS in Parkinson's disease (PD) patients at 1- and 3-year follow-up.

METHODS
Consecutive PD patients who underwent bilateral STN-DBS with a manual adjustable frameless system were included in the study. The data were collected retrospectively.

RESULTS
Eighteen PD patients underwent bilateral STN-DBS implant and were included in the study. All patients completed 1-year observation and ten of them completed 3-year observation. At 1-year follow-up, motor efficacy of STN stimulation in off-med condition was of 30.1% (P = 0.003) and at 3-year follow-up was of 36.3%, compared with off-stim condition at 3-year follow-up (P = 0.005). Dopaminergic drugs were significantly reduced by 31.2% 1 year after the intervention (P = 0.003) and 31.7% 3 years after the intervention (P = 0.04). No serious adverse events occurred during surgery.

CONCLUSIONS
Frameless stereotaxy is an effective and safe technique for DBS surgery at 1- and 3-year follow-up, with great advantages for patients' discomfort during surgery.

D046690:Deep Brain Stimulation
D006801:Humans
D038361:Neuronavigation
D010300:Parkinson Disease
D012189:Retrospective Studies
D020531:Subthalamic Nucleus
D016896:Treatment Outcome

Frameless
Deep brain stimulation
Subthalamic nucleus
Parkinson’s disease
Personalized medicine


Is the diatom sex clock a clock?

Abstract: The unique life cycle of diatoms with continuous decreasing and restoration of the cell size leads to periodic fluctuations in cell size distribution and has been regarded as a multi-annual clock. To understand the long-term behaviour of a population analytically, generic mathematical models are investigated algebraically and numerically for their capability to describe periodic oscillations. Whereas the generally accepted simple concepts for the proliferation dynamics do not sustain oscillating behaviour owing to broadening of the size distribution, simulations show that a proposed limited lifetime of a newly synthesized cell wall slows down the relaxation towards a time-invariant equilibrium state to the order of a hundred thousand generations. In combination with seasonal perturbation events, the proliferation scheme with limited lifetime is able to explain long-lasting rhythms that are characteristic for diatom population dynamics. The life cycle thus resembles a pendulum clock that has to be wound up from time to time by seasonal perturbations rather than an oscillator represented by a limit cycle.

Fuhrmann-Lieker|Thomas|T| Kubetschek|Nico|N| Ziebarth|Jonas|J| Klassen|Roland|R| Seiler|Werner|W|

diatoms
clocks
oscillations
discrete models
matrix models


Quantification of anatomical variation at the atlanto-occipital articulation: morphometric resolution of commingled human remains within the repatriation documentation process.

Abstract: Within many institutional collections are skeletal and mummified human remains representing a part of our species' adaptation and evolution to various biocultural environments. Archaeologically recovered individuals come from deep into our past, and possess information that provides insight into population history, genetics, diet, health and other questions relevant to all living peoples. Academic concerns have been raised regarding the reinterment of these collections due to the rise of the international repatriation movement, the passage of various laws and implementation of institutional policies. While all potential research questions cannot be anticipated, the proactive documentation of collections is one way to ensure primary data are maintained for future study. This paper explores developments in digitization technology that allow the archive of virtual copies of human remains, and an example of how anatomical and archaeological collections can be digitized towards pragmatic research goals. The anatomical variability of the human atlanto-occipital (AO) articular surfaces was studied using non-metric categorical shape, 2D measurement and 3D morphometric analyses to provide reference standards for the reassociation of individuals from commingled skeletal remains, such as found in some archaeological sites or forensic investigations including mass grave or mass disaster recovery scenes. Results suggest that qualitative shape observations and caliper-derived measurements of the articulating AO condyles tend to display significant sexual dimorphism and biological ancestry-related size and shape differences. Variables derived from a scanned 3D mesh, such as condylar angle and articular surface curvature, quantify biomechanical variation and display a stronger congruency within individuals. It is recommended that a two-stage approach involving initial screening and identification of possible reassociation candidates is accomplished with a linear osteometric approach, followed by 3D laser scanning of the candidate joint surfaces for morphometric analyses to confirm reassociations when destructive DNA typing is not allowed or otherwise impractical due to cost or other resource restrictions.

Dudar|J Christopher|JC|
Castillo|Eric R|ER|

morphometric
commingled human remains
repatriation
3D digitization
atlanto-occipital joint
atlas vertebra
occipital condyles


Head injury metric response in finite element ATDs and a human body model in multidirectional loading regimes.

Abstract: Objective: The objective was to quantify head injury metric sensitivity of the 50th percentile male Hybrid III, THOR, and Global Human Body Models Consortium simplified occupant (GHBMC M50-OS) to changes in loading conditions in loading regimes that may be experienced by occupants of spaceflight vehicles or highly autonomous vehicles (HAVs) with nontraditional seating configurations.Methods: A Latin hypercube (LHD) design of experiments (DOE) was employed to develop boundary conditions for 455 unique acceleration profiles. Three previously validated finite element (FE) models of the Hybrid III anthropomorphic test device (ATD), THOR ATD, and GHBMC M50-OS were positioned in an upright 90°-90°-90° seat and with a 5-point belt. Acceleration pulses were applied to each of the three occupants in the ± X, +Y, and ± Z directions, with peak resultant acceleration magnitudes ranging from 5 to 20 G and times to peak ranging from 32.5 to 120.8 ms with duration 250 ms, resulting in 1,248 simulations. Head injury metrics included peak linear head acceleration, peak rotational head acceleration, head injury criteria (HIC15), and brain injury criteria (BrIC). Injury metrics were regressed against boundary condition parameters using 2nd order multiple polynomial regression, and compared between occupants using matched pairs Wilcoxon signed rank analysis.Results: Across the 416 matched-simulations that reached normal termination with all three models, HIC15 values ranged from 1.0-396.5 (Hybrid III), 1.2-327.9 (THOR), and 0.6-585.6 (GHBMC). BrIC ranged from 0.03-0.95 (Hybrid III), 0.03-1.21 (THOR), and 0.04-0.84 (GHBMC). Wilcoxon signed rank analysis demonstrated significant pairwise differences between each of the three occupant models for head injury metrics. For HIC15, the largest divergence between GHBMC and the ATDs was observed in simulations with components of combined underbody and rear impact loading. The three models performed most similarly with respect to BrIC output when loaded in a frontal direction. Both the GHBMC and the Hybrid III produced lower values of BrIC than the THOR on average, with the differences most pronounced in rear impact loading.Conclusion: In conclusion, observed differences between the occupant models' head injury metric output were quantified. Loading direction had a large effect on metric outcome and metric comparability across models, with frontal and rear impacts with low vertical acceleration tending to be the most similar. One explanation for these differences could be the differences in neck stiffness between the models that allowed more rotation in the GHBMC and THOR. Care should be taken when using ATDs as human volunteer surrogates in these low energy events.

Jones|Derek A|DA|
Gaewsky|James P|JP|
Somers|Jeffrey T|JT|
Gayzik|F Scott|FS|
Weaver|Ashley A|AA|0000-0002-4383-0106
Stitzel|Joel D|JD|


Zinc Protects against Heat Stress-Induced Apoptosis via the Inhibition of Endoplasmic Reticulum Stress in TM3 Leydig Cells.

Abstract: Heat stress (HS)-induced apoptosis in Leydig cells is mediated by various molecular mechanisms, including endoplasmic reticulum (ER) stress. Zinc, an inorganic mineral element, exhibits several cytoprotective properties, but its potential protective action against Leydig cell apoptosis and the related molecular mechanisms has not been fully elucidated. In this study, we evaluated the effects of zinc sulfate, a predominant chemical form of zinc, exerted on cell viability, apoptosis, and testosterone production in HS-treated TM3 Leydig cells and investigated the underlying signaling pathways. HS treatment inhibited cell viability and induced apoptosis, which was accompanied by the induction of the activity of caspase 3, an executioner of apoptosis, involved in the expression of pro-apoptotic protein B cell lymphoma 2-associated X protein (Bax), and in the reduction of the expression of anti-apoptotic protein B cell lymphoma 2 (Bcl-2), thereby activating ER stress marker protein expression (glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP)). However, zinc sulfate led to the attenuation of deleterious effects, including increases in apoptosis, caspase-3 activity, Bax, GRP78, and CHOP expression, and decreases in cell viability and Bcl-2 protein expression in cells treated with HS or thapsigargin (an ER stress activator). Furthermore, 4-phenylbutyric acid (an ER stress inhibitor) treatment markedly alleviated the HS-induced adverse effects in cells exposed to HS, which was similar to zinc sulfate. Additionally, zinc sulfate supplementation in the culture medium effectively restored the HS-induced decrease in testosterone levels in HS-treated cells. In summary, these findings indicate that HS triggers apoptosis in TM3 Leydig cells via the ER stress pathway and that zinc confers protection against these detrimental effects. This study provides new insights into the benefits of using zinc against HS-induced apoptosis and cell injury.

Zinc
Apoptosis
Endoplasmic reticulum stress
Leydig cells
Heat stress


Stability of Individuals' Definitions of Success and the Influence of Perceived Motivational Climate: A Longitudinal Perspective.

Abstract: In the present study, we investigated the stability and malleability of cadets' definitions of success (mastery and performance goal orientations) contextualized within a certain motivational climate (mastery and performance climates). Based on data from three military academies, the results revealed that cadets' goal orientations and their perceptions of the motivational climate remained relatively stable throughout the 2 years of study across three time-points. We also found that a mastery climate predicted individual mastery orientation, and that a performance climate predicted individual performance orientation. These findings contribute to achievement goal theory by clarifying the importance of considering goal orientation contextualized within a certain motivational climate over time. Implications for future research and practice are discussed.

Nerstad|Christina G L|CGL|
Buch|Robert|R|
Dysvik|Anders|A|
Säfvenbom|Reidar|R|

stability
perceived motivational climate
cadets
goal orientation
longitudinal design


M2 Macrophages in Crystal Storing Histiocytosis Associated with Plasma Cell Myeloma.

Abstract: Crystal Storing Histiocytosis (CSH) is a rare entity occurring in association with underlying lymphoproliferative disorders and plasma cell neoplasms. It denotes accumulation of immunoglobulin crystals in the histiocyte cytoplasm. In this study, we report a patient with plasma cell myeloma who presented with bilateral comminuted femur fractures. Histological examination of fracture tissue revealed hypercellular (~100%) marrow with extensive involvement by sheets of histiocytes with abundant eosinophilic cytoplasm admixed with scattered plasma cells. Intracytoplasmic diamond and rhomboid crystals within histiocytes were demonstrated by electron microscopy. Immunohistochemistry highlighted monotypic plasma cells with kappa restriction, representing 20-30% of marrow cellularity; however, non-polarizable cytoplasmic striations in histiocytes were negative for light chain expression. A diagnosis of crystal-storing histiocytosis associated with plasma cell myeloma was rendered. Further evaluation of these macrophages is positive for CD163 and COX2 and shows pSTAT3 with variable nuclear staining in some histiocytes. This case demonstrates that numerous M2 macrophages are present as crystal storing histiocytosis; and this knowledge might convey prognostic and therapeutic significance for the patients with crystal storing histiocytosis.

Jaitly|Vanya|V|
Hu|Zhihong|Z|
Ayala|Gustavo|G|
Wahed|Md Amer|MA|
Nguyen|Nghia D|ND|
Brown|Robert E|RE|

M2 macrophages
crystal storing histiocytosis
plasma cell myeloma
therapeutic significance
STAT3
Tumor associated macrophages (TAMs)
prognosis


Occurrence of human-pathogenic Enterocytozoon bieneusi, Giardia duodenalis and Cryptosporidium genotypes in laboratory macaques in Guangxi, China.

Abstract: Captive nonhuman primates have been identified as common hosts of Enterocytozoon bieneusi, Giardia duodenalis, Cryptosporidium hominis, and Cyclospora spp., thus are potential reservoirs of some enteric parasites in humans. However, few studies have examined the source and human-infective potential of enteric parasites in laboratory nonhuman primates. In the present work, 205 fecal specimens were collected from three groups of captive Macaca fascicularis kept in different densities in a laboratory animal facility in Guangxi, China, and examined by PCR for E. bieneusi, G. duodenalis, Cryptosporidium spp., and Cyclospora spp. The infection rates of E. bieneusi and G. duodenalis were 11.3% and 1.2% in Group 1 (young animals kept individually; n=168), 72.2% and 11.1% in Group 2 (young animals kept in groups; n=18), and 31.6% and 5.3% in Group 3 (adults kept in groups; n=19), respectively. Sequence analysis of PCR products showed the presence of five E. bieneusi genotypes, with genotype D (in 16/36 genotyped specimens) and a new genotype (in 15/36 genotyped specimens) as the dominant genotypes. All five E. bieneusi genotypes belonged to the zoonotic group (Group 1). The G. duodenalis genotypes (assemblages AII and B) in five specimens and C. hominis subtype (IdA14) in one specimen were also known human-pathogens, although the Cyclospora seen in one animal appeared to be unique to macaque monkeys. The higher infection rate in younger animals reared in groups and common occurrence of zoonotic genotypes indicated that human-pathogenic E. bieneusi could be transmitted efficiently in captive nonhuman primates, and group-housing was a risk factor for transmission of zoonotic pathogens in young nonhuman primates in research facilities.

Ye|Jianbin|J|
Xiao|Lihua|L|
Li|Jian|J|
Huang|Weiyi|W|
Amer|Said E|SE|
Guo|Yaqiong|Y|
Roellig|Dawn|D|
Feng|Yaoyu|Y|

Enterocytozoon bieneusi
Giardia
Cryptosporidium
Cyclospora
Macaca fascicularis


Limb apraxia and the left parietal lobe.

Abstract: Limb apraxia is a heterogeneous disorder of skilled action and tool use that has long perplexed clinicians and researchers. It occurs after damage to various loci in a densely interconnected network of regions in the left temporal, parietal, and frontal lobes. Historically, a highly classificatory approach to the study of apraxia documented numerous patterns of performance related to two major apraxia subtypes: ideational and ideomotor apraxia. More recently, there have been advances in our understanding of the functional neuroanatomy and connectivity of the left-hemisphere "tool use network," and the patterns of performance that emerge from lesions to different loci within this network. This chapter focuses on the left inferior parietal lobe, and its role in tool and body representation, action prediction, and action selection, and how these functions relate to the deficits seen in patients with apraxia subsequent to parietal lesions. Finally, suggestions are offered for several future directions that will benefit the study of apraxia, including increased attention to research on rehabilitation of this disabling disorder.

limb apraxia
parietal
action
tool use
body representations
prediction
action selection
gestures
imitation
praxis


Aberrant Default Mode Network Underlying the Cognitive Deficits in the Patients With Late-Onset Depression.

Abstract: Late-onset depression (LOD) is regarded as a risk factor or a prodrome of Alzheimer's disease (AD). Moreover, LOD patients with cognitive deficits have the higher risk of subsequent AD. Thus, it is necessary to understand the neural underpinnings of cognitive deficits and its pathological implications in LOD. Consistent findings show that the default mode network (DMN) is an important and potentially useful brain network for the cognitive deficits in LOD patients. In recent years, genetics has been actively researched as a possible risk factor in the pathogenesis of LOD. So, in this review, we discuss the current research progress on the cognitive deficits and DMN in LOD through a combined view of brain network and genetics. We find that different structural and functional impairments of the DMN might be involved in the etiological mechanisms of different cognitive impairments in LOD patients.

default mode network
cognitive deficits
late-onset depression
genetics
Alzheimer’s disease


Effect of in-hospital glycemic variability on mortality in patients with diabetes.

Abstract:
INTRODUCTION
The aim of this study was to evaluate the impact of mean blood glucose (MBG) and glycaemic variability (GV) during hospitalisation on mortality after discharge.

MATERIAL AND METHODS
We conducted a retrospective longitudinal analytical cohort study that included patients discharged form a department of internal medicine with a diabetes-related diagnosis. The evaluated prognosis was mortality. During hospitalisation, the patients' clinical, laboratory and glycaemic control-related variables were recorded (MBG, GV and hypoglycaemia). The GV was measured with the coefficient of variation (CV). We calculated the mortality rates for every 1000 patient-years and compared them with Kaplan-Meier curves. We determined the predictors of mortality by performing a Cox regression.

RESULTS
The study included 276 patients with a mean age of 77.6 (SD, 10.2) years. The median outpatient follow-up duration was 2.7 years. In the multivariate analysis, an MBG > 140 mg/dL (HR = 1.72; 95% CI 1.14-2.61; p = .01) and a CV > 0.29 (HR = 1.52; 95% CI 1.12-2.06; p = .006), but not the presence of hypoglycaemia, were additively and independently associated with an increased risk of mortality. An MG > 140 mg/dL with a CV > 0.29 increased the mortality rates (123 vs. 317 per 1000 patient-year; p < .001) and the adjusted mortality risk (HR = 2.70; 95% CI 1.71-4.27; p < .001) compared with having an MBG ≤ 140 mg/dL.

CONCLUSION
The simultaneous presence of a high MBG level and CV constitutes a powerful tool for stratifying mortality risk after hospital discharge.

Jordán-Domingo|M|M|
Gimeno-Orna|J A|JA|
Lahoza-Pérez|M C|MC|
Ilundain-González|A I|AI|
Agudo-Tabuenca|A|A|
Sáenz-Abad|D|D|

Diabetes
Glycaemic variability
Insulin
Insulina
Long-term mortality
Mortalidad a largo plazo
Variabilidad glucémica


Impaired speed encoding and grid cell periodicity in a mouse model of tauopathy.

Abstract: Dementia is associated with severe spatial memory deficits which arise from dysfunction in hippocampal and parahippocampal circuits. For spatially sensitive neurons, such as grid cells, to faithfully represent the environment these circuits require precise encoding of direction and velocity information. Here, we have probed the firing rate coding properties of neurons in medial entorhinal cortex (MEC) in a mouse model of tauopathy. We find that grid cell firing patterns are largely absent in rTg4510 mice, while head-direction tuning remains largely intact. Conversely, neural representation of running speed information was significantly disturbed, with smaller proportions of MEC cells having firing rates correlated with locomotion in rTg4510 mice. Additionally, the power of local field potential oscillations in the theta and gamma frequency bands, which in wild-type mice are tightly linked to running speed, was invariant in rTg4510 mice during locomotion. These deficits in locomotor speed encoding likely severely impact path integration systems in dementia.

Ridler|Thomas|T|0000-0002-8236-9033
Witton|Jonathan|J|
Phillips|Keith G|KG|
Randall|Andrew D|AD|0000-0001-8852-3671
Brown|Jonathan T|JT|0000-0001-5269-7661

grid cell
mouse
dementia
entorhinal cortex
running speed
Tau
neuroscience


Progress in rapid optical assays for heavy metal ions based on the use of nanoparticles and receptor molecules.

Abstract: This review (with 230 refs.) covers recent progress in rapid optical assays for heavy metals (primarily lead and mercury as the most relevant) based on the use of nanoparticles and receptor molecules. An introduction surveys the importance, regulatory demands (such as maximum permissible concentrations) and potential and limitations of various existing methods. This is followed by a general discussion on the use of nanoparticles in optical assays of heavy metals (including properties, basic mechanisms of signal generation). The next sections cover methods for the functionalization of nanoparticles with (a) sulfur-containing compounds (used for modification of nanoparticles or added to the reaction medium), (b) nitrogen-containing compounds (such as amino acids, polypeptides, and heterocyclic molecules), and (c) oxygen-containing species (such as hydroxy and carbonyl compounds). This is continued by a specific description of specific assays based on the use of aptamers as receptors, on the use of deoxyribozymes as synthetic reaction catalysts, of G-quadruplex aptamers, of aptamers in logic gate-type of assays of linear (unstructured) aptamers ("hairpins"), and on the use of aptamers in lateral flow assays. A next section covers assays based on the employment of antibodies as receptors (used in the immunoassay development). The properties of various nanoparticles and their applicability in optical assays are also discussed in some detail. Final sections discuss the selectivity of assays, potential interferences by other cations, methods for their elimination, and also matrix effects and approaches for sample pretreatment. A concluding section discusses current challenges and future trends. Analysis based on enzyme inhibition assay is not treated here but enzyme-like action of some receptor molecules such as DNAzymes is discussed. Graphical abstract Schematic presentation of main principles of application of various nanoparticles with receptor molecules (S-, N-, O-containing, heterocyclic compounds, proteins, antibody, aptamers) for heavy metals ions detection. The included methods cover optical assays with description of mechanisms of interactions and signal generation.

Berlina|Anna N|AN|
Zherdev|Anatoly V|AV|
Dzantiev|Boris B|BB|

Lead
Mercury
Modification
Detection
Carbon nanoparticles
Gold nanoparticles
Magnetic particles
Nanoclusters
Quantum dots
Silver nanoparticles


Molecular detection of metallo-β-lactamase genes, bla IMP-1, bla VIM-2 and bla SPM-1 in imipenem resistant Pseudomonas aeruginosa isolated from clinical specimens in teaching hospitals of Ahvaz, Iran.

Abstract:
BACKGROUND AND OBJECTIVES
Carbapenem resistant Pseudomonas aeruginosa is a serious cause of nosocomial infections. The main purpose of the study is to determine the prevalence rate of imipenem resistant Pseudomonas aeruginosa carrying metallo-ß-lactamase (MBL) genes.

MATERIAL AND METHODS
236 Pseudomonas aeruginosa isolates were collected from teaching hospitals of Ahvaz University of Medical Sciences during a period of 9 months in 2012. These strains were identified using conventional microbiological tests. The susceptibility of isolates to antibiotics were assessed using disk diffusion test. The IMP-EDTA combination disk phenotypic test was performed for detection of MBL producing strains. Finally, polymerase chain reaction (PCR) was performed to detect MBL genes, bla IMP-1, bla VIM-2 and bla SPM-1 in imipenem resistant strains.

RESULTS
Out of 236 examined isolates, 122 isolates (51.4%) were resistant to imipenem. The IMP-EDTA combination test showed that among 122 imipenem resistant strains, 110 strains (90%) were phenotipically MBL producers. Additionally, the results of PCR method showed that 2 strains (1.6%) and 67strains (55%) of imipenem resistant Pseudomonas aeruginosa isolates contained bla VIM-2 and bla IMP-1 genes respectively. No SPM-1gene was found in the examined samples.

CONCLUSION
Resistance of P. aeruginosa isolates to imipenem due to MBL enzymes is increasing in Ahavaz. Because of clinical significance of this kind of resistance, rapid detection of MBL producing strains and followed by appropriate treatment is necessary to prevent the spreading of these organisms.


A polymeric silver thiosaccarinate complex with a two-dimensional triply entangled mesh and argentophilic interactions.

Abstract: Silver(I) complexes with sulfur-donor ligands have a broad range of pharmacological applications. One of the most important factors for tuning the biological activity is the type of donor atom and the ease of ligand replacement. Silver thiosaccharinates display a wide range of structures from mono- to polynuclear complexes. We report the synthesis, crystal structure and vibrational spectroscopic analysis of a two-dimensional Ag(I)-thiosaccharinate coordination polymer, namely poly[tris(μ2-4,4'-bipyridine-κ(2)N:N')bis(μ3-1,1-dioxo-1,2-benzisothiazole-3-thiolato-κ(3)N:S(3):S(3))bis(μ2-1,1-dioxo-1,2-benzisothiazole-3-thiolato-κ(2)S(3):S(3))tetrasilver(I)], [Ag2(C7H4NO2S2)2(C10H8N2)1.5]n, with 4,4'-bipyridine acting as a spacer. A relevant feature of the structure is the presence of an unusually short Ag...Ag separation of 2.8859 (10) Å, well within the range of argentophilic interactions and confirmed as such by Raman analysis of the low-frequency spectrum. From a topological point of view, the structure presents interpenetration in the form of a threefold entangled 2D→2D mesh (2D is two-dimensional).

Dennehy|Mariana|M| Delgado|Fermín|F| Freire|Eleonora|E| Halac|Emilia|E| Baggio|Ricardo|R|

two-dimensional silver(I) coordination polymer


Acute aflatoxin B1 - Induced hepatotoxicity alters gene expression and disrupts lipid and lipoprotein metabolism in rats.

Abstract: In this study, alterations in lipid metabolism associated with acute aflatoxin B1 (AFB1) induced hepatotoxicity and gene expression changes underlying these effects were investigated. Rats were orally administered three doses (0.25 mg/kg, 0.5 mg/kg and 1.0 mg/kg) of AFB1 for seven days; after which blood was collected and liver excised. Lipid profiles of plasma and liver were determined spectrophotometrically while the expression of genes associated with lipid and lipoprotein metabolism was assayed by reverse transcriptase polymerase chain reaction. Acute exposure to AFB1 increased the levels of plasma and liver cholesterol, triglycerides and phospholipids. AFB1 at 0.5 mg/kg and 1.0 mg/kg resulted in a dose-dependent (1.2 and 1.5 fold, respectively) downregulation of hepatic Cpt1a with a concomitant 1.2 and 1.5 fold increase in the level of plasma FFA, respectively. A similar observation of 1.2 and 1.3 fold increase was also observed in plasma triglyceride concentration, at both respective doses. AFB1 also decreased the relative expression of Ahr, Lipc and Lcat whereas, it upregulated Scarb1 in a dose dependent manner. AFB1-induced dysregulation of the expression of lipid and lipoprotein metabolizing genes may be one mechanism linking AFB1 to altered lipid metabolism and ultimately risk for coronary heart disease.

Rotimi|Oluwakemi Anuoluwapo|OA|
Rotimi|Solomon Oladapo|SO|
Duru|Chibueze Uchechukwu|CU|
Ebebeinwe|Ogheneworo Joel|OJ|
Abiodun|Anthonia Obhio|AO|
Oyeniyi|Boluwaji Oluwamayowa|BO|
Faduyile|Francis Adedayo|FA|

Cpt1a, carnitine palmitoyl transferase 1A

Lcat, lecithin – cholesterol acyltransferase

Scarb1, scavenger receptor class B member 1


Distinguishing anemia and iron deficiency of heart failure: signal for severity of disease or unmet therapeutic need?

Abstract: Despite advances in the management of heart failure (HF), quality of life and other outcomes remain suboptimal for many patients. Anemia and iron deficiency are comorbidities associated with adverse outcomes, although their pathophysiology in the setting of HF is not entirely understood. Anemia and iron deficiency may exist independently and may be a consequence of the systemic inflammatory state characterized by chronic HF. However, it is unclear whether serum hemoglobin concentrations and other hematologic parameters serve as markers for the severity of disease or represent novel therapeutic targets. Research in this area has focused primarily on therapies known to be effective for these conditions in other chronic disease states with similar pathophysiologic features (e.g., end-stage renal disease). Despite its many practical advantages, minimal evidence exists to support the use of oral iron supplementation in this setting. In contrast, intravenous iron has been the subject of several recent investigations, demonstrating improvements in both surrogate and clinical end points, although benefits seem to be the most substantial in patients with concomitant anemia. Erythropoietin-stimulating agents demonstrated early promise in retrospective analyses and small prospective trials, but their benefit was outweighed by a lack of improvement in clinical outcomes and an excess number of thromboembolic events in the largest trial of patients with anemia and HF to date. For acute symptomatic anemia, blood transfusion may be considered, although few trials have included patients with HF, and caution must be exerted in those who are hemodynamically unstable. Based on the currently available evidence, treatment of iron deficiency appears to confer benefit in patients with HF, whereas strategies aimed at improving hemoglobin alone do not. Included is a review of the pathophysiology of these conditions in the setting of HF, clinical trials evaluating pharmacologic therapy, and recommendations for management.

Beavers|Craig J|CJ|
Alburikan|Khalid A|KA|
Rodgers|Jo E|JE|
Dunn|Steven P|SP|
Reed|Brent N|BN|

D006301:Health Services Needs and Demand

anemia
iron deficiency
heart failure
iron supplementation
erythropoietin-stimulating agents
transfusion
cardiology


Inosine in Biology and Disease.

Abstract: The nucleoside inosine plays an important role in purine biosynthesis, gene translation, and modulation of the fate of RNAs. The editing of adenosine to inosine is a widespread post-transcriptional modification in transfer RNAs (tRNAs) and messenger RNAs (mRNAs). At the wobble position of tRNA anticodons, inosine profoundly modifies codon recognition, while in mRNA, inosines can modify the sequence of the translated polypeptide or modulate the stability, localization, and splicing of transcripts. Inosine is also found in non-coding and exogenous RNAs, where it plays key structural and functional roles. In addition, molecular inosine is an important secondary metabolite in purine metabolism that also acts as a molecular messenger in cell signaling pathways. Here, we review the functional roles of inosine in biology and their connections to human health.

inosine
translation
RNA modification
adenosine deaminase acting on RNAs
deamination


Recent Developments in Folate Nutrition.

Abstract: The term folate (vitamin B9) refers to a group of water-soluble compounds that are nutritionally essential for the support of optimal human health and development. Folates participate in numerous one-carbon transfer reactions, including the methylation of important biomolecules (lipids, amino acids, DNA). A deficiency of folate leads to pathological outcomes including anemia and impairments in reproductive health and fetal development. Due to the linkage of impaired folate status with an increased prevalence of neural tube defects (NTDs) in babies, several jurisdictions required the fortification of the food supply with folic acid, a synthetic and stable form of folate. Data from the postfortification era have provided strong evidence for the reduction of NTDs due to folic acid fortification. However, concern is now growing with respect to the amount of synthetic folic acid within the human food supply. Excess folic acid intake has been linked to a masking of vitamin B12 deficiency, and concerns regarding the promotion of folate-sensitive cancers, including colorectal cancer. New strategies to ensure the supply of optimal folate to at-risk populations may be needed, including the use of biofortification approaches, in order to address recent concerns.

Folate
Vitamin B9
Folic acid
Synthetic folic acid
Biofortification approach
Folacin


Human-armadillo interaction in Ceará, Brazil: Potential for transmission of Mycobacterium leprae.

Abstract: Several factors suggest that armadillos present an important risk for human leprosy infection. This study uses semi-structured interviews to better illustrate how human interaction with armadillos may increase the risk of leprosy transmission. The participants were all residents of the state of Ceará, in northeastern Brazil, all acknowledged contact with armadillos either through hunting, through cooking, or through consumption of its meat. This study raises important issues about contact between human beings and armadillos. The interviews provide evidence of numerous situations in which leprosy transmission via the armadillo is possible. At a minimum, people who hunt armadillos need to be made aware of the risk of infection.

Kerr|Ligia|L|
Kendall|Carl|C|
Sousa|Cesar Augusto Barros de|CAB|
Frota|Cristiane Cunha|CC|
Graham|Jove|J|
Rodrigues|Laura|L|
Fernandes|Rafael Lima|RL|
Barreto|Maurício Lima|ML|

Transmission Armadillo Leprosy Infection


Treatment of Leishmania (Leishmania) Amazonensis-Infected Mice with a Combination of a Palladacycle Complex and Heat-Killed Propionibacterium acnes Triggers Protective Cellular Immune Responses.

Abstract: Palladacycle complex DPPE 1.2 was previously reported to inhibit the in vitro and in vivo infection by Leishmania (Leishmania) amazonensis. The aim of the present study was to compare the effect of DPPE 1.2, in association with heat-killed Propionibacterium acnes, on L. (L.) amazonensis infection in two mouse strains, BALB/c and C57BL/6, and to evaluate the immune responses of the treated animals. Foot lesions of L. (L.) amazonensis-infected mice were injected with DPPE 1.2 alone, or associated with P. acnes as an adjuvant. Analysis of T-cell populations in the treated mice and in untreated controls was performed by FACS. Detection of IFN-γ-secreting lymphocytes was carried out by an ELISPOT assay and active TGF-β was measured by means of a double-sandwich ELISA test. The treatment with DPPE 1.2 resulted in a significant reduction of foot lesion sizes and parasite burdens in both mouse strains, and the lowest parasite burden was found in mice treated with DPPE 1.2 plus P. acnes. Mice treated with DPPE 1.2 alone displayed a significant increase of TCD4+ and TCD8+ lymphocytes and IFN-γ secretion which were significantly higher in animals treated with DPPE 1.2 plus P. acnes. A significant reduction of active TGF-β was observed in mice treated with DPPE 1.2 alone or associated with P. acnes. Moreover, DPPE 1.2 associated to P. acnes was non-toxic to treated animals. The destruction of L. (L.) amazonensis by DPPE 1.2 was followed by host inflammatory responses which were exacerbated when the palladacycle complex was associated with P. acnes.

Paladi|Carolina S|CS|
da Silva|Danielle A M|DA|
Motta|Priscila D|PD|
Garcia|Daniel M|DM|
Teixeira|Daniela|D|
Longo-Maugéri|Ieda M|IM|
Katz|Simone|S|
Barbiéri|Clara L|CL|

palladacycle complex
Propionibacterium acnes
Leishmania (Leishmania) amazonensis
adjuvant
cutaneous leishmaniasis


Metabolic rate and resource depletion in the tick Ixodes ricinus in response to temperature.

Abstract: Understanding the effects of temperature on the metabolic activity and the rate of depletion of energy reserves by Ixodes ricinus can represent an important contribution to explaining patterns of tick activity and the likely impacts of environmental change on tick and tick-borne disease risk. Here, a cohort of I. ricinus nymphs, males, and females was collected and placed into incubators at temperatures of between 5 and 30 °C. The protein, carbohydrate, total lipid, neutral lipid, and glycogen levels were measured for nymphs for up to 70 days and adults up to 42 days. In nymphs, at day 0, glycogen was the most abundant metabolite followed by carbohydrate, with relatively low concentrations of protein and lipids. For males, the concentrations of different metabolites were relatively similar. In contrast, for females, concentrations of glycogen and carbohydrate were relatively low compared to those of protein and neutral lipids. Significant exponential declines in metabolite concentrations of all metabolites were detected over time for all life-cycle stages and at all temperatures. Nymphs generally showed lower rates of resource depletion than adults at all temperatures. The lower thresholds for metabolic activity were estimated to be between -10 and -5 °C. The Q10 values, which describe the thermal sensitivity of metabolic rate, were estimated to be relatively low (1.5 for nymphs, 1.71 for males, and 1.63 for females) compared to insects where they are typically around 2.5 (range: 1.5-3), and this is considered to be an adaptation to increase survival during the extended inter-feed intervals.

Ixodes
Metabolite
Blood-feeding
Climate change
Temperature threshold


Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway.

Abstract:
BACKGROUND
Besides its neurotransmitter and vasoconstriction functions, serotonin is an important mediator of numerous biological processes in peripheral tissues including cell proliferation, steatosis, and fibrogenesis. Recent reports indicate that serotonin may promote tumor growth in liver cancer, however, the molecular mechanisms remain elusive. n this study, we investigated the role and molecular signaling mechanisms mediated by serotonin in liver cancer cell survival, drug resistance, and steatosis.

METHODS
Effect of serotonin on modulation of cell survival/proliferation was determined by MTT/WST1 assay. Effect of serotonin on the regulation of autophagy biomarkers and lipid/fatty acid proteins expression, AKT/mTOR and Notch signaling was evaluated by immunoblotting. The role of serotonin in normal human hepatocytes and liver cancer cell steatosis was analyzed by Oil Red O staining. The mRNA expression levels of lipid/fatty acid proteins and serotonin receptors were validated by qRT-PCR. The important roles of autophagy, Notch signaling, serotonin receptors and serotonin re-uptake proteins on serotonin-mediated cell steatosis were investigated by using selective inhibitors or antagonists. The association of peripheral serotonin, autophagy, and hepatic steatosis was also investigated using chronic EtOH fed mouse model.

RESULTS
Exposure of liver cancer cells to serotonin induced Notch signaling and autophagy, independent of AKT/mTOR pathway. Also, serotonin enhanced cancer cell proliferation/survival and drug resistance. Furthermore, serotonin treatment up-regulated the expression of lipogenic proteins and increased steatosis in liver cancer cells. Inhibition of autophagy or Notch signaling reduced serotonin-mediated cell steatosis. Treatment with serotonin receptor antagonists 5-HTr1B and 5-HTr2B reduced serotonin-mediated cell steatosis; in contrast, treatment with selective serotonin reuptake inhibitors (SSRIs) increased steatosis. In addition, mice fed with chronic EtOH resulted in increased serum serotonin levels which were associated with the induction of hepatic steatosis and autophagy.

CONCLUSIONS
Serotonin regulates liver cancer cell steatosis, cells survival, and may promote liver carcinogenesis by activation of Notch signaling and autophagy.

Niture|Suryakant|S|
Gyamfi|Maxwell A|MA|
Kedir|Habib|H|
Arthur|Elena|E|
Ressom|Habtom|H|
Deep|Gagan|G|
Kumar|Deepak|D|

D065626:Non-alcoholic Fatty Liver Disease

Serotonin
Autophagy
Notch signaling
Drug resistance
Cell steatosis


MiR-362 suppresses cervical cancer progression via directly targeting BAP31 and activating TGFβ/Smad pathway.

Abstract: BAP31 (B-cell receptor-associated protein 31) is an important regulator of intracellular signal transduction and highly expressed in several cancer tissues or testicular tissues. Our previous study had revealed that elevated BAP31 plays a crucial role in the progress and metastasis of cervical cancer. Even so, the precise mechanism of abnormal BAP31 elevation in cervical cancer has not been fully elucidated. We revealed that the expression of BAP31 was mainly regulated by microRNA-362 (miR-362), which was markedly downregulated in cervical cancer tissues and negatively correlated with clinical tumor staging. Overexpression of miR-362 inhibited cervical cancer cell proliferation and increased the proportion of apoptotic cells. Furthermore, miR-362 reduced the tumor sizes and prolonged mice survival time in xenograft nude mice model. Finally, we demonstrated that the BAP31/SPTBN1 complex regulated tumor progression through the Smad 2/3 pathway under the control of miR-362. Collectively, our findings demonstrated that miR-362 could work as an anti-oncomiR that inhibits proliferation and promotes apoptosis in cervical cancer cells via BAP31 and TGFβ/Smad pathway. Overexpression of miR-362 might be a potential therapeutic strategy for cervical cancer.

Yang|Shuya|S| Sun|Yuanjie|Y| Jiang|Dongbo|D| Wang|Jing|J| Dang|Erle|E| Li|Zichao|Z| Zhou|Jiayi|J| Lu|Yuchen|Y| Shi|Jingqi|J| Tao|Liang|L| Wang|Jun|J| Jin|Boquan|B| Zheng|Lianhe|L| Yang|Kun|K|0000-0003-0305-6256

D015972:Gene Expression Regulation, Neoplastic


Influence of clamping parameters on the trauma of rabbit small intestine tissue.

Abstract:
BACKGROUND
During clamping operation for minimally invasive intestinal surgery, patients often suffer from small intestine trauma. This phenomenon will lead to various complications, increase recovery time and cause pain for patients.

METHODS
In this paper, preliminary simulations of small intestine clamping operations in the minimally invasive surgery were made by conducting compression tests under different clamping stresses, durations and loading rates. A pathological grading system was designed after microscope observation to quantitatively evaluate the trauma of small intestine tissue.

FINDINGS
Results showed that different traumas: inflammatory cell infiltration, hyperemia, hemorrhage and rupture between serosa and muscularis, as well as villi destruction could be observed on the clamping sites of the small intestine tissue. When the clamping parameters (clamping stress, duration and loading rate) increased, the degree of the tissue trauma increased. There existed safe thresholds for clamping operations, at which severe trauma of small intestine tissues could be avoided in the clamping process.

INTERPRETATION
As the clamping parameters increased, the strain, that is the deformation of the small intestine tissue increased. The increase in the deformation would induce the aggravation of trauma degree.

Wang|Jin|J| Li|Wei|W| Wang|Bingrui|B| Zhou|Zhongrong|Z|

D019060:Minimally Invasive Surgical Procedures

Trauma
Rabbit small intestine
Compression
Laparoscopic grasper
Pathological assessment


Impact of interprofessional service-learning on the effectiveness of knowledge transfer of antimicrobial resistance to Hong Kong elders: a quasi-experiment.

Abstract:
BACKGROUND
Community perception on antimicrobials plays a role in driving the development of antimicrobial resistance (AMR). The aim of the study was to evaluate the impact of interprofessional service-learning on the effectiveness of AMR knowledge transfer in Hong Kong elders aged 65 or above and students from university and secondary schools.

METHODS
A quasi-experimental pretest-posttest controlled study was carried out from July 2018 to March 2019 for elderly subjects and a pre- and post-test were conducted in students from May to August 2018. Elderly subjects were recruited from the university-based community outreach program. The community outreach team consisted of both university and secondary school students. Students were provided with training of geriatric care and AMR before they reached out to the community. The one-to-one intervention with the aid of video and verbal explanation to educate the elderly about the definition, causes, and consequences of AMR, and preventive measures against AMR was provided. Questionnaires on knowledge of antibiotics and AMR were used as tools to reflect on the effectiveness for both students and elderly subjects. The questionnaire was completed twice, before and 1 week after the intervention. Chi-square test, t tests and regression analysis were used to analyze the data.

RESULTS
A total of 93 Chinese elders, 61 of them in the intervention group and 32 in the control group participated in the study. The score obtained by the intervention group increased from 40.1 to 83.3% (p < 0.001) following intervention, while that of control group increased from 33.0 to 44.0% (p < 0.001). The increase attained in the intervention group was significantly greater than that of the control group (p < 0.001). A total of 95 secondary students and 88 university students have completed the pre-post questionnaires with 42.21% and 13% increment in AMR knowledge after the training (p < 0.001).

CONCLUSION
The significant change in knowledge level showed effective AMR knowledge transfer to both elders and students. The study could be used as a reference when allocating resources to implement effective interprofessional service-learning for better community health education in elderly populations.

TRIAL REGISTRATION
This study was approved by the Chinese University of Hong Kong Survey and Behavioural Research Ethics Committee in December 2018 (Ref no. SBRE-18-214).

Lo|Anna C Y|ACY|
Li|Joyce T S|JTS|
Chau|Janita P C|JPC|
Wong|Samuel Y S|SYS|
Hui|David S C|DSC|
Lee|Vivian W Y|VWY|0000-0001-5802-8899

Service-learning
Knowledge transfer
Antimicrobial resistance
Elderly
Interprofessional education


One-shot dilation versus serial dilation technique for access in percutaneous nephrolithotomy: a systematic review and meta-analysis.

Abstract:
OBJECTIVE
The purpose of this study was to systematically review the outcomes of the use of one-shot dilation (OSD) and serial tract dilation for percutaneous nephrolithotomy (PCNL).

METHODS
A systematic review and meta-analysis was conducted. The randomised controlled trials (RCTs) included in the study were identified from EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials. The last search was performed on 30 April 2018. Summary effects were calculated as risk ratios (RRs) with 95% CIs or mean differences (MDs) with 95% CIs. The endpoints included access time, fluoroscopy time, successful dilation rate, stone-free rate, postoperative decrease in haemoglobin levels, transfusion rate, complication rate and length of postoperative hospital stay.

RESULTS
A total of seven RCTs were included in the study, with clinical data reported for 697 patients. The overall access time was approximately 110 s shorter in the OSD group than in the serial dilation group (MD, -110.14; 95% CI -161.99 to -58.30; p<0.0001). The fluoroscopy time was shorter with OSD in all RCTs. In addition, the decrease in postoperative haemoglobin levels was approximately 2.3g/L less in patients in the OSD group than in those in the serial dilation group (MD, -0.23; 95% CI-0.39 to -0.07; p=0.004). No relationship was found between the successful dilation rate, stone-free rate, transfusion rate, or complication rate and the method of tract dilation.

CONCLUSION
OSD is a safe and efficacious tract dilation technique that can reduce the access time, fluoroscopy time and postoperative decrease in haemoglobin level. No difference was found in the successful dilation rate, stone-free rate, transfusion rate or rate of complications between the OSD and serial dilation groups. The difference in the length of postoperative hospital stay was uncertain. OSD may be a better method of tract creation for PCNL.

Peng|Pan-Xin|PX| Lai|Shi-Cong|SC| Ding|Zhen-Shan|ZS| He|Yu-Hui|YH| Zhou|Li-Hua|LH| Wang|Xu-Ming|XM| Zhang|Guan|G|0000-0002-5942-2481

D016032:Randomized Controlled Trials as Topic

one-shot dilation
percutaneous nephrolithotomy
meta-analysis
tract dilatation


Prevalence and Molecular Characterization of mcr-1-Positive Salmonella Strains Recovered from Clinical Specimens in China.

Abstract: The recently discovered colistin resistance element, mcr-1, adds to the list of antimicrobial resistance genes that rapidly erode the antimicrobial efficacy of not only the commonly used antibiotics but also the last-line agents of carbapenems and colistin. This study investigated the prevalence of the mobile colistin resistance determinant mcr-1 in Salmonella strains recovered from clinical settings in China and the transmission potential of mcr-1-bearing mobile elements harbored by such isolates. The mcr-1 gene was recoverable in 1.4% of clinical isolates tested, with the majority of them belonging to Salmonella enterica serotype Typhimurium. These isolates exhibited diverse pulsed-field gel electrophoresis (PFGE) profiles and high resistance to antibiotics other than colistin and particularly to cephalosporins. Plasmid analysis showed that mcr-1 was carried on a variety of plasmids with sizes ranging from ∼30 to ∼250 kb, among which there were conjugative plasmids of ∼30 kb, ∼60 kb, and ∼250 kb and nonconjugative plasmids of ∼140 kb, ∼180 kb, and ∼240 kb. Sequencing of representative mcr-1-carrying plasmids revealed that all conjugative plasmids belonged to the IncX4, IncI2, and IncHI2 types and were highly similar to the corresponding types of plasmids reported previously. Nonconjugative plasmids all belonged to the IncHI2 type, and the nontransferability of these plasmids was attributed to the loss of a region carrying partial or complete tra genes. Our data revealed that, similar to the situation in Escherichia coli, mcr-1 transmission in Salmonella was accelerated by various plasmids, suggesting that transmission of mcr-1-carrying plasmids between different species of Enterobacteriaceae may be a common event.

Cui|Mingquan|M|
Zhang|Jinfei|J|
Gu|Zhen|Z|
Li|Ruichao|R|
Chan|Edward Wai-Chi|EW|
Yan|Meiyin|M|
Wu|Congming|C|
Xu|Xuebin|X|
Chen|Sheng|S|

D024901:Drug Resistance, Multiple, Bacterial


Inhibition of microRNA-500 has anti-cancer effect through its conditional downstream target of TFPI in human prostate cancer.

Abstract:
PURPOSE
We investigated the prognostic potential and regulatory mechanism of microRNA-500 (miR-500), and human gene of tissue factor pathway inhibitor (TFPI) in prostate cancer.

METHODS
MiR-500 expression was assessed by qRT-PCR in prostate cancer cell lines and primary tumors. Cancer patients' clinicopathological factors and overall survival were analyzed according to endogenous miR-500 level. MiR-500 was downregulated in DU145 and VCaP cells. Its effect on prostate cancer proliferation, invasion in vitro, and tumorigenicity in vivo, were probed. Possible downstream target of miR-500, TFPI was assessed by luciferase assay and qRT-PCR in prostate cancer cells. In miR-500-downregulated DU145 and VCaP cells, TFPI was silenced to see whether it was directly involved in the regulation of miR-500 in prostate cancer. TFPI alone was either upregulated or downregulated in DU145 and VCaP cells. Their effect on prostate cancer development was further evaluated.

RESULTS
MiR-500 is upregulated in both prostate cancer cells and primary tumors. In prostate cancer patients, high miR-500 expression is associated with poor prognosis and overall survival. In DU145 and VCaP cells, miR-500 downregulation inhibited cancer proliferation, invasion in vitro, and explant growth in vivo. TFPI was verified to be associated with miR-500 in prostate cancer. Downregulation of TFPI reversed anti-cancer effects of miR-500 downregulation in prostate cancer cells. However, neither TFPI upregulation nor downregulation alone had any functional impact on prostate cancer development.

CONCLUSION
MiR-500 may be a potential biomarker and molecular target in prostate cancer. TFPI may conditionally regulate prostate cancer in miR-500-downregualted prostate cancer cells.

TFPI
prostate
miR-500
cancer proliferation
biomarker
cancer migration


Gene editing of MPS I human fibroblasts by co-delivery of a CRISPR/Cas9 plasmid and a donor oligonucleotide using nanoemulsions as nonviral carriers.

Abstract: Mucopolysaccharidosis type I (MPS I) is an inherited disease caused by the deficiency of alpha-L-iduronidase (IDUA). This study shows the use of nanoemulsions co-complexed with the plasmid of CRISPR/Cas9 system and a donor oligonucleotide aiming at MPS I gene editing in vitro. Nanoemulsions composed of MCT, DOPE, DOTAP, DSPE-PEG, and water were prepared by high-pressure homogenization. The DNA was complexed by adsorption (NA) or encapsulation (NE) of preformed DNA/DOTAP complexes with nanoemulsions at +4/-1 charge ratio. The incubation in pure DMEM or supplemented with serum showed that the complexation with DNA was stable after 1 h of incubation, but the complexes tended to release the adsorbed DNA after 24 h of incubation, while the encapsulated DNA remained complexed in the oil core of the nanoemulsions even 48 h after incubation with DMEM. The treatment of MPS I patient's fibroblasts homozygous for the p.Trp402∗ mutation led to a significant increase in IDUA activity at 2, 15, and 30 days when compared to MPS I untreated fibroblasts. Flow cytometry and confocal microscopy demonstrated that there was a reduction in the area of lysosomes to values similar to normal, an indicator of correction of the cellular phenotype. These results show that the nanoemulsions co-complexed with the CRISPR/Cas9 system and a donor oligonucleotide could effectively transfect MPS I p.Trp402∗ patient's fibroblasts, as well as enable the production of IDUA, and represent a potential new treatment option for MPS I.

Schuh|Roselena Silvestri|RS|
de Carvalho|Talita Giacomet|TG|
Giugliani|Roberto|R|
Matte|Ursula|U|
Baldo|Guilherme|G|
Teixeira|Helder Ferreira|HF|

Gene editing
CRISPR/Cas9
Nanoemulsion
Mucopolysaccharidosis type I
Gene therapy
Nonviral vectors


Nodding syndrome in Mundri county, South Sudan: environmental, nutritional and infectious factors.

Abstract:
BACKGROUND
Nodding Syndrome is a seizure disorder of children in Mundri County, Western Equatoria, South Sudan. The disorder is reported to be spreading in South Sudan and northern Uganda.

OBJECTIVE
To describe environmental, nutritional, infectious, and other factors that existed before and during the de novo 1991 appearance and subsequent increase in cases through 2001.

METHODS
Household surveys, informant interviews, and case-control studies conducted in Lui town and Amadi village in 2001-2002 were supplemented in 2012 by informant interviews in Lui and Juba, South Sudan.

RESULTS
Nodding Syndrome was associated with Onchocerca volvulus and Mansonella perstans infections, with food use of a variety of sorghum (serena) introduced as part of an emergency relief program, and was inversely associated with a history of measles infection. There was no evidence to suggest exposure to a manmade neurotoxic pollutant or chemical agent, other than chemically dressed seed intended for planting but used for food. Food use of cyanogenic plants was documented, and exposure to fungal contaminants could not be excluded.

CONCLUSION
Nodding Syndrome in South Sudan has an unknown etiology. Further research is recommended on the association of Nodding Syndrome with onchocerciasis/mansonelliasis and neurotoxins in plant materials used for food.

Spencer|P S|PS|
Vandemaele|K|K|
Richer|M|M|
Palmer|V S|VS|
Chungong|S|S|
Anker|M|M|
Ayana|Y|Y|
Opoka|M L|ML|
Klaucke|B N|BN|
Quarello|A|A|
Tumwine|J K|JK|

D000818:Animals
D003141:Communicable Diseases
D016001:Confidence Intervals
D004781:Environmental Exposure
D005506:Food Contamination
D006306:Health Surveys
D006801:Humans
D064128:Nodding Syndrome
D016017:Odds Ratio
D036301:Qualitative Research
D013397:Sudan
D015047:Zoonoses

sorghum neurotoxins Dinka Epilepsy Moru filariasis


Computer-aided detection of cerebral microbleeds in susceptibility-weighted imaging.

Abstract: Susceptibility-weighted imaging (SWI) is recognized as the preferred MRI technique for visualizing cerebral vasculature and related pathologies such as cerebral microbleeds (CMBs). Manual identification of CMBs is time-consuming, has limited reliability and reproducibility, and is prone to misinterpretation. In this paper, a novel computer-aided microbleed detection technique based on machine learning is presented: First, spherical-like objects (potential CMB candidates) with their corresponding bounding boxes were detected using a novel multi-scale Laplacian of Gaussian technique. A set of robust 3-dimensional Radon- and Hessian-based shape descriptors within each bounding box were then extracted to train a cascade of binary random forests (RF). The cascade consists of consecutive independent RF classifiers with low to high posterior probability constraints to handle imbalanced training sets (CMBs and non-CMBs), and to progressively improve detection rates. The proposed method was validated on 66 subjects whose CMBs were manually stratified into "possible" and "definite" by two medical experts. The proposed technique achieved a sensitivity of 87% and an average false detection rate of 27.1 CMBs per subject on the "possible and definite" set. A sensitivity of 93% and false detection rate of 10 CMBs per subject was also achieved on the "definite" set. The proposed automated approach outperforms state of the art methods, and promises to enhance manual expert screening. Benefits include improved reliability, minimization of intra-rater variability and a reduction in assessment time.

Fazlollahi|Amir|A|
Meriaudeau|Fabrice|F|
Giancardo|Luca|L|
Villemagne|Victor L|VL|
Rowe|Christopher C|CC|
Yates|Paul|P|
Salvado|Olivier|O|
Bourgeat|Pierrick|P|
|||

D038524:Diffusion Magnetic Resonance Imaging

Cerebral microbleed
Susceptibility-weighted imaging
Multi-scale Laplacian of Gaussian
Random forests
Radon transform


Less is more: Parahippocampal resection or endoscopic assistance in ambient cistern surgery? Qualitative and quantitative assessment of subtemporal approach.

Abstract: The ambient cistern is an arachnoid complex that extends from the crural cistern to lateral border of cerebral colliculi. The subtemporal approach has been recognized as the best access to reach pathologies in the ambient cistern, however many disadvantages exist. The present work aims to analyze quantitatively the area of exposure provided by the subtemporal access. The objective is to evaluate if there are advantages of using the neuroendoscope in conventional subtemporal access when compared to the subtemporal access with resection of the parahippocampal gyrus. A subtemporal approach was performed in six brain hemispheres. Qualitative and quantitative analyses were made. The linear exposition of the vascular structures and the surgical exposure area were evaluated. The linear exposure to the posterior cerebral artery was 5.95 for subtemporal access (ST) and 13.6 for subtemporal access with resection of the parahippocampal gyrus (STh) (p = 0.019). The total exposure area was 104.8 mm2 for ST and 210.5 for STh (p = 0.0001). Regarding endoscope assistance the medial area, ST was 81.0 mm2, and STend was 176.2 mm2 (p = 0.038). For the total area of exposure, we obtained a value of 210.5 mm2 for ST and a value of 391.3 mm2 for STend (p = 0.041). In conventional subtemporal access, the use of the neuroendoscopes avoids the need for resection of the parahippocampal gyrus for better visualization of the ambient cistern structures.

Welling|Leonardo C|LC|
Figueiredo|Eberval Gadelha|EG|
Nakaji|Peter|P|
Welling|Mariana S|MS|
Schafranski|Marcelo D|MD|
Teixeira|Manoel Jacobsen|MJ|
Spetzler|Robert F|RF|
Preul|Mark C|MC|


A steroid-resistant cryptogenic multifocal ulcerous stenosing enteritis.

Abstract: Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is a rare chronic and recurrent disease with unknown etiology. It characterized by shallow ulcers, submucosa thickness, and no signs of systematic inflammation. Now, steroids are the principle therapy for CMSUE. However, still, there were few patients who did not response to it. Here, we present a young woman who diagnosed with CMUSE. She underwent a surgery because of capsule endoscopy retention. After relapse, she had received budesonide and methylprednisolone separately while both of them did not stop her disease. Till now, 24 years after her initial symptom, there are no signs of carcinoma yet.


Efficacy of psychological treatment for headache disorder: a systematic review and meta-analysis.

Abstract:
BACKGROUND
Headache disorder is not only a common complaint but also a global burden. Pharmacotherapeutic and non-pharmacotherapeutic approaches have been developed for its treatment and prophylaxis. The present study included a systematic review of psychological treatments for primary headache disorder accessible in Korea.

METHODS
We included English and Korean articles from EMBASE, MEDLINE, Cochrane library database, SCOPUS, ScienceDirect, Web of Science, CINAHL, PsycArticles and Korean database, KoreaMed and KMBASE which studied primary headache and medication-overuse headache. The primary efficacy measure was the number of headache days per month, while secondary efficacy measures were the number of headache attacks per week, headache index, treatment response rate, and migraine disability assessment. The meta-analysis was performed using R 3.5.1. to obtain pooled mean difference and pooled relative risk with 95% confidence interval (CI) for continuous data and dichotomous data, respectively.

RESULTS
From 12,773 identified articles, 27 randomized clinical trials were identified. Primary outcome showed significant superiority of psychological treatments (pooled mean difference = - 0.70, 95% CI [- 1.22, - 0.18]). For the secondary outcomes, the number of headache attacks (pooled mean difference = - 1.15, 95% CI [- 1.63, - 0.67]), the headache index (pooled mean difference = - 0.92, 95% CI [- 1.40 to - 0.44]) and the treatment response rate (pooled relative risk = 3.13, 95% CI [2.24, 4.37]) demonstrated significant improvements in the psychological treatment group over the control group.

CONCLUSION
Psychological treatments for primary headache disorder reduced headache frequency and the headache index. Future research using standardized outcome measures and strategies for reducing bias is needed.

NICE National Institute for Health and Care Excellence


Effects of dairy intake on anthropometric failure in children ages 6 to 23 mo consuming vegetarian diets and fulfilling minimum dietary diversity in India.

Abstract:
OBJECTIVES
In India, although nutritional conditions have improved, a high prevalence of anthropometric failure is still reported in children. Unfortunately, there are knowledge gaps surrounding nutrient and anthropometric shortcomings as well as dietary patterns. More than half of children are consuming a vegetarian diet. This study aimed to evaluate the effects of dietary adequacy levels on anthropometric failure in 5772 vegetarian children (ages 6-23 mo) satisfying minimum dietary diversity.

METHODS
Data were collected from the National Family Health Survey 2015-16. We created three food combinations: maximum adequacy (dairy and four food groups), medium adequacy (dairy and three food groups), and minimum adequacy (four food groups excluding dairy). We calculated odds ratios (ORs) for the association between dietary adequacy levels and anthropometric failures with 95% confidence intervals (CIs) using logistic regression models. The modification effect of breastfeeding status was also explored.

RESULTS
Approximately 35% of children had stunted growth. ORs showed a significant increase in the risk of anthropometric failure, notably wasting, and underweight in children with minimum-adequacy diets (OR, 1.46; 95% CI, 1.15-1.86) compared with children with maximum-adequacy diets. Those associations were more pronounced among children who were not breastfed (OR, 2.44; 95% CI, 1.19-5.00) than among children who were (OR, 1.35; 95% CI, 1.04-1.74; P value for the interaction = 0.07). Similar associations were observed for wasting among children who were not breastfed (OR, 2.82; 95% CI, 1.34-5.95) and who were breastfed(OR, 1.12; 95% CI, 0.85-1.5; P value for the interaction = 0.03).

CONCLUSIONS
Dairy is an essential source of nutrients that are required for healthy growth and development in children younger than 2 y, even if they satisfy minimum dietary diversity conditions in India.

Stunting
Wasting
Underweight
Breast milk
Dairy product
Epidemiology


Factors influencing utilization of reproductive health services among mothers in Meghalaya, India.

Abstract:
Background
Antenatal care (ANC) is one of the basic components where it can provide pregnant women with an expansive scope of well-being, health promotion, and preventive health services. However, still 830 women die every day from preventable pregnancy-related causes, and 99% of these deaths occur in developing countries, out of which 20% of these deaths were from India.

Objectives
The objective of this study is to explore the factors influencing the utilization of reproductive health services among mothers and to find the association between various factors and utilization of reproductive health services.

Methods
A community-based cross-sectional study was conducted during January-June 2017 among 160 mothers who had an infant aged <6 months in Mawkyrwat Block, South West Khasi Hills District in Meghalaya. Respondents were selected through simple random sampling, and semi-structured questionnaire was used for data collection. Data were analyzed using SPSS 16.

Results
Mothers attending four or more antenatal checkups were 10.6%, where 53.5% of the mothers registered their first ANC checkups only by the second trimester and 57.5% preferred home delivery. Nearly 52.9% of the mothers were staying more than 5 km away from the health-care facilities. The usage of family planning methods was very low, i. e., 96.9% of the mothers are not using any of the family planning methods.

Conclusion
Study finding reveals that the utilization of health-care services was low. Area-specific approaches such as health camps and mobile clinics might result in improved utilization of reproductive health services.

Nongdhar|Jurysha|J|
Vyas|Navya|N|
Rao|P Arathi|PA|
Narayanan|Prakash|P|
Pala|Star|S|

utilization
reproductive health
antenatal care
Antenatal care services
intranatal care


Novel Bicomponent Functional Fibers with Sheath/Core Configuration Containing Intumescent Flame-Retardants for Textile Applications.

Abstract: The objective of this study is to examine the effect of intumescent flame-retardants (IFR's) on the spinnability of sheath/core bicomponent melt-spun fibers, produced from Polylactic acid (PLA) single polymer composites, as IFR's have not been tested in bicomponent fibers so far. Highly crystalline PLA-containing IFR's was used in the core component, while an amorphous PLA was tested in the sheath component of melt-spun bicomponent fibers. Ammonium polyphosphate and lignin powder were used as acid, and carbon source, respectively, together with PES as a plasticizing agent in the core component of bicomponent fibers. Multifilament fibers, with sheath/core configurations, were produced on a pilot-scale melt spinning machine, and the changes in fibers mechanical properties and crystallinity were recorded in response to varying process parameters. The crystallinity of the bicomponent fibers was studied by differential scanning calorimetry and thermal stabilities were analyzed by thermogravimetric analysis. Thermally bonded, non-woven fabric samples, from as prepared bicomponent fibers, were produced and their fire properties, such as limiting oxygen index and cone calorimetry values were measured. However, the ignitability of fabric samples was tested by a single-flame source test. Cone calorimetry showed a 46% decline in the heat release rate of nonwovens, produced from FR PLA bicomponent fibers, compared to pure PLA nonwovens. This indicated the development of an intumescent char by leaving a residual mass of 34% relative to the initial mass of the sample. It was found that the IFRs can be melt spun into bicomponent fibers by sheath/core configuration, and the enhanced functionality in the fibers can be achieved with suitable mechanical properties.

intumescent flame-retardants
bicomponent fibers
cone calorimetry
nonwovens


Comparison of gene expression of Toll-like receptors and cytokines between Piau and Commercial line (Landrace×Large White crossbred) pigs vaccinated against Pasteurella multocida type D.

Abstract: We aimed to compare Toll-like receptors (TLR) and cytokines expression in local Piau breed and a Commercial line (Landrace×Large White crossbred) pigs in response to vaccination against Pasteurella multocida type D. Seronegative gilts for Pasteurella multocida type D and Mycoplasma hyopneumoniae were used, from which peripheral blood mononuclear cells (PBMC) were collected in four time points (T0, T1, T2 and T3; before and after each vaccination dose). For bronchoalveolar lavage fluid cells (BALF), we set groups of vaccinated and unvaccinated animals for both genetic groups. Gene expression was evaluated on PBMC and BALF. In PBMC, when we analyzed time points within breeds, significant differences in expression for TLRs and cytokines, except TGFβ, were observed for Commercial animals. For the Piau pigs, only TGFβ showed differential expression. Comparing the expression among genetic groups, the Commercial pigs showed higher expression for TLRs after first vaccination dose, while for IL2, IL6, IL12 and IL13, higher expression was also observed in T3 and IL8 and IL10, in T1 and T3. Still comparing the breeds, the crossbred animals showed higher expression for TNFα in T1 and T2, while for TGFβ only in T2. For gene expression in BALF, vaccinated Commercial pigs showed higher expression of TLR6, TLR10, IL6, IL8, IL10, TNFα and TGFβ genes than vaccinated Piau pigs. The Commercial line pigs showed higher sensitivity to vaccination, while in local Piau breed lower responsiveness, which may partly explain genetic variability in immune response and will let us better understand the tolerance/susceptibility for pasteurellosis.

Sousa|Katiene Régia Silva|KRS|
Ribeiro|André Mauric Frossard|AMF|
Dantas|Waleska de Melo Ferreira|WMF|
Oliveira|Leandro Licursi de|LL|
Gasparino|Eliane|E|
Guimarães|Simone Eliza Facioni|SEF|

Cytokines
Immune response
Pasteurellosis
Disease resistance
Swine


Clinical concepts on thyroid emergencies.

Abstract:
OBJECTIVE
Thyroid-related emergencies are caused by overt dysfunction of the gland which are so severe that require admission to intensive care units (ICU) frequently. Nonetheless, in the ICU setting, it is crucial to differentiate patients with non-thyroidal illness and alterations in thyroid function tests from those with intrinsic thyroid disease. This review presents and discusses the main etiopathogenetical and clinical aspects of hypothyroid coma (HC) and thyrotoxic storm (TS), including therapeutic strategy flow-charts. Furthermore, a special chapter is dedicated to the approach to massive goiter, which represents a surgical thyroid emergency.

DATA SOURCE
We searched the electronic MEDLINE database on September 2013. Data Selection and Data Extraction: Reviews, original articles, and case reports on "myxedematous coma," "HC," "thyroid storm," "TS," "massive goiter," "huge goiter," "prevalence," "etiology," "diagnosis," "therapy," and "prognosis" were selected.

DATA SYNTHESIS AND CONCLUSION
Severe excess or defect of thyroid hormone is rare conditions, which jeopardize the life of patients in most cases. Both HC and TS are triggered by precipitating factors, which occur in patients with severe hypothyroidism or thyrotoxicosis, respectively. The pillars of HC therapy are high-dose l-thyroxine and/or tri-iodothyroinine; i.v. glucocorticoids; treatment of hydro-electrolyte imbalance (mainly, hyponatraemia); treatment of hypothermia; often, endotracheal intubation and assisted mechanic ventilation are needed. Therapy of TS is based on beta-blockers, thyrostatics, and i.v. glucocorticoids; eventually, high-dose of iodide compounds or lithium carbonate may be of benefit. Surgery represents the gold standard treatment in patients with euthyroid massive nodular goiter, although new techniques - e.g., percutaneous laser ablation - are helpful in subjects at high surgical risk or refusing operation.

Papi|Giampaolo|G|
Corsello|Salvatore Maria|SM|
Pontecorvi|Alfredo|A|

hypothyroid coma
hypothyroidism
thyrotoxic storm
massive goiter
thyrotoxicosis
hyperthyroidism


Definitive radiotherapy plus regional hyperthermia for high-risk and very high-risk prostate carcinoma: Thermal parameters correlated with biochemical relapse-free survival.

Abstract:
PURPOSE
The aim of this study was to assess the efficacy of definitive radiotherapy (RT) plus regional hyperthermia (HT) and investigate the potential contribution of HT to clinical outcomes in patients with prostate carcinoma.

MATERIALS AND METHODS
Following our institution's treatment protocol, HT was combined with RT to improve clinical outcomes in selected patients with high-risk or very high-risk prostate cancer. Data from 82 patients treated with RT plus HT and 64 patients treated with RT alone were retrospectively analysed.

RESULTS
Median follow-up duration was 61 months. The 5-year biochemical disease-free survival (bDFS) rate for the 82 patients treated with RT plus HT was 78%, whereas bDFS for the 64 patients treated with RT alone was 72%; this difference was not significant. Among the 75 patients treated with RT plus HT who underwent intra-rectal temperature measurements, higher thermal parameters were significant prognostic indicators of improved bDFS by univariate analysis. A higher CEM43 °CT90 thermal parameter and a T stage of T1-2 were significant prognostic factors based on multivariate analysis. The 5-year bDFS rates for the 40 patients with a higher CEM43 °CT90 and the 64 patients treated with RT alone were significantly different, whereas 5-year bDFS for the 35 patients with a lower CEM43 °CT90 and the 64 patients treated with RT alone were not.

CONCLUSIONS
The addition of HT with higher thermal parameters to RT may improve bDFS for patients with high-risk or very high-risk prostate cancer. These findings also demonstrate the importance of careful selection of treatable patients with higher thermal parameters.

Yahara|Katsuya|K| Ohguri|Takayuki|T| Yamaguchi|Shinsaku|S| Imada|Hajime|H| Narisada|Hiroyuki|H| Ota|Shin|S| Tomura|Kyosuke|K| Sakagami|Mai|M| Fujimoto|Naohiro|N| Korogi|Yukunori|Y|

radiotherapy
Hyperthermia
thermal parameter
prostate cancer
radiosensitisation


Netrin-DCC signaling regulates corpus callosum formation through attraction of pioneering axons and by modulating Slit2-mediated repulsion.

Abstract: The left and right sides of the nervous system communicate via commissural axons that cross the midline during development using evolutionarily conserved molecules. These guidance cues have been particularly well studied in the mammalian spinal cord, but it remains unclear whether these guidance mechanisms for commissural axons are similar in the developing forebrain, in particular for the corpus callosum, the largest and most important commissure for cortical function. Here, we show that Netrin1 initially attracts callosal pioneering axons derived from the cingulate cortex, but surprisingly is not attractive for the neocortical callosal axons that make up the bulk of the projection. Instead, we show that Netrin-deleted in colorectal cancer signaling acts in a fundamentally different manner, to prevent the Slit2-mediated repulsion of precrossing axons thereby allowing them to approach and cross the midline. These results provide the first evidence for how callosal axons integrate multiple guidance cues to navigate the midline.

Fothergill|Thomas|T|
Donahoo|Amber-Lee S|AL|
Douglass|Amelia|A|
Zalucki|Oressia|O|
Yuan|Jiajia|J|
Shu|Tianzhi|T|
Goodhill|Geoffrey J|GJ|
Richards|Linda J|LJ|

D036341:Intercellular Signaling Peptides and Proteins

corpus callosum
DCC
Robo1
axon guidance
commissure formation
cortical development
neocortex
silencing


The why, when and how to test for obstructive sleep apnea in patients with atrial fibrillation.

Abstract: Sleep apnea is associated with increased cardiovascular risk and may be important in atrial fibrillation (AF) management. It is present in up to 62% of the AF population and is highly under-recognized and underdiagnosed. Obstructive sleep apnea (OSA) is strongly associated with AF and non-randomized trials have shown that its treatment can help to reduce AF recurrences and maintain sinus rhythm. The 2016 European Society of Cardiology guidelines for the management of AF recommend that AF patients should be questioned regarding the symptoms of OSA and that OSA-treatment should be optimized to improve AF treatment results. However, strategies on how to implement OSA testing in the standard work-up of AF patients are not provided in the guidelines. Additionally, overnight OSA monitoring rather than interrogation for OSA-related clinical signs alone may be necessary to reliably identify OSA in the majority of AF patients. This review summarizes the available clinical data on OSA in AF patients, and discusses the following key questions: Why and When is testing for OSA needed in AF patients? How and Where should it be performed and coordinated? and Who should test for OSA? To implement OSA testing in a cardiology or electrophysiology clinic, we propose a multidisciplinary integrated care approach based on a chronic care model. We describe the tools, infrastructure and coordination needed to test for OSA in the standard workup of patients with symptomatic AF prior to the initiation of directed invasive or pharmacological rhythm control management.

Obstructive sleep apnea
Atrial fibrillation
Integrated care
Diagnosis


In Vivo Base Editing of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) as a Therapeutic Alternative to Genome Editing.

Abstract:
OBJECTIVE
High-efficiency genome editing to disrupt therapeutic target genes, such as PCSK9 (proprotein convertase subtilisin/kexin type 9), has been demonstrated in preclinical animal models, but there are safety concerns because of the unpredictable nature of cellular repair of double-strand breaks, as well as off-target mutagenesis. Moreover, precise knock-in of specific nucleotide changes-whether to introduce or to correct gene mutations-has proven to be inefficient in nonproliferating cells in vivo. Base editors comprising CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]-CRISPR-associated 9) fused to a cytosine deaminase domain can effect the alteration of cytosine bases to thymine bases in genomic DNA in a sequence-specific fashion, without the need for double-strand DNA breaks. The efficacy of base editing has not been established in vivo. The goal of this study was to assess whether in vivo base editing could be used to modify the mouse Pcsk9 gene in a sequence-specific fashion in the liver in adult mice.

APPROACH AND RESULTS
We screened base editors for activity in cultured cells, including human-induced pluripotent stem cells. We then delivered a base editor into the livers of adult mice to assess whether it could introduce site-specific nonsense mutations into the Pcsk9 gene. In adult mice, this resulted in substantially reduced plasma PCSK9 protein levels (>50%), as well as reduced plasma cholesterol levels (≈30%). There was no evidence of off-target mutagenesis, either cytosine-to-thymine edits or indels.

CONCLUSIONS
These results demonstrate the ability to precisely introduce therapeutically relevant nucleotide variants into the genome in somatic tissues in adult mammals, as well as highlighting a potentially safer alternative to therapeutic genome editing.

Chadwick|Alexandra C|AC|
Wang|Xiao|X|
Musunuru|Kiran|K|

D015971:Gene Expression Regulation, Enzymologic

PCSK9
nucleotides
gene therapy
lipids and lipoprotein metabolism
molecular biology


In vitro and in vivo anti-cancer activity of dichloromethane fraction of Triticum aestivum sprouts.

Abstract: Triticum aestivum sprouts (TA) contain significant amounts of chlorophyll, minerals, enzymes, and other functional entities. Furthermore, TA extracts have been shown to possess anti-obesity, anti-diabetic and hepatoprotective effects and are believed to help blood flow, digestion, and general detoxification of the body. In this study, the mechanism underlying the anti-cancer effects of a dichloromethane fraction of TA (TDF) was investigated in vitro and in vivo. In vitro study was done by examining cancer cells growth, morphological changes, cell cycles, expressions of death receptors and apoptosis-linked proteins in wide range of human cancer cell lines. To investigate the effect of TDF in vivo, C57BL/6 mice were injected with B16 melanoma cells and orally administered TDF. TDF markedly inhibited cancer cell growth and induced cellular morphological alterations, cell cycle arrest and apoptosis, and enhanced the expressions of death receptors (DR)-4, 5, and 6 in cell lines. In addition, TDF regulated the expressions mitochondrial apoptosis-linked proteins and induced caspase-dependent cell death. It also significantly enhanced phosphorylation of ERK1/2 and JNK, but not p38, whereas inhibited the activation of NF-κB in cancer cells. In our mouse model, TDF significantly suppressed B16 melanoma growth, to an extent similar to cisplatin (reference control) and augmented immunomodulatory cytokines. In brief, this study presents the mechanism responsible for the anti-cancer effects of TDF in vitro and in vivo.

Ki|Hyeon-Hui|HH| Poudel|Barun|B| Lee|Ji-Hyun|JH| Lee|Young-Mi|YM| Kim|Dae-Ki|DK|

Triticum aestivum sprouts
Cancer
B16 melanoma
Apoptosis


Drug Design Inspired by Nature: Crystallographic Detection of an Auto-Tailored Protease Inhibitor Template.

Abstract: De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X-ray crystallography, which was auto-tailored by the therapeutic target MMP-13 through partial self-degradation and subsequent structure-based optimization to a highly potent and selective β-sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non-proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC50 of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC50 : 170 nm) and MMP-9 (IC50 : 140 nm).

D019714:Tissue Inhibitor of Metalloproteinases

drug design
peptidomimetics
medicinal chemistry
structural biology
structure-activity relationship


Structural changes of fat tissue after nonaspirative ultrasonic hydrolipoclasy.

Abstract:
BACKGROUND
Hydrolipoclasy is an alternative technique less invasive than liposuction. Hydrolipoclasy uses normal saline or hypotonic solution and ultrasound waves that act directly on local adiposity. In the literature there are few reports of morphostructural changes on adipose tissue.

MATERIALS AND METHODS
This study was aimed to evaluate the amount of fat cells injured immediately after treatment and after three days and also cell migration to the area treated using 8 pigs as experimental models, as well as cellular changes by transmission electron microscopy (TEM).

RESULTS
The Wilcoxon test was conducted, and a difference was found between the treated side and the corresponding control side on the number of viable cells. The treated side showed a smaller number of viable cells compared to the control side both immediately after treatment and 3 days later. Also occurring 3 days after treatment was the migration of lymphoid cells and fibroblasts, which shows the local inflammatory process and conjunctive neoformation. Soon after treatment there was fluid accumulation within adipocytes.

CONCLUSIONS
The results shown in this paper demonstrate Ultrasonic Hydrolipoclasy as a viable alternative for the treatment of localized fat deposits without the side effects of traditional surgical procedures. Better results are expected when hypotonic solution is used, since it penetrates into the cell.

Godoy|Fúlvio B|FB|
Fonseca|Belchiolina B|BB|
Levenhagen|Marcelo A|MA|
Franco|Mariane A|MA|
Melo|Roberta T|RT|
Beletti|Marcelo E|ME|

alternative technique
ultrasound
Adipose tissue


Correlation of radiographic measurements of structures of the equine foot with lesions detected on magnetic resonance imaging.

Abstract:
REASONS FOR PERFORMING STUDY
There are few studies on the correlations between radiographic measurements of the foot and abnormalities of specific structures found with magnetic resonance imaging (MRI).

OBJECTIVES
To document the relationship between radiographic measurements of the equine foot and the presence of lesions in the foot on MRI. We hypothesised that different radiographic measurements would be associated with specific lesions detected by MRI.

STUDY DESIGN
Retrospective analysis of radiographs and MRI studies.

METHODS
Seventy-four feet from 52 lame horses were included. Twenty parameters were measured on radiographs, whereas the signal intensity, homogeneity and size of each structure in the foot were evaluated on magnetic resonance images. The data were analysed using simple linear correlation analysis and classification and regression trees (CARTs).

RESULTS
Linear correlations were found between the navicular bone compacta thickness and injuries of the deep digital flexor tendon, collateral sesamoidean ligament, navicular spongiosa and navicular bone proximal border. Long-toed horses had a high incidence of lesions involving the spongiosa and proximal border of the navicular bone. Elongation of the navicular bone was associated with proximal and distal border injuries. A reduced palmar angle and increased angle between the middle and distal phalanx were observed in horses with alterations of collateral ligaments of the distal interphalangeal joint and navicular bone spongiosa, respectively. For each structure under investigation, CARTs predicting the presence of MRI pathology based on radiographic measurements had excellent performance, with >80% correct classification of cases, when using one of 3 data sources.

CONCLUSIONS
This study demonstrated a relationship between radiographic measurements of the foot and the presence of lesions detected on MRI, while CARTs illustrated that different radiographic measurements were associated with different MRI lesions.

de Zani|D|D|
Polidori|C|C|
di Giancamillo|M|M|
Zani|D D|DD|

measurements
magnetic resonance imaging
lameness
horse
classification and regression tree
radiography


Screening for language delay after life-saving therapies in term-born infants.

Abstract:
BACKGROUND
Strong recommendations have been made for the periodic developmental surveillance, screening, and evaluation of children with CHD. This supports similar calls for all at-risk children in order to provide timely, structured early developmental intervention that may improve outcomes. The aim of this study was to determine the accuracy of screening for language delay after life-saving therapies using the parent-completed vocabulary screen of the language Development Survey, by comparing screening with the individually administered language scores of the Bayley Scales of Infant and Toddler Development, Third edition.

METHOD
In total, 310 (92.5%) of 335 eligible term-born children, born between 2004 and 2011, receiving complex cardiac surgery, heart or liver transplantation, or extracorporeal membrane oxygenation in infancy, were assessed at 21.5 (2.8) months of age (lost, 25 (7.5%)), through developmental/rehabilitation centres at six sites as part of the Western Canadian Complex Pediatric Therapies Follow-up Group.

RESULTS
Vocabulary screening delay was defined as scores ⩽15th percentile. Language delay defined as scores >1 SD below the mean was calculated for language composite score, receptive and expressive communication scores of the Bayley-III. Delayed scores for the 310 children were as follows: vocabulary, 144 (46.5%); language composite, 125 (40.3%); receptive communication, 98 (31.6%); and expressive communication, 124 (40%). Sensitivity, specificity, positive predictive values, and negative predictive values of screened vocabulary delay for tested language composite delay were 79.2, 75.7, 68.8, and 84.3%, respectively.

CONCLUSION
High rates of language delay after life-saving therapies are concerning. Although the screening test appears to over-identify language delay relative to the tested Bayley-III, it may be a useful screening tool for early language development leading to earlier referral for intervention.

Clark|Brenda G|BG|
Acton|Bryan V|BV|
Alton|Gwen Y|GY|
Joffe|Ari R|AR|
Dinu|Irina A|IA|
Robertson|Charlene M T|CM|

screening
language delay
Life-saving therapies
infancy


A novel cholinergic epithelial cell with chemosensory traits in the murine conjunctiva.

Abstract: We recently identified a specialized cholinergic cell type in tracheal and urethral epithelium that utilizes molecules of the canonical taste transduction signaling cascade to sense potentially harmful substances in the luminal content. Upon stimulation, this cell initiates protective reflexes. Assuming a sentinel role of such cells at mucosal surfaces exposed to bacteria, we hypothesized their occurrence also in ocular mucosal surfaces. Utilizing a mouse strain expressing eGFP under the promoter of the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT-eGFP), we observed a cholinergic cell in the murine conjunctiva. Singular cholinergic cells reaching the epithelial surface with slender processes were detected in fornical, but neither in bulbar nor palpebral epithelia. These cells were found neither in the lacrimal canaliculi, nor in the lacrimal sac and the nasolacrimal duct. Cholinergic conjunctival epithelial cells were immunoreactive for components of the canonical taste transduction signaling cascade, i.e. α-gustducin, phospholipase Cβ2 and the monovalent cation channel TRPM5. Calcitonin gene-related peptide- and substance P-immunoreactive sensory nerve fibers were observed extending into the conjunctival epithelium approaching slender ChAT-eGFP-positive cells. In addition, we noted both ChAT-eGFP expression and α-gustducin-immunoreactivity, albeit in different cell populations, in occasionally occurring lymphoid follicles of the nictitating membrane. The data show a previously unidentified cholinergic cell in murine conjunctiva with chemosensory traits that presumably utilizes acetylcholine for signaling. In analogy to similar cells described in the respiratory and urethral epithelium, it might serve to detect bacterial products and to initiate protective reflexes.

Wiederhold|Stephanie|S| Papadakis|Tamara|T| Chubanov|Vladimir|V| Gudermann|Thomas|T| Krasteva-Christ|Gabriela|G| Kummer|Wolfgang|W|

Conjunctiva
Taste
Brush cell
Non-neuronal acetylcholine


Temperature affects maximum H-reflex amplitude but not homosynaptic postactivation depression.

Abstract: This study aimed to determinate the effect of hyperthermia on transmission efficacy of the Ia-afferent spinal pathway. Recruitment curves of the Hoffman reflex (H-reflex) and compound motor potential (M-wave) along with homosynaptic postactivation depression (HPAD) recovery curves were obtained in 14 volunteers in two controlled ambient temperatures that resulted in significantly different core temperatures (CON, core temperature ∼37.3°C; and HOT, core temperature ∼39.0°C). Electromyographic responses were obtained from the soleus (SOL) and medial gastrocnemius (MG) muscles following electrical stimulation of the tibial nerve at varying intensities and paired pulse frequencies (0.07-10 Hz). Results showed that maximal amplitude of the H-reflex was reached for a similar intensity of stimulation in CON and HOT (both muscles P > 0.47), with a similar associated M-wave (both muscles P > 0.69) but was significantly decreased in HOT as compared to CON (all P < 0.05), whether expressed in absolute terms (-50% in SOL, -32% in MG) or when normalized to the maximum M-wave (-23% in SOL, -32% in MG). The HPAD recovery curve was not affected by the elevated core temperature (both muscles P > 0.23). Taken together, these results suggest that hyperthermia can alter neuromuscular transmission across the neuromuscular junction and/or muscle membrane as well as transmission efficacy of the Ia-afferent pathway, albeit the latter not via an increase in HPAD.

hyperthermia
muscle
Exercise
neuromuscular function
spinal reflex


Cancer as an infectious disease: A different treatment alternative using a combination of tigecycline and pyrvinium pamoate - An example of breast cancer.

Abstract:
BACKGROUND
Tigecycline is an antibiotic that well tolerated for treating complicated infections. It has received attention as an anti-cancer agent and expected to solve two major obstacles, sides effects that accompany chemotherapy and drug resistance, in the breast cancer treatment. However, previous studies reported that the levels in the blood are typically low of tigecycline, so higher doses are needed to treat cancer, that may increase the risk of side effects. To achieve better anti-cancer effects for tigecycline, we need to find a novel adjunct agent.

METHODS
In this study, we used different concentration of pyrvinium pamoate combined with tigecycline to treat cell. And assess the effect of two drugs in inhibit cell proliferation, induce cell autophagy, or increase cell apoptosis to evaluate the consequent of combined therapy.

RESULTS
We observed that after the combined therapy, the cell cycle arrest at G1/s phase, the level of p21 increased, but decreased the levels of CDK2. Others, two drugs via different mechanisms to inhibit cancer cell proliferation and with selective cytotoxic to different cell lines. That could enhance the effect of breast cancer treatment.

CONCLUSION
Combining low dose of tigecycline use with pyrvinium pamoate is a novel approach for breast cancer treatment. Appropriate combined therapy in breast cancer is recommended to improve outcomes. Other problems like drug resistance occur in patients or the microbes surrounding breast tissues would confer susceptibility to cancers then influence the effectiveness of treatment, which could be improved through combined therapy.

Huang|Shu-Wei|SW| Sun|Ming-Tsung|MT| Lee|Wen-Sen|WS| Su|Ying-Shih|YS| Lee|Yi-Tzu|YT| Chiang|Ming-Hsien|MH| Wang|Yung-Chih|YC| Yang|Ya-Sung|YS| Tzeng|Shian-Chiuan|SC| Huang|Yu-Min|YM| Lin|Feng-Huei|FH|

Tigecycline
Pyrvinium pamoate
Breast cancer
Combination therapy


"What's Cooking?": Qualitative Evaluation of a Head Start Parent-Child Pilot Cooking Program.

Abstract: Providing access to nutritious foods is crucial for low-income populations, but increasing nutrition-related skills and attitudes such as food preparation, feeding practices, and positive perceptions around healthy foods to establish sustainable behavior change are paramount for the development of healthy lifestyles. This qualitative study was designed to evaluate the What's Cooking pilot program. A total of 15 participants were recruited from two Head Start schools through flyers, text messages, and e-mails. Two focus group sessions were audiotaped to obtain information related to the program implementation and perceived outcomes and behavior change. Recordings of the sessions were transcribed and analyzed using constant comparative analysis. Resulting themes included children's asking behavior for healthy foods, family connection, parent comfort in cooking, and development of child attitude, knowledge, and skills. The qualitative analysis provided foundational information for the development of a framework for other nutrition program providers to understand the role of the child in a cooking class as a mediator for lifestyle change. The What's Cooking program increased the implementation of sustainable food practices and healthy nutrition behaviors through educating families on how to involve their children in positive mealtime practices.

Miller|M Elizabeth|ME|
Kaesberg|Julia L|JL|
Thompson|Victoria B|VB|
Wyand|Rachel A|RA|

D007722:Health Knowledge, Attitudes, Practice

cooking
Head Start
parent–child
preschool
program evaluation