Chemodiversity of Nepeta menthoides Boiss. & Bohse. essential oil from Iran and antimicrobial, acetylcholinesterase inhibitory and cytotoxic properties of 1,8-cineole chemotype.

Abstract: The essential oil of Nepeta menthoides Boiss. & Bohse., from Iran, was analysed by GC/MS. Two types of multivariate analyses were done based on the chemical composition of the investigated sample in this study and 12 other samples reported in the literature to show the chemodiversity in essential oil composition. Antimicrobial, acetylcholinesterase inhibitory and cytotoxic activities of the essential oil and its major component were assessed. Twenty-one compounds were identified, representing 96.81% of the total oil and the major constituent was 1,8-cineole (70.06%). Multivariate analyses revealed two chemotypes, i.e. nepetalactone and 1,8-cineole. The essential oil of the sample investigated in this study which was a 1,8-cineole chemotype and 1,8-cineole showed moderate antimicrobial activity and significantly inhibited the activity of acetylcholinesterase enzyme. Cytotoxicity evaluation against three breast cancer cell lines showed a potent inhibitory activity. Further investigations are necessary to confirm the variety in several populations of N. menthoides.

Nepeta menthoides
antimicrobial
cytotoxic
acetylcholinesterase inhibition
multivariate analysis


Thermally reversible self-assembly of nanoparticles via polymer crystallization.

Abstract: The directed self-assembly of gold nanoparticles through the crystallization of surface-grafted polyethylene oxide (PEO) in ethanol-water mixtures is described. This process is fully reversible and tunable through either the size of the core or the polymeric coating. Characterization by X-ray scattering and electron microscopy of the self-assembled structures reveals order at the nanoscale, typically not the case for thermoresponsive gold nanoparticles coated with lower or upper critical solution temperature polymers. A further novelty is the result of selective binding of calcium ions to the PEO in the fluid state: a reversible thermoresponsive transition become irreversible.

Kinnear|Calum|C| Balog|Sandor|S| Rothen-Rutishauser|Barbara|B| Petri-Fink|Alke|A|

reversible self-assembly nanoparticles crystallization gold


Characteristics Regarding Lift-Off Intersection of Pulse-Modulation Eddy Current Signals for Evaluation of Hidden Thickness Loss in Cladded Conductors.

Abstract: The cladded conductor is broadly utilized in engineering fields, such as aerospace, energy, and petrochemical; however, it is vulnerable to thickness loss occurring in the clad layer and nonconductive protection coating due to abrasive and corrosive environments. Such a flaw severely undermines the integrity and safety of the mechanical structures. Therefore, evaluating the thickness loss hidden inside cladded conductors via reliable nondestructive evaluation techniques is imperative. This paper intensively investigates the pulse-modulation eddy current technique (PMEC) for the assessment of thickness loss in a cladded conductor. An analytical model of the ferrite-cored probe is established for analyzing PMEC signals and characteristics of lift-off intersection (LOI) in testing signals. Experiments are conducted for evaluation of the thickness loss in cladded conductors. An inverse scheme based on LOI for estimation of the thickness-loss depth is proposed and further verified. Through simulations and experiments, it is found that the influences of the thickness loss in the clad layer and protective coating on the PMEC signals can be decoupled in virtue of the LOI characteristics. Based on LOI, the hidden thickness loss can be efficiently evaluated without much of a reduction in accuracy by using the PMEC probe for dedicated inspection of the cladded conductor.

Li|Yong|Y|0000-0003-4257-2771
Wang|Yi|Y|
Liu|Zhengshuai|Z|
Zainal Abidin|Ilham Mukriz|IM|
Chen|Zhenmao|Z|

pulse-modulation eddy current inspection


Differential virulence of camel Trypanosoma evansi isolates in mice.

Abstract: This study assessed the virulence of Trypanosoma evansi, the causative agent of camel trypanosomiasis (surra), affecting mainly camels among other hosts in Africa, Asia and South America, with high mortality and morbidity. Using Swiss white mice, we assessed virulence of 17 T. evansi isolates collected from surra endemic countries. We determined parasitaemia, live body weight, packed cell volume (PCV) and survivorship in mice, for a period of 60 days' post infection. Based on survivorship, the 17 isolates were classified into three virulence categories; low (31-60 days), moderate (11-30 days) and high (0-10 days). Differences in survivorship, PCV and bodyweights between categories were significant and correlated (P < 0.05). Of the 10 Kenyan isolates, four were of low, five moderate and one (Type B) of high virulence. These findings suggest differential virulence between T. evansi isolates. In conclusion, these results show that the virulence of T. evansi may be region specific, the phenotype of the circulating parasite should be considered in the management of surra. There is also need to collect more isolates from other surra endemic regions to confirm this observation.

Kamidi|Christine M|CM|
Auma|Joanna|J|
Mireji|Paul O|PO|
Ndungu|Kariuki|K|
Bateta|Rosemary|R|
Kurgat|Richard|R|
Ouma|Collins|C|
Aksoy|Serap|S|
Murilla|Grace|G|

Trypanosoma evansi
Packed cell volume
virulence.
survival


Assessment of hot-processability and performance of ethylcellulose-based materials for injection-molded prolonged-release systems: An investigational approach.

Abstract: The present work focuses on application of an investigational approach to assess the hot-processability of pharmaceutical-grade polymers with a potential for use in the manufacturing of reservoir drug delivery systems via micromolding, and the performance of resulting molded barriers. An inert thermoplastic polymer, ethylcellulose (EC), widely exploited for preparation of prolonged-release systems, was employed as a model component of the release-controlling barriers. Moldability studies were performed with plasticized EC, as such or in admixture with release modifiers, by the use of disk-shaped specimens ≥ 200 µm in thickness. The disks turned out to be a suitable tool for evaluation of the dimensional stability and diffusional barrier performance of the investigated materials after demolding. The effect of the amount of triethyl citrate, used as a plasticizer, on hot-processability of EC was assessed. The rate of a model drug diffusion across the polymeric barriers was shown to be influenced by the extent of porosity from the incorporated additives. The investigational approach proposed, of simple and rapid execution, holds potential for streamlining the development of prolonged-release systems produced by micromolding in the form of drug reservoirs, with no need for molds and molding processes to be set up on a case-by-case basis.

Casati|F|F| Briatico-Vangosa|F|F| Baldi|F|F| Melocchi|A|A| Maroni|A|A| Gazzaniga|A|A| Zema|L|L|

Drug delivery
Micromolding
Ethylcellulose
Melt rheology
Microcompounder
Prolonged release


Nonmetric analysis of caroticoclinoid foramen in foothills of Himalayas: Its clinicoanatomic perspective.

Abstract:
OBJECTIVE OF THE STUDY
Study was conducted to evaluate the incidence of caroticoclinoid foramen in north Indian population. Authors have also endeavoured to discuss its clinical and embryological implications.

MATERIALS AND METHODS
Study was conducted on 108 dry human skulls in department of anatomy SGRR medical college, Dehradun. Incidence of caroticoclinoid foramen was evaluated in accordance with side.

RESULTS
A percentage of 22.22 skulls presented with the caroticoclinoid foramen with maximum incidence of unilateral and incomplete type. Incidence revealed no bias towards side.

CONCLUSION
Anatomical knowledge about CCF may be helpful to radiologists and neurosurgeons in providing an additional insight into the diagnosis and management of various pathologies around sellar region.

Jha|S|S| Singh|S|S| Bansal|R|R| Chauhan|P|P| Shah|M-P|MP| Shah|A|A|

Caroticoclinoid foramen
Incidence
Artère carotide interne
Foramen caroticoclinoïdien
Internal carotid artery


Zirconia-based dental crown to support a removable partial denture: a three-dimensional finite element analysis using contact elements and micro-CT data.

Abstract: Veneer fracture is the most common complication in zirconia-based restorations. The aim of this study was to evaluate the mechanical behavior of a zirconia-based crown in a lower canine tooth supporting removable partial denture (RPD) prosthesis, varying the bond quality of the veneer/coping interface. Microtomography (μCT) data of an extracted left lower canine were used to build the finite element model (M) varying the core material (gold core - MAu; zirconia core - MZi) and the quality of the veneer/core interface (complete bonded - MZi; incomplete bonded - MZi-NL). The incomplete bonding condition was only applied for zirconia coping by using contact elements (Target/Contact) with 0.3 frictional coefficients. Stress fields were obtained using Ansys Workbench 10.0. The loading condition (L = 1 N) was vertically applied at the base of the RPD prosthesis metallic support towards the dental apex. Maximum principal (σmax) and von Mises equivalent (σvM) stresses were obtained. The σmax (MPa) for the bonded condition was similar between gold and zirconia cores (MAu, 0.42; MZi, 0.40). The incomplete bonded condition (MZi-NL) raised σmax in the veneer up to 800% (3.23 MPa) in contrast to the bonded condition. The peak of σvM increased up to 270% in the MZi-NL. The incomplete bond condition increasing the stress in the veneer/zirconia interface.

Rocha|Eduardo Passos|EP|
Anchieta|Rodolfo Bruniera|RB|
de Almeida|Erika Oliveira|EO|
Freitas|Amilcar Chagas|AC|
Martini|Ana Paula|AP|
Sotto-Maior|Bruno Sales|BS|
Luersen|Marco Antonio|MA|
Ko|Ching Chang|CC|

removable partial denture
finite element analysis
fixed partial denture
zirconium oxide


Therapeutic potential of spinal GLP-1 receptor signaling.

Abstract: GLP-1 signaling pathway has been well studied for its role in regulating glucose homeostasis, as well as its beneficial effects in energy and nutrient metabolism. A number of drugs based on GLP-1 have been used to treat type 2 diabetes mellitus. GLP-1R is expressed in multiple organs and numerous experimental studies have demonstrated that GLP-1 signaling pathway exhibits pro-survival functions in various disorders. In the central nervous system, stimulation of GLP-1R produces neuroprotective effects in specific neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. The preproglucagon neurons located in the brainstem can also produce GLP-1. GLP-1 analogs have a long-acting effect and are able to pass the blood-brain barrier, which probably extends the therapeutic efficacy of GLP-1R activation. Neurodegenerative or traumatic conditions can damage the spinal cord and result in motor and sensory dysfunction. Evidence supports that GLP-1R activation in the spinal cord possesses beneficial effects and significant therapeutic potential. Herein, we review studies that have focused on GLP-1 and the spinal cord, and summarize the expression of GLP-1R and the innervation of PPG neurons in the spinal cord, as well as the potential therapeutic benefits of GLP-1R activation.

Spinal cord
Glucagon-like peptide-1
Glucagon-like peptide-1 receptor


Weight gain and antipsychotics: a drug safety review.

Abstract:
INTRODUCTION
Second-generation antipsychotics (SGAs) are widely used in several psychiatric disease entities and exert to a different extent a risk for antipsychotic-induced weight gain (AIWG). As AIWG is associated with an increase in metabolic syndrome or cardiovascular events, knowledge of these risks is crucial for further monitoring and the initiation of counteractive measures.

AREAS COVERED
We searched PubMed and Web of Sciences for randomized-controlled trials and naturalistic observational studies published between 2010 and 2014 with sample sizes exceeding 100, including all marketed SGAs apart from zotepine, and providing data on weight increase. We also summarized relevant systematic reviews and meta-analyses of head-to-head comparisons.

EXPERT OPINION
Recently published data still support the hierarchical ranking of SGAs already proposed in previous reviews ranking clozapine and olanzapine as having the highest risk, followed by amisulpride, asenapine, iloperidone, paliperidone, quetiapine, risperidone and sertindole in the middle, and aripiprazole, lurasidone and ziprasidone with the lowest risk. Number needed to harm varied considerably in our meta-analysis. Younger patients and patients with a lower baseline body mass index are most vulnerable. The greatest amount of weight gain occurs within the first weeks of treatment. AIWG occurs in all diagnostic groups and is also common in treatment with first-generation antipsychotics; therefore, awareness of this adverse event is essential for anyone prescribing antipsychotics.

Musil|Richard|R| Obermeier|Michael|M| Russ|Paul|P| Hamerle|Michael|M|

D000367:Age Factors
D014150:Antipsychotic Agents
D015992:Body Mass Index
D006801:Humans
D015430:Weight Gain

weight gain
clozapine
olanzapine
amisulpride
asenapine
iloperidone
paliperidone
quetiapine
risperidone
sertindole
aripiprazole
lurasidone
ziprasidone
first-generation antipsychotic agents
haloperidol
second-generation antipsychotic agents


Mechanism for the primary transformation of acetaminophen in a soil/water system.

Abstract: The transformation of acetaminophen (APAP) in a soil/water system was systematically investigated by a combination of kinetic studies and a quantitative analysis of the reaction intermediates. Biotransformation was the predominant pathway for the elimination of APAP, whereas hydrolysis or other chemical transformation, and adsorption processes made almost no contribution to the transformation under a dark incubation. Bacillus aryabhattai strain 1-Sj-5-2-5-M, Klebsiella pneumoniae strain S001, and Bacillus subtilis strain HJ5 were the main bacteria identified in the biotransformation of APAP. The soil-to-water ratio and soil preincubation were able to alter the transformation kinetic pattern. Light irradiation promoted the overall transformation kinetics through enhanced biotransformation and extra photosensitized chemical reactions. The transformation pathways were strongly dependent on the initial concentration of APAP. The main primary transformation products were APAP oligomers and p-aminophenol, with the initial addition of 26.5 and 530 μM APAP, respectively. APAP oligomers accounted for more than 95% of transformed APAP, indicating that almost no bound residues were generated through the transformation of APAP in the soil/water system. The potential environmental risks of APAP could increase following the transformation of APAP in the soil/water system because of the higher toxicity of the transformation intermediates.

Liang|Chuanzhou|C| Lan|Zhonghui|Z| Zhang|Xu|X| Liu|Yingbao|Y|

Acetaminophen Soil/water Biotransformation Polymerization


Physiological and Pathophysiological Responses to Ultramarathon Running in Non-elite Runners.

Abstract: Ultramarathon running represents a major physical challenge even for elite athletes. Runners wellbeing may be challenged by fluid and electrolyte disturbances, hemolysis and skeletal muscle damage, decline in hepatic function and kidney injury. We hypothesized that these effects may even be exacerbated in non-elite runners. Physiological, hematological and biochemical parameters of ten males (26-45 years, weekly training time 8.5 h), participating in a mountain ultramarathon (67 km; approximately 4,500 m of total ascent), were determined before (PRE), immediately after finishing the ultramarathon (POST), and 24 h after the individual finish (REC). Race times of the 8 finishers (2 drop-outs due to hot ambient temperature) varied between 10.4 and 16.1 h, which almost represents the range of the entire starter field (8.82 h-17.47 h). The following changes in mean values of selected markers for skeletal muscle damage and kidney injury were observed from PRE to POST: creatine kinase (CK) + 1289%, lactate dehydrogenase (LDH) + 87%, serum creatinine (CR) + 72%, blood urea nitrogen (BUN) + 96%, and estimated glomerular filtration rate (eGFR) - 45%. Values of CK + 1447%, LDH + 56%, and BUN + 71% remained elevated at REC. White blood cells were increased (+ 137%) only POST. In conclusion, CK and LDH levels and leucocytosis may be considered to be relatively harmless "side-effects" of prolonged running in this group of male subjects with rather moderate ultramarathon experience and training status. However, acute kidney injury may become clinically relevant in this population under the certain conditions, which should be considered by responsible race managers and medical advisors.

Hoppel|Florian|F| Calabria|Elisa|E| Pesta|Dominik|D| Kantner-Rumplmair|Wilhelm|W| Gnaiger|Erich|E| Burtscher|Martin|M|

ultramarathon running
muscle damage
acute kidney injury
health effects
immune system


Foot-and-Mouth Disease Virus Lacking the Leader Protein and Containing Two Negative DIVA Markers (FMDV LL3B3D A24) Is Highly Attenuated in Pigs.

Abstract: Inactivated whole-virus vaccines are widely used for the control of foot-and-mouth disease (FMD). Their production requires the growth of large quantities of virulent FMD virus in biocontainment facilities, which is expensive and carries the risk of an inadvertent release of virus. Attenuated recombinant viruses lacking the leader protease coding region have been proposed as a safer alternative for the production of inactivated FMD vaccines (Uddowla et al., 2012, J Virol 86:11675-85). In addition to the leader deletion, the marker vaccine virus FMDV LL3BPVKV3DYR A24 encodes amino acid substitutions in the viral proteins 3B and 3D that allow the differentiation of infected from vaccinated animals and has been previously shown to be effective in cattle and pigs. In the present study, two groups of six pigs each were inoculated with live FMDV LL3BPVKV3DYR A24 virus either intradermally into the heel bulb (IDHB) or by intra-oropharyngeal (IOP) deposition. The animals were observed for 3 or 5 days after inoculation, respectively. Serum, oral and nasal swabs were collected daily and a thorough postmortem examination with tissue collection was performed at the end of the experiment. None of the animals had any signs of disease or virus shedding. Virus was reisolated from only one serum sample (IDHB group, sample taken on day 1) and one piece of heel bulb skin from the inoculation site of another animal (IDHB group, necropsy on day 3), confirming that FMDV LL3BPVKV3DYR A24 is highly attenuated in pigs.

Eschbaumer|Michael|M|
Dill|Veronika|V|
Carlson|Jolene C|JC|
Arzt|Jonathan|J|
Stenfeldt|Carolina|C|
Krug|Peter W|PW|
Hardham|John M|JM|
Stegner|Jacob E|JE|
Rodriguez|Luis L|LL|
Rieder|Elizabeth|E|

foot-and-mouth disease virus
DIVA
attenuated
leaderless
marker virus


Ageing and chronic disease-related changes in the morphometric characteristics of ovarian follicles in cynomolgus monkeys (Macaca fascicularis).

Abstract:
STUDY QUESTION
How is the localisation of ovarian follicles affected by ageing and chronic diseases?

SUMMARY ANSWER
Ovarian follicles shift deeper towards the medulla, due to thickening of the tunica albuginea (TA), with ageing and some major common chronic diseases.

WHAT IS KNOWN ALREADY
The ovary undergoes morphological and functional changes with ageing. The follicular pool follows these changes with alterations in the amount and distribution of residual follicles. Diseases causing a chronic inflammatory process are associated with morphological changes and impaired ovarian function.

STUDY DESIGN, SIZE, DURATION
We conducted a cross-sectional study, examining 90 ovaries from 90 female monkeys. The samples were collected from April 2018 to March 2019 at Tsukuba Primate Research Center in National Institutes of Biomedical Innovation, Health and Nutrition, Japan.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Ovarian samples were obtained from cynomolgus monkeys that died from natural causes or were euthanised. Ovarian sections were stained with haematoxylin and eosin (H&E) for histological analyses. In ovarian sections from 64 female macaques aged 0-25 years, a total of 13 743 follicles at different developmental stages (primordial, intermediary, primary, early secondary and late secondary) were assessed to determine the depth of each follicle from the outer surface of the ovarian cortex to the far end of the follicle, by using a digital imaging software. TA thickness was measured as sum of basal membrane and tunica collagen layer for each ovary under H&E staining. To explore the possibility of age-related trends in ovarian morphometric characteristics, samples were divided into four different age groups (0-3 years (pre-menarche), 4-9 years, 10-14 years and 15-20 years). To evaluate the effect of common chronic diseases on ovarian morphometric characteristics, macaques with diabetes mellitus (DM) (n = 10), endometriosis (n = 8) or inflammatory bowel disease (IBD) (n = 8) were compared to age-matched controls without chronic diseases.

MAIN RESULTS AND THE ROLE OF CHANCE
Ovarian morphometric analysis revealed that the relative location of follicles became deeper in all age groups according to development of follicles (P < 0.05). Total follicle distance from the ovarian surface was increased with ageing (P < 0.05). In a sub-analysis according to developmental stage, only primordial and intermediary follicles were localised deeper with increasing age (P < 0.05). TA thickness was also increased with ageing (P < 0.05). The localisation of the total number of follicles became deeper in ovaries from monkeys with DM, endometriosis or IBD as compared to the control group (P < 0.05). With DM, analysis of follicles distance at almost each developmental stage was significantly deeper compared to controls (P < 0.05) with the exception of early secondary follicles. With endometriosis, follicles at primary and early and late secondary stages were significantly deeper compared to controls (P < 0.05). Also with IBD, follicles at primary and early and late secondary follicles were significantly deeper compared to controls (P < 0.001). The TA was thicker with DM and endometriosis compared to controls (P < 0.05), but not with IBD (P = 0.16).

LARGE SCALE DATA
NA.

LIMITATIONS, REASONS FOR CAUTION
Two-dimensional histology was used to assess follicle localisation. The possibility of minimal variations between the measured distance to the actual distance in a spherical structure cannot be excluded. Additionally, the severity of disease was not assessed.

WIDER IMPLICATIONS OF THE FINDINGS
This study is the first step towards enhancing our understanding of how ageing and chronic diseases affect the relative localisation of dormant and developing follicles. These observations, combined with possible future human studies, may have managerial implications in the field of fertility preservation and other conditions involving ovarian tissue cryopreservation.

STUDY FUNDING/COMPETING INTEREST(S)
The present work was supported by the Grant-in-Aid for Scientific Research B (19H03801) (to K.K.), Challenging Exploratory Research (18K19624), Japan Agency for Medical Research and Development, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Takeda Science Foundation and Naito Foundation (to K.K.). All authors have no conflicts of interest directly relevant to the content of this article.

D000818:Animals
D002908:Chronic Disease
D003430:Cross-Sectional Studies
D005260:Female
D059247:Fertility Preservation
D008252:Macaca fascicularis
D006080:Ovarian Follicle

ageing
ovary
diabetes mellitus
endometriosis
fertility preservation


Genetic Drivers of von Willebrand Factor Levels in an Ischemic Stroke Population and Association With Risk for Recurrent Stroke.

Abstract:
BACKGROUND AND PURPOSE
von Willebrand factor (vWF) plays an important role in thrombus formation during cerebrovascular damage. We sought to investigate the potential role of circulating vWF in recurrent cerebrovascular events and identify genetic contributors to variation in vWF level in an ischemic stroke population.

METHODS
We analyzed the effect of circulating vWF on risk of recurrent stroke using survival models in the VISP trial (Vitamin Intervention for Stroke Prevention) and the use of vWF in reclassification over traditional factors. We conducted a genome-wide association study) with imputation, based on 1000 Genomes Project data, for circulating vWF levels and then interrogated loci previously associated with vWF levels. We performed expression quantitative trait locus analysis for vWF across different tissues.

RESULTS
Elevated vWF levels were associated with increased risk for recurrent stroke in VISP. Adding vWF to traditional clinical parameters also improved recurrent stroke risk prediction. We identified single-nucleotide polymorphisms significantly associated with circulating vWF at the ABO locus (P<5×10-8) and replicated findings from previous genetic associations of vWF levels in humans. Expression quantitative trait locus analyses demonstrate that most associated ABO single-nucleotide polymorphisms were also associated with vWF gene expression.

CONCLUSIONS
Elevated vWF levels are associated with recurrent stroke in VISP. In the VISP population, genetic determinants of vWF levels that impact vWF gene expression were identified. These data add to our knowledge of the pathophysiologic and genetic basis for recurrent stroke risk and may have implications for clinical care decision making.

Williams|Stephen R|SR|
Hsu|Fang-Chi|FC|
Keene|Keith L|KL|
Chen|Wei-Min|WM|
Dzhivhuho|Godfrey|G|
Rowles|Joe L|JL|
Southerland|Andrew M|AM|
Furie|Karen L|KL|
Rich|Stephen S|SS|
Worrall|Bradford B|BB|
Sale|Michèle M|MM|
|||

von Willebrand factor
stroke
risk
vitamins
decision making
genetic association studies


Infection of Mycobacterium tuberculosis Promotes Both M1/M2 Polarization and MMP Production in Cigarette Smoke-Exposed Macrophages.

Abstract: Pulmonary tuberculosis (PTB) is a risk factor for COPD. Our previous study revealed more severe emphysema in COPD patients (mostly smokers) with prior tuberculosis. However, the mechanisms of interactions between cigarette smoke (CS) and Mycobacterium tuberculosis (Mtb) are unknown. In this study, we found that the frequencies of both M1 and M2 macrophages, and levels of MMP9 and MMP12 in bronchoalveolar lavage were increased in PTB patients with smoking. Between-group analysis showed that the frequency of M1 macrophages was higher in non-smoker PTB patients while more M2 macrophages were found in smokers without PTB, as compared to the non-smoker healthy controls. Bacille Calmette-Guérin (BCG) infection in CS extract (CSE)-incubated MH-S cells further enhanced secretion of M1-related (iNOS, IFN-γ and TNF-α) and M2-related (TGF-β and IL-10) cytokines, reactive oxygen species (ROS) production and cellular apoptosis, concomitantly with up-regulation of MMP9 and MMP12, but not TIMP1. Moreover, BCG infection in acutely CS-exposed mice promoted macrophage polarization toward both M1 and M2 phenotypes, along with increased lung inflammatory infiltration. MMP9 and MMP12, but not TIMP1, were further up-regulated in lung tissues and BAL fluid after BCG infection in this model. Taken together, Mtb Infection promoted CS-exposed macrophages to polarize toward both M1 and M2 phenotypes, along with enhanced production of MMP9 and MMP12. These findings provide insights into the mechanistic interplay between CS exposure and tuberculosis in the pathogenesis of COPD.

Le|Yanqing|Y| Cao|Wenli|W| Zhou|Lu|L| Fan|Xin|X| Liu|Qiangui|Q| Liu|Fusheng|F| Gai|Xiaoyan|X| Chang|Chun|C| Xiong|Jing|J| Rao|Yafei|Y| Li|Aling|A| Xu|Wei|W| Liu|Beibei|B| Wang|Tong|T| Wang|Beinan|B| Sun|Yongchang|Y|

D029424:Pulmonary Disease, Chronic Obstructive

D019715:Tissue Inhibitor of Metalloproteinase-1

Mycobacterium tuberculosis
cigarette smoke
macrophage polarization
chronic obstructive pulmonary disease
matrix metalloproteinase


Anti-oxidative feedback and biomarkers in the intertidal seagrass Zostera japonica induced by exposure to copper, lead and cadmium.

Abstract: To investigate the potential influences of anthropogenic pollutants, we evaluated the responses of the intertidal seagrass Zostera japonica to three heavy metals: copper (Cu), lead (Pb), and cadmium (Cd). Z. japonica was exposed to various concentrations of Cu, Pb, and Cd (0, 0.5, 5, 50μM) over seven days. The effects were then analyzed using the antioxidant enzyme catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione peroxidase (GPX), and lipid peroxidation measured using malondialdehyde (MDA) as proxy. Metal accumulation in the above-ground tissues and phenotypic changes were also investigated. Our results revealed that heavy metal concentration increased in seagrass exposed to high levels of metals. Z. japonica has great potential for metal accumulation and a suitable candidate for the decontamination of moderately Cu contaminated bodies of water and can also potentially enhanced efforts of environmental decontamination, either through phytoextraction abilities or by functioning as an indicator for monitoring programs that use SOD, CAT, GPX, POD and MDA as biomarkers.

Lin|Haiying|H| Sun|Tao|T| Zhou|Yi|Y| Zhang|Xiaomei|X|

Biomarker
Seagrass
Zostera japonica
Heavy metals
Antioxidant response


Impact of Ph.D. training: a comprehensive analysis based on a Japanese national doctoral survey.

Abstract: Ph.D. training in academic labs offers the foundation for the production of knowledge workers, indispensable for the modern knowledge-based society. Nonetheless, our understanding on Ph.D. training has been insufficient due to limited access to the inside of academic labs. Furthermore, early careers of Ph.D. graduates are often difficult to follow, which makes the evaluation of training effects challenging. To address these limitations, this study aims to illustrate the settings of Ph.D. training in academic labs and examine their impact on several training outcomes, drawing on a national survey of a cohort of 5000 Ph.D. graduates from Japanese universities. The result suggests that a supervising team structure as well as the frequency of supervision, contingent to a few contextual factors, determine the Ph.D. graduates' career decisions, performance, and degrees of satisfaction with the training programs.

Ph.D. training
Academic career
Academic training
Higher education
Postgraduate education


Defective DNA repair and chromatin organization in patients with quiescent systemic lupus erythematosus.

Abstract:
BACKGROUND
Excessive autoantibody production characterizing systemic lupus erythematosus (SLE) occurs irrespective of the disease's clinical status and is linked to increased lymphocyte apoptosis. Herein, we tested the hypothesis that defective DNA damage repair contributes to increased apoptosis in SLE.

METHODS
We evaluated nucleotide excision repair at the N-ras locus, DNA double-strand breaks repair and apoptosis rates in peripheral blood mononuclear cells from anti-dsDNA autoantibody-positive patients (six with quiescent disease and six with proliferative nephritis) and matched healthy controls following ex vivo treatment with melphalan. Chromatin organization and expression levels of DNA repair- and apoptosis-associated genes were also studied in quiescent SLE.

RESULTS
Defective nucleotide excision repair and DNA double-strand breaks repair were found in SLE, with lupus nephritis patients showing higher DNA damage levels than those with quiescent disease. Melphalan-induced apoptosis rates were higher in SLE than control cells and correlated inversely with DNA repair efficiency. Chromatin at the N-ras locus was more condensed in SLE than controls, while treatment with the histone deacetylase inhibitor vorinostat resulted in hyperacetylation of histone H4, chromatin decondensation, amelioration of DNA repair efficiency and decreased apoptosis. Accordingly, genes involved in DNA damage repair and signaling pathways, such as DDB1, ERCC2, XPA, XPC, MRE11A, RAD50, PARP1, MLH1, MLH3, and ATM were significantly underexpressed in SLE versus controls, whereas PPP1R15A, BARD1 and BBC3 genes implicated in apoptosis were significantly overexpressed.

CONCLUSIONS
Epigenetically regulated functional abnormalities of DNA repair machinery occur in SLE, regardless of clinical disease activity, and may promote lymphocyte apoptosis. Approaches to correct these abnormalities may be of therapeutic value in SLE.

Souliotis|Vassilis L|VL|
Vougas|Konstantinos|K|
Gorgoulis|Vassilis G|VG|
Sfikakis|Petros P|PP|

Chromatin organization
Systemic lupus erythematosus
Apoptosis
Nucleotide excision repair
DNA double-strand breaks repair
Histone deacetylase inhibitor


Formation of Subwavelength Periodic Triangular Arrays on Tungsten through Double-Pulsed Femtosecond Laser Irradiation.

Abstract: We present a mask-free strategy for fabricating two-dimensional subwavelength periodic triangular arrays on tungsten, by focusing two orthogonally polarized and temporally delayed femtosecond laser beams using a cylindrical lens. In stark contrast to the commonly observed structures of either a single ablation spot or a one-dimensional grating, we obtained highly uniform periodic triangular arrays on the laser-exposed surface, with three equilateral sides each of 480 nm in length and about 100 nm in modulation depth. The triangular features varied with both the laser energy and the scanning speed. We found that the optical reflectivity of such a surface reduces significantly within the spectral range of 700⁻2500 nm. The triangular structure morphology can also be controlled by varying the time delay between the two laser beams.

Qiao|Hongzhen|H| Yang|Jianjun|J| Li|Jing|J| Liu|Qi|Q| Liu|Jie|J| Guo|Chunlei|C|

tungsten
orthogonal polarizations
subwavelength triangular structures
time-delayed femtosecond lasers


Pseudomonas chlororaphis metabolites as biocontrol promoters of plant health and improved crop yield.

Abstract: The Pseudomonas fluorescens complex contains at least eight phylogenetic groups and each of these includes several bacterial species sharing ecological and physiological traits. Pseudomonas chlororaphis classified in a separate group is represented by three different subspecies that show distinctive traits exploitable for phytostimulation and biocontrol of phytopathogens. The high level of microbial competitiveness in soil as well as the effectiveness in controlling several plant pathogens and pests can be related to the P. chlororaphis ability to implement different stimulating and toxic mechanisms in its interaction with plants and the other micro- and macroorganisms. Pseudomonas chlororaphis strains produce antibiotics, such as phenazines, pyrrolnitrine, 2-hexyl, 5-propyl resorcinol and hydrogen cyanide, siderophores such as pyoverdine and achromobactine and a complex blend of volatile organic compounds (VOCs) that effectively contribute to the control of several plant pathogens, nematodes and insects. Phenazines and some VOCs are also involved in the induction of systemic resistance in plants. This complex set of beneficial strategies explains the high increasing interest in P. chlororaphis for commercial and biotechnological applications. The aim of this review is to highlight the role of the different mechanisms involved in the biocontrol activity of P. chlororaphis strains.

D061046:Biological Control Agents
D060467:Disease Resistance
D010802:Phylogeny
D063245:Plant Development
D000070096:Pseudomonas chlororaphis
D064210:Secondary Metabolism

Pseudomonas chlororaphis
Biocontrol
Induced systemic resistance
Rhizobacteria


An App-Delivered Self-Management Program for People With Low Back Pain: Protocol for the selfBACK Randomized Controlled Trial.

Abstract:
BACKGROUND
Low back pain (LBP) is prevalent across all social classes, in all age groups, and across industrialized and developing countries. From a global perspective, LBP is considered the leading cause of disability and negatively impacts everyday life and well-being. Self-management is a recommended first-line treatment, and mobile apps are a promising platform to support self-management of conditions like LBP. In the selfBACK project, we have developed a digital decision support system made available for the user via an app intended to support tailored self-management of nonspecific LBP.

OBJECTIVE
The trial aims to evaluate the effectiveness of using the selfBACK app to support self-management in addition to usual care (intervention group) versus usual care only (control group) in people with nonspecific LBP.

METHODS
This is a single-blinded, randomized controlled trial (RCT) with two parallel arms. The selfBACK app provides tailored self-management plans consisting of advice on physical activity, physical exercises, and educational content. Tailoring of plans is achieved by using case-based reasoning (CBR) methodology, which is a branch of artificial intelligence. The core of the CBR methodology is to use data about the current case (participant) along with knowledge about previous and similar cases to tailor the self-management plan to the current case. This enables a person-centered intervention based on what has and has not been successful in previous cases. Participants in the RCT are people with LBP who consulted a health care professional in primary care within the preceding 8 weeks. Participants are randomized to using the selfBACK app in addition to usual care versus usual care only. We aim to include a total of 350 participants (175 participants in each arm). Outcomes are collected at baseline, 6 weeks, and 3, 6, and 9 months. The primary end point is difference in pain-related disability between the intervention group and the control group assessed by the Roland-Morris Disability Questionnaire at 3 months.

RESULTS
The trial opened for recruitment in February 2019. Data collection is expected to be complete by fall 2020, and the results for the primary outcome are expected to be published in fall 2020.

CONCLUSIONS
This RCT will provide insights regarding the benefits of supporting tailored self-management of LBP through an app available at times convenient for the user. If successful, the intervention has the potential to become a model for the provision of tailored self-management support to people with nonspecific LBP and inform future interventions for other painful musculoskeletal conditions.

TRIAL REGISTRATION
ClinicalTrial.gov NCT03798288; https://clinicaltrials.gov/ct2/show/NCT03798288.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
DERR1-10.2196/14720.

self-management
low back pain
app
decision support system
case-based reasoning
eHealth
mHealth


Yield of concurrent systemic biopsy during MRI-targeted biopsy according to Prostate Imaging Reporting and Data System version 2 in patients with suspected prostate cancer.

Abstract:
OBJECTIVES
To investigate the yield of concurrent systemic biopsy (SB) during MRI-targeted biopsy (MRTB) as Prostate Imaging Reporting and Data System (PI-RADS) version 2 (v2) interpretations in patients with suspected prostate cancer (PCa).

METHODS
A total of 285 patients with suspected PCa underwent prebiopsy 3-T MRI, followed by MRI-transrectal ultrasound fusion targeted biopsy and concurrent standard SB for lesions with PI-RADS v2 scores 3-5. Detection rates and positive core rates of PCa and clinically significant cancer (CSC) were evaluated.

RESULTS
In concurrent MRTB and SB, PCa and CSC detection rates were 18.9% and 9.4% for PI-RADS score 3, 45.9% and 32.4% for PI-RADS score 4, and 82.1% and 72.6% for PI-RADS score 5, respectively. Overall detection rate of CSCs (40.0%) for concurrent MRTB and SB was significantly higher than that of MRTB (34.4%, p = 0.004) or SB alone (27.7%, p < 0.001): an increase of 5.6% (16 patients) compared with MRTB alone. For patients with PI-RADS score 4 or 5, the CSC detection rate of concurrent MRTB and SB was 47.0%, an increase of 6.1% when compared with MRTB (40.9%) only (p < 0.001). Of the 110 patients with both MRTB- and SB-positive findings, 22 (20.0%) had the highest Gleason score in SB compared with that in MRTB. In 9.5% (27/285) patients including 12 patients with CSCs, only SB was positive, with negative MRTB.

CONCLUSION
Concurrent SB with MRTB based on PI-RADS v2 can yield a higher CSC detection rate compared with MRTB alone in patients with suspected PCa.

KEY POINTS
• Concurrent SB with MRTB yields an increase of 5.6% CSC detection compared with MRTB alone. • Of both MRTB- and SB-positive findings, 20.0% patients have upgraded Gleason score in SB. • In 18.4% patients, only SB was positive, with negative MRTB. Adding MRTB to SB is helpful for adequate risk stratification, reducing diagnostic uncertainty of PCa.

D006801:Humans
D061705:Image-Guided Biopsy
D008279:Magnetic Resonance Imaging
D008297:Male
D060787:Neoplasm Grading
D011471:Prostatic Neoplasms

Biopsy
Prostate cancer
Image-guided biopsy
Magnetic resonance imaging


Ultrasensitive SERS immunoassay based on diatom biosilica for detection of interleukins in blood plasma.

Abstract: An ultrasensitive surface-enhanced Raman scattering (SERS) immunoassay based on diatom biosilica with integrated gold nanoparticles (AuNPs) for the detection of interleukin 8 (IL-8) in blood plasma has been developed. The SERS sensing originates from unique features of the diatom frustules, which are capable of enhancing the localized surface-plasmon resonance of metal nanostructures. The SERS immune tags ware fabricated by functionalizing 70-nm Au nanoparticles with DTNB (i.e., 5,5'-dithiobis(2-nitrobenzoic acid)), which acted as a Raman reporter molecule, as well as the specific antibodies. These DTNB-labeled immune-AuNPs can form a sandwich structure with IL-8 antigens (infection marker) and the antibodies immobilized on the biosilica material. Our method showed an improved IL-8 detection limit in comparison to standard ELISA methods. The current detection limit for IL-8 using a conventional ELISA test is about 15.6 pg mL-1. The lower detection limit for IL-8 in blood plasma was estimated to be 6.2 pg mL-1. To the best of our knowledge, this is the first report on the recognition of IL-8 in human samples using a SERS-based method. This method clearly possesses high sensitivity to clinically relevant interleukin concentrations in body fluids. The average relative standard deviation of this method is less than 8%, which is sufficient for analytical analysis and comparable to those of classical ELISA methods. This SERS immunoassay also exhibits high biological specificity for the detection of IL-8 antigens. The established SERS immunoassay offers a valuable platform for the ultrasensitive and highly specific detection of immune biomarkers in a clinical setting for medical diagnostics. Graphical Abstract The SERS-based immunoassay based on naturally generated photonic biosilica for the detection of interleukin 8 (IL-8) in human plasma samples.

Kamińska|Agnieszka|A| Sprynskyy|Myroslav|M| Winkler|Katarzyna|K| Szymborski|Tomasz|T|

Surface-enhanced Raman spectroscopy (SERS)


Efficacy and Safety of Tedizolid and Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Injection Drug Users: Analysis of Two Clinical Trials.

Abstract:
INTRODUCTION
Injection drug users (IDUs) often develop acute bacterial skin and skin structure infections (ABSSSI) and use emergency departments as their primary source for medical care.

METHODS
A post hoc subgroup analysis of two randomized trials examined the efficacy and safety of tedizolid in the treatment of ABSSSI in IDUs. IDUs (n = 389) were identified from two pooled phase 3 trials (NCT01170221, NCT01421511) in patients with ABSSSI (n = 1333). Patients were randomly assigned to tedizolid phosphate (200 mg once daily, 6 days) or linezolid (600 mg twice daily, 10 days). Primary endpoint was ≥ 20% reduction in lesion area from baseline at 48 -72 h. Secondary endpoints included investigator-assessed clinical and microbiological response at the post-therapy evaluation (PTE).

RESULTS
Wound infection was more common in IDUs (52.2%), while cellulitis/erysipelas was more common in non-IDUs (55.9%). Most infections were due to Staphylococcus aureus (IDUs, 75.2%; non-IDUs, 85.6%), while oral pathogens were more prevalent in IDUs. Early clinical success rates for tedizolid and linezolid were 82.5% and 79.6% in IDUs and 81.3% and 79.3% for non-IDUs, respectively; responses at PTE were similar. Microbiological response per pathogen was similar between treatment groups. Rates of treatment-emergent adverse events (AEs) in IDUs were comparable between tedizolid (46.2%) and linezolid (47.8%) arms, while lower incidence of gastrointestinal AEs was observed with tedizolid (20.3%) than with linezolid (25.1%).

CONCLUSION
Efficacy and safety of tedizolid and linezolid in the treatment of ABSSSI was similar in IDUs and non-IDUs, supporting the use of oxazolidinones in treating ABSSSIs in IDUs.

FUNDING
Merck & Co., Inc., Kenilworth, NJ, USA.

Moran|Gregory J|GJ|
De Anda|Carisa|C|
Das|Anita F|AF|
Green|Sinikka|S|
Mehra|Purvi|P|
Prokocimer|Philippe|P|

Tedizolid
Linezolid
Injection drug user
ABSSSI


Mendelian randomization analysis of cholesteryl ester transfer protein and subclinical atherosclerosis: A population-based study.

Abstract:
BACKGROUND
Several trials to prevent cardiovascular disease by inhibiting cholesteryl ester transfer protein (CETP) have failed, except Randomized EValuation of the Effects of Anacetrapib through Lipid-modification. Thus far, it is unclear to what extent CETP is causally related to measures of atherosclerosis.

OBJECTIVE
The aim of the article was to study the causal relationship between genetically determined CETP concentration and carotid intima-media thickness (cIMT) in a population-based cohort study.

METHODS
In the Netherlands Epidemiology of Obesity study, participants were genotyped, and cIMT was measured by ultrasonography. We examined the relation between a weighted genetic risk score for CETP concentration, based on 3 single-nucleotide polymorphisms that have previously been shown to largely determine CETP concentration and cIMT using Mendelian randomization in the total population and in strata by sex, Framingham 10-year risk, (pre)diabetes, high-density lipoprotein cholesterol, triglycerides, and statin use.

RESULTS
We analyzed 5655 participants (56% women) with a mean age of 56 (range 44-66) years, body mass index of 26 (range 17-61) kg/m2, and serum CETP of 2.47 (range 0.68-5.33) μg/mL. There was no evidence for a causal relation between genetically determined CETP and cIMT in the total population, but associations were differently directed in men (16 μm per μg/mL increase in genetically determined CETP; 95% confidence interval: -8, 39) and women (-8 μm; -25, 9). Genetically determined CETP appeared to be associated with cIMT in normoglycemic men (26 μm; -1, 52) and in (pre)diabetic women (48 μm; -2, 98).

CONCLUSION
In this population-based study, there was no causal relation between genetically determined CETP concentration and cIMT in the total population although we observed directionally differing effects in men and women. Stratified results suggested associations in individuals with different cardiometabolic risk factor profiles, which require replication.

Christen|Tim|T|
Trompet|Stella|S|
Noordam|Raymond|R|
Blauw|Lisanne L|LL|
Gast|Karin B|KB|
Rensen|Patrick C N|PCN|
Willems van Dijk|Ko|K|
Rosendaal|Frits R|FR|
de Mutsert|Renée|R|
Jukema|J Wouter|JW|
|||

D053480:Cholesterol Ester Transfer Proteins

Mendelian randomization
Atherosclerosis
Cohort
Epidemiology
Reverse cholesterol transport


Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells.

Abstract: Haptenation of model nucleophiles, representing the key MIE in skin sensitisation, is routinely measured in chemico to provide data for skin allergy risk assessment. Better understanding of the dynamics of haptenation in human skin could provide the metrics required to improve determination of sensitiser potency for risk assessment of chemicals. We have previously demonstrated the applicability and sensitivity of the dual stable isotope labelling approach to detect low level haptenation in complex mixtures of proteins. In the present study, we investigated haptenation in a relevant living cell model over time at a subtoxic concentration. DNCB, an extremely potent sensitiser, caused minimal changes in overall protein differential expression in HaCaT cells and haptenated approximately 0.25 % of all available nucleophiles when applied at a subtoxic concentration (10μM) for 4 h. The data shows that the maximum level of haptenation occurs at 2 h and that DNCB, whilst being a promiscuous hapten, shows a preference for Cys residues, despite the considerably higher concentration of amine-based nucleophiles. Although a proportion of highly abundant proteins were haptenated, numerous haptenated sites were also detected on low abundant proteins. Certain proteins were modified at residues buried deep inside the protein structure which are less accessible to haptenation compared with surface exposed nucleophiles. The microenvironment of the buried residues may be a result of several factors influencing the reactivity of both the target nucleophile and the hapten.

Parkinson|Erika|E| Aleksic|Maja|M| Kukic|Predrag|P| Bailey|Alistair|A| Cubberley|Richard|R| Skipp|Paul|P|

Proteomics
Cellular response
Sensitisation
Haptenation
DNCB
Allergic contact dermatitis


A melt-electrowritten filter for capture and culture of circulating colon cancer cells.

Abstract: Metastasis is the major cause of death in cancer patients accounting for about 90% of the mortality. The detection and analysis of the hallmark of metastasis, circulating tumor cells (CTCs), have significant impact in cancer biology and clinical practice. However, the scarcity of CTCs in blood, particularly in that of colorectal cancer patients, is a serious bottleneck in the development of CTC-based precision medicine. Herein, the melt electrowriting (MEW) technology was used for reproductive fabrication of a biocompatible antibody-presenting polycaprolactone filter with tailored porous structure. It is demonstrated, for the first time, that such filter can be used not only to catch cancer cells spiked in whole blood but also to culture the cancer cells directly on site. Specifically, HT29 colon cancer cells can be captured with an efficiency of 85%, and when spiked into 4 mL of whole blood, 47% were captured on one Ø12mm filter. Furthermore, repeated capture and culture experiments have shown that as few as 20 HT29 colon cancer cells spiked into 4 mL of whole blood can be captured on the filter and within 2 weeks be expanded on site to become tumor bodies that are visible to the untrained eye. This filter allows for downstream analysis, such as flow cytometry, immunocytochemistry, Western blotting, and rt-qPCR. This technology represents a simple and cost-effective platform that potentially enables fast and efficient culture of rare CTCs from patients' blood. This provides non-invasive alternatives for solid biopsy tumor materials for treatment screening, with great potential to realize precision medicine for cancer treatment.

Jørgensen|M L|ML|
Müller|C|C|
Sikkersoq|M|M|
Nadzieja|M|M|
Zhang|Z|Z|
Su|Y|Y|
Just|J|J|
Garm Spindler|K-L|KL|
Chen|M|M|

Circulating tumor cells
Colorectal cancer
Polycaprolactone
Bioconjugation
Melt electrospinning writing
On-site culture


Design and Implementation of a Tool for Pharmacists to Register Potential Errors in Prescribed Medication.

Abstract: Adverse drug events are frequent and may be mitigated with the implementation of functionalities within Health Information Systems. We developed a tool that allows Pharmacists to register and communicate to providers potential errors in prescribed drugs in terms of medication omission, unjustified stop of medication or other reasons. We included all interventions performed by Pharmacists for admitted patients between July, 31st 2018 and October, 23rd 2018. During the study period, 193 interventions were carried out by Pharmacists. 117 (60%) were intended for registering medication omission, 7 (4%) for unjustified stop of medication and 69 (36%) for other reasons. 112 interventions lead to the provider performing the suggested action (58%), 77 (40%) were rejected and 4 (2%) required no action. Although there were errors in the use of the tool, a great amount of interventions were accepted, thus representing a better quality of care for patients.

Frid|Santiago|S| Zapico|Valeria|V| Mansilla|Adriana|A| Álvarez|Matías|M| López|Gastón|G| Otero|Carlos|C| Luna|Daniel|D|

D064420:Drug-Related Side Effects and Adverse Reactions

Electronic prescribing
medication errors
patient safety


Morphometric evaluation of traumatic axonal injury and the correlation with post-traumatic cerebral atrophy and functional outcome.

Abstract:
INTRODUCTION
Imaging plays a crucial role in the diagnosis, prognosis and follow-up of traumatic brain injury. Whereas computed tomography plays a pivotal role in the acute setting, magnetic resonance imaging is best suited to detect the true extent of traumatic brain injury, and more specifically diffuse axonal injury. Post-traumatic brain atrophy is a well-known complication of traumatic brain injury.

PURPOSE
This study investigated the correlation between diffuse axonal injury detected with fluid-attenuated inversion recovery and susceptibility-weighted imaging magnetic resonance imaging, post-traumatic brain atrophy and functional outcome (Glasgow outcome scale - extended).

MATERIALS AND METHODS
Twenty patients with a closed head injury and diffuse axonal injury detected with fluid-attenuated inversion recovery and susceptibility-weighted imaging were included. The total volumes of the diffuse axonal injury fluid-attenuated inversion recovery lesions were determined for each subject's initial (<14 days) and follow-up magnetic resonance scan (average: day 303 ± 83 standard deviation). The different brain volumes were automatically quantified using a validated and both US Food and Drug Administration-cleared and CE-marked machine learning algorithm (icobrain). The number of susceptibility-weighted imaging lesions and functional outcome scores (Glasgow outcome scale - extended) were retrieved from the Collaborative European NeuroTrauma Effectiveness Research Traumatic Brain Injury dataset.

RESULTS
The volumetric fluid-attenuated inversion recovery diffuse axonal injury lesion load showed a significant inverse correlation with functional outcome (Glasgow outcome scale - extended) (r = -0.57; P = 0.0094) and white matter volume change (r = -0.50; P = 0.027). In addition, white matter volume change correlated significantly with the Glasgow outcome scale - extended score (P = 0.0072; r = 0.58). Moreover, there was a strong inverse correlation between longitudinal fluid-attenuated inversion recovery lesion volume change and whole brain volume change (r = -0.63; P = 0.0028). No significant correlation existed between the number of diffuse axonal injury susceptibility-weighted imaging lesions, brain atrophy and functional outcome.

CONCLUSIONS
Volumetric analysis of diffuse axonal injury on fluid-attenuated inversion recovery imaging and automated brain atrophy calculation are potentially useful tools in the clinical management and follow-up of traumatic brain injury patients with diffuse axonal injury.

functional outcome
brain atrophy
FLAIR
SWI
Traumatic brain injury (TBI)
magnetic resonance imaging (MRI)


Application of metabolic modeling for targeted optimization of high seeding density processes.

Abstract: Process intensification by application of perfusion mode in pre-stage bioreactors and subsequent inoculation of cell cultures at high seeding densities (HSD) has the potential to meet the increasing requirements of future manufacturing demands. However, process development is currently restrained by a limited understanding of the cell's requirements under these process conditions. The goal of this study was to use extended metabolite analysis and metabolic modeling for targeted optimization of HSD cultivations. The metabolite analysis of HSD N-stage cultures revealed accumulation of inhibiting metabolites early in the process and flux balance analysis led to the assumption that reactive oxygen species (ROS) were contributing to the fast decrease in cell viability. Based on the metabolic analysis an optimized feeding strategy with lactate and cysteine supplementation was applied, resulting in an increase in antibody titer of up to 47%. Flux balance analysis was further used to elucidate the surprisingly strong synergistic effect of lactate and cysteine, indicating that increased lactate uptake led to reduced ROS formation under these conditions whilst additional cysteine actively reduced ROS via the glutathione pathway. The presented results finally demonstrate the benefit of modeling approaches for process intensification as well as the potential of HSD cultivations for biopharmaceutical manufacturing.

Brunner|Matthias|M|0000-0003-3816-9365 Kolb|Klara|K| Keitel|Alena|A| Stiefel|Fabian|F| Wucherpfennig|Thomas|T| Bechmann|Jan|J| Unsoeld|Andreas|A| Schaub|Jochen|J|

high seeding density
process intensification
cell culture
N-1 perfusion


Digital inbound marketing: Measuring the economic performance of grocery e-commerce in Europe and the USA.

Abstract: This research investigates the cost-result relationship of the Inbound Marketing actions used by grocery e-commerce. The analysis is based on the application of the Dorfman and Steiner (1954) model for optimal advertising budget, which is adapted by the authors to digital marketing and verified with empirical statistical analysis. Considering 29 leading companies in six countries over a time horizon of six years, an analysis of the mix of SEO and SEM techniques aimed at the attraction and conversion of Internet users to the web pages of their companies is carried out. The results confirm that e-commerce is optimizing Digital Inbound Marketing in line with the established model. Differences are identified depending on the type of format (pure player versus brick and mortar) and at the country level (UK and USA versus others).

Inbound marketing
Economic performance
E-commerce
Digital marketing
Marketing investment optimization
Retailing


What's wrong with evolutionary biology?

Abstract: There have been periodic claims that evolutionary biology needs urgent reform, and this article tries to account for the volume and persistence of this discontent. It is argued that a few inescapable properties of the field make it prone to criticisms of predictable kinds, whether or not the criticisms have any merit. For example, the variety of living things and the complexity of evolution make it easy to generate data that seem revolutionary (e.g. exceptions to well-established generalizations, or neglected factors in evolution), and lead to disappointment with existing explanatory frameworks (with their high levels of abstraction, and limited predictive power). It is then argued that special discontent stems from misunderstandings and dislike of one well-known but atypical research programme: the study of adaptive function, in the tradition of behavioural ecology. To achieve its goals, this research needs distinct tools, often including imaginary agency, and a partial description of the evolutionary process. This invites mistaken charges of narrowness and oversimplification (which come, not least, from researchers in other subfields), and these chime with anxieties about human agency and overall purpose. The article ends by discussing several ways in which calls to reform evolutionary biology actively hinder progress in the field.

Adaptation
Extended evolutionary synthesis
Inclusive fitness
Neo-Darwinism


Convolutional neural network scoring and minimization in the D3R 2017 community challenge.

Abstract: We assess the ability of our convolutional neural network (CNN)-based scoring functions to perform several common tasks in the domain of drug discovery. These include correctly identifying ligand poses near and far from the true binding mode when given a set of reference receptors and classifying ligands as active or inactive using structural information. We use the CNN to re-score or refine poses generated using a conventional scoring function, Autodock Vina, and compare the performance of each of these methods to using the conventional scoring function alone. Furthermore, we assess several ways of choosing appropriate reference receptors in the context of the D3R 2017 community benchmarking challenge. We find that our CNN scoring function outperforms Vina on most tasks without requiring manual inspection by a knowledgeable operator, but that the pose prediction target chosen for the challenge, Cathepsin S, was particularly challenging for de novo docking. However, the CNN provided best-in-class performance on several virtual screening tasks, underscoring the relevance of deep learning to the field of drug discovery.

Sunseri|Jocelyn|J|
King|Jonathan E|JE|
Francoeur|Paul G|PG|
Koes|David Ryan|DR|0000-0002-9043-6267

D000465:Algorithms
D001665:Binding Sites
D002403:Cathepsins
D030562:Databases, Protein
D055808:Drug Discovery
D008024:Ligands
D062105:Molecular Docking Simulation
D016571:Neural Networks, Computer
D011485:Protein Binding
D011487:Protein Conformation
D013329:Structure-Activity Relationship

Neural networks
D3R
Virtual screening
Drug design data
Machine learning
Protein–ligand scoring


CCL2 mediates the circadian response to low dose endotoxin.

Abstract: The mammalian circadian system is mainly originated in a master oscillator located in the suprachiasmatic nuclei (SCN) in the hypothalamus. Previous reports from our and other groups have shown that the SCN are sensitive to systemic immune activation during the early night, through a mechanism that relies on the action of proinflammatory factors within this structure. Chemokine (C-C motif) ligand 2 (CCL2) is induced in the brain upon peripheral immune activation, and it has been shown to modulate neuronal physiology. In the present work we tested whether CCL2 might be involved in the response of the circadian clock to peripheral endotoxin administration. The CCL2 receptor, C-C chemokine receptor type 2 (CCR2), was detected in the SCN of mice, with higher levels of expression during the early night, when the clock is sensitive to immune activation. Ccl2 was induced in the SCN upon intraperitoneal lipopolysaccharide (LPS) administration. Furthermore, mice receiving an intracerebroventricular (Icv) administration of a CCL2 synthesis inhibitor (Bindarit), showed a reduction LPS-induced circadian phase changes and Icv delivery of CCL2 led to phase delays in the circadian clock. In addition, we tested the possibility that CCL2 might also be involved in the photic regulation of the clock. Icv administration of Bindarit did not modify the effects of light pulses on the circadian clock. In summary, we found that CCL2, acting at the SCN level is important for the circadian effects of immune activation.

Duhart|José M|JM|
Brocardo|Lucila|L|
Mul Fedele|Malena L|ML|
Guglielmotti|Angelo|A|
Golombek|Diego A|DA|

Ccl2 Circadian Suprachiasmatic Immune Chemokine Ccr2 Lipopolysaccharide Bindarit


Patterns of Family Functioning and Diabetes-Specific Conflict in Relation to Glycemic Control and Health-Related Quality of Life Among Youth With Type 1 Diabetes.

Abstract:
Objectives
General and diabetes-specific family functioning may be associated with youth’s adaptation to type 1 diabetes (T1D); however, empirically derived patterns of family functioning and diabetes-specific conflict among youth have not been explored in relation to T1D adaptation.

Methods
Youth (N = 161, aged 12–18) with T1D and caregivers completed measures of family functioning and diabetes-specific conflict that served as indicators in latent profile analyses. Differences in glycemic control (measured by hemoglobin A1cs [HbA1c] and health-related quality of life [HRQoL]) were compared across profiles.

Results
Four profiles that varied by levels of family functioning, diabetes-specific conflict, and congruence between youth and caregiver perspectives emerged and related to T1D adaptation differently. Greater agreement between caregiver and youth and lower diabetes-specific conflict was associated with lower HbA1c and greater HRQoL.

Conclusions
Person-centered approaches are useful to quantify how many individuals fit into a particular pattern and determine how specific family dynamics may function together differently in relation to T1D adaptation for various subgroups of the population.

Rybak|Tiffany M|TM|
Ali|Jeanelle S|JS|
Berlin|Kristoffer S|KS|
Klages|Kimberly L|KL|
Banks|Gabrielle G|GG|
Kamody|Rebecca C|RC|
Ferry|Robert J|RJ|
Alemzadeh|Ramin|R|
Diaz-Thomas|Alicia M|AM|
|||

family functioning
conflict
quality of life
type 1 diabetes
adolescence
chronic illness
latent profile analysis


Carriage of Neisseria meningitidis in the Hajj and Umrah mass gatherings.

Abstract: Meningococcal disease is a serious public health threat, especially during mass gatherings such as Hajj and Umrah which provide optimal conditions for disease transmission. The disease is caused by Neisseria meningitidis and transmitted mainly via asymptomatic carriers. A review of the literature on asymptomatic N. meningitidis carriage among Hajj and Umrah pilgrims and their household contacts was performed. Carriage studies reported carriage rates to be higher in Hajj pilgrims compared to Umrah pilgrims and that these events promote acquisition of carriage among pilgrims. With some outliers, most studies found carriage rates among pilgrims to be comparable to those in populations under non-epidemic settings. However, these results should be interpreted with caution, taking into account the limitations within the studies identified. A wide variety of N. meningitidis serogroups appear to be circulating among Hajj and Umrah pilgrims, with serogroups W135 and B being most prominent. Current Hajj and Umrah meningococcal disease preventative measures do not necessarily prevent carriage and transmission, which may result in local and international outbreaks among susceptible populations. Monitoring carriage states of visitors and local inhabitants in the Kingdom of Saudi Arabia, as well as the implementation of preventive measures that impact carriage, are warranted to reduce the risk of Hajj and Umrah-related meningococcal disease outbreaks.

Yezli|Saber|S|
Wilder-Smith|Annelies|A|
Bin Saeed|Abdulaziz A|AA|

D002353:Carrier State
D003441:Crowding
D004196:Disease Outbreaks
D049673:History, 20th Century
D049674:History, 21st Century
D006801:Humans
D007514:Islam
D008589:Meningococcal Infections
D009345:Neisseria meningitidis
D011634:Public Health
D012529:Saudi Arabia
D014195:Travel

Carriage
Neisseria meningitidis
Hajj
Umrah
Mass gatherings
Meningococcal disease


Randomized trial of omega-3 for autism spectrum disorders: Effect on cell membrane composition and behavior.

Abstract: A high ω6/ω3 ratio [fatty acid (FA) index] in the cell membrane has been associated with inadequate brain development. It has started to be used as a biomarker of treatment efficacy in human diseases. The aim of this study was to investigate if omega-3 supplementation improves erythrocyte membrane ω6/ω3, plasma antioxidant status (TAS) and autistic behaviors. A randomized, crossover, placebo-controlled study was designed to investigate the effect of 8 weeks of supplementation with ω3 (962mg/d and 1155mg/d for children and adolescents, respectively). Sixty-eight children and adolescents with Autism Spectrum Disorders (ASD) completed the full protocol. Primary outcome measures were erythrocyte membrane FA composition and TAS. Secondary outcome measures were Social Responsiveness Scale and Clinical Global Impression-Severity. Treatment with ω3 improved the erythrocyte membrane ω6/ω3 ratio (treatment effect p<0.008, d=0.66; within subjects effect p<0.007, d=0.5) without changing TAS. There was a within subjects significant improvement in Social Motivation and Social Communication subscales scores, with a moderate to large effect size (p=0.004, d=0.73 and p=0.025, d=0.79 respectively), but no treatment effect (treatment-placebo order). Carryover effects cannot be discarded as responsible for the results in behavioral measures. In conclusion, supplementation with ω3 FA might be studied as an add-on to behavioral therapies in ASD. Optimal duration of treatment requires further investigation. With regard to side effects, the effect of this supplementation on the lipid profile needs monitoring.

Parellada|Mara|M|
Llorente|Cloe|C|
Calvo|Rosa|R|
Gutierrez|Silvia|S|
Lázaro|Luisa|L|
Graell|Montserrat|M|
Guisasola|Maria|M|
Dorado|Maria Luisa|ML|
Boada|Leticia|L|
Romo|Jose|J|
Dulin|Elena|E|
Sanz|Inmaculada|I|
Arango|Celso|C|
Moreno|Carmen|C|

Autism Spectrum Disorder
Biomarkers
Fatty acids, omega-3
Fatty acids, unsaturated
Randomized controlled trials


TCF7L2 silencing results in altered gene expression patterns accompanied by local genomic reorganization.

Abstract: Canonical Wnt signaling is crucial for intestinal homeostasis as TCF4, the major Wnt signaling effector in the intestines, is required for stem cell maintenance. The capability of TCF4 to maintain the stem cell phenotype is contingent upon β-catenin, a potent transcriptional activator, which interacts with histone acetyltransferases and chromatin remodeling complexes. We used RNAi to explore the influence of TCF4 on chromatin structure (Hi-C) and gene expression (RNA sequencing) across a 72-hour time series in colon cancer. We found that TCF4 reduction results in a disproportionate up-regulation of gene expression, including a powerful induction of SOX2. Integration of RNA sequencing and Hi-C data revealed a TAD boundary loss, which occurred concomitantly with the over-expression of a cluster of CEACAM genes on chromosome 19. We identified EMT and E2F as the 2 most deregulated pathways upon TCF4 depletion and LUM, TMPO, and AURKA as highly influential genes in these networks using measures of centrality. Results from gene expression, chromatin structure, and centrality analyses were integrated to generate a list of candidate transcription factors crucial for colon cancer cell homeostasis. The top ranked factor was c-JUN, an oncoprotein known to interact with TCF4 and β-catenin, confirming the usefulness of this approach.

Brown|Markus A|MA|
Dotson|Gabrielle A|GA|
Ronquist|Scott|S|
Emons|Georg|G|
Rajapakse|Indika|I|
Ried|Thomas|T|

D058118:Transcription Factor 7-Like 2 Protein


Ypt/Rab GTPases: principles learned from yeast.

Abstract: Ypt/Rab GTPases are key regulators of all membrane trafficking events in eukaryotic cells. They act as molecular switches that attach to membranes via lipid tails to recruit their multiple downstream effectors, which mediate vesicular transport. Originally discovered in yeast as Ypts, they were later shown to be conserved from yeast to humans, where Rabs are relevant to a wide array of diseases. Major principles learned from our past studies in yeast are currently accepted in the Ypt/Rab field including: (i) Ypt/Rabs are not transport-step specific, but are rather compartment specific, (ii) stimulation by nucleotide exchangers, GEFs, is critical to their function, whereas GTP hydrolysis plays a role in their cycling between membranes and the cytoplasm for multiple rounds of action, (iii) they mediate diverse functions ranging from vesicle formation to vesicle fusion and (iv) they act in GTPase cascades to regulate intracellular trafficking pathways. Our recent studies on Ypt1 and Ypt31/Ypt32 and their modular GEF complex TRAPP raise three exciting novel paradigms for Ypt/Rab function: (a) coordination of vesicular transport substeps, (b) integration of individual transport steps into pathways and (c) coordination of different transport pathways. In addition to its amenability to genetic analysis, yeast provides a superior model system for future studies on the role of Ypt/Rabs in traffic coordination due to the smaller proteome that results in a simpler traffic grid. We propose that different types of coordination are important also in human cells for fine-tuning of intracellular trafficking, and that coordination defects could result in disease.

Lipatova|Zhanna|Z|
Hain|Adelaide U|AU|
Nazarko|Volodymyr Y|VY|
Segev|Nava|N|

D001692:Biological Transport
D005057:Eukaryotic Cells
D005656:Fungal Proteins
D006801:Humans
D021381:Protein Transport
D022161:Transport Vesicles
D033921:Vesicular Transport Proteins
D015003:Yeasts
D020691:rab GTP-Binding Proteins


An economic analysis of trial of labor after cesarean delivery.

Abstract:
OBJECTIVE
Given that cesarean delivery is one of the most commonly performed surgical procedures in the United States and an important contributor to obstetric care costs, this analysis sought to examine maternal hospital costs associated with trial of labor after cesarean delivery (TOLAC) versus repeat cesarean delivery (RCD).

METHODS
A national sample was used to identify women with singleton pregnancy who underwent either TOLAC or RCD from 2006 to 2012. Women with diagnoses that could confound cost via extended hospital length of stay prior to delivery were excluded. Other medical and obstetric covariates that could influence cost were included in an adjusted model.

RESULTS
A total of 485,247 women were identified, including 365,596 (75.3%) cesarean deliveries without labor, 41,988 (8.6%) successful and 77,663 (16.0%) unsuccessful TOLAC deliveries. The inflation-adjusted median costs in this cohort were $5512 for cesarean without labor, $4175 for successful TOLAC, $5166 for all TOLAC attempts, and $5759 for failed TOLAC. In a multivariable model, hospital region was a major predictor of median cost as were demographic variables and medical comorbidities.

CONCLUSION
TOLAC is associated with modest reductions of cost for maternal hospitalizations. However, other medical, demographic and hospital factors appear to be more important factors.

Friedman|Alexander M|AM|
Ananth|Cande V|CV|
Chen|Ling|L|
D'Alton|Mary E|ME|
Wright|Jason D|JD|

D000293:Adolescent
D000328:Adult
D017604:Cesarean Section, Repeat
D003362:Cost-Benefit Analysis
D005260:Female
D006801:Humans
D007231:Infant, Newborn
D007902:Length of Stay
D008875:Middle Aged
D007744:Obstetric Labor Complications
D011247:Pregnancy
D012307:Risk Factors
D014219:Trial of Labor
D014481:United States
D014597:Uterine Rupture
D016064:Vaginal Birth after Cesarean
D055815:Young Adult


Outcomes for split-thickness skin transplantation in high-risk patients using octenidine.

Abstract: Skin transplantation is a commonly used surgical technique; however, the complication rate, including postoperative infection and delayed wound healing due to inefficient perfusion, is significantly higher in patients suffering from comorbidities. Hence, a subsequent repeat procedure is often necessary. In this report, two case studies are presented in which an octenidine-based antiseptic is used with a tie-over dressing (TOD) instead of povidone iodine (PVP-iodine), following a split-thickness skin graft. The two patients selected were deemed to be at high risk of impaired wound healing due to comorbidities. The first patient, a confirmed smoker with diabetes, presented with a nodular melanoma that was resected and covered with a split-thickness skin graft. After 5 days of negative pressure wound therapy as a TOD, in combination with PVP-iodine, the graft became necrotic. A second split-thickness skin graft was performed and an antiseptic regimen with octenidine in combination with the same TOD resulted in a completely healed transplant. The second patient, also a confirmed smoker with diabetes and receiving oral corticosteroid treatment, was diagnosed with a skin necrosis on her leg. Following the split-thickness skin graft, octenidine and TOD were applied. The patient's skin graft completely healed without any adverse events. These two case studies indicate that the combination of octenidine and TOD following split-thickness skin transplantation is safe, well-tolerated and appears to have positive benefits in the reconstruction of defects in patients with impaired wound healing.

Matiasek|J|J|
Djedovic|G|G|
Unger|L|L|
Beck|H|H|
Mattesich|M|M|
Pierer|G|G|
Koller|R|R|
Rieger|U M|UM|

octenidine
tie-over dressing
split-thickness skin graft
antiseptic wound management
cortisone therapy
diabetes mellitus


Is preoperative anemia a risk factor for upper tract urothelial carcinoma following radical nephroureterectomy?

Abstract:
PURPOSE
We aimed to identify the effect of preoperative anemia on oncologic outcomes in patients with upper tract urothelial carcinoma (UTUC) who had different levels of renal function.

METHODS
Between 2000 and 2013, we enrolled 370 patients who underwent radical nephroureterectomy for nonmetastatic UTUC. Preoperative anemia was defined as hemoglobin <130g/l in men and <120g/l in women based on the World Health Organization classification. Kaplan-Meier method was applied to estimate the effect anemia on survival, and hazard ratios (HR) of anemia and other clinicopathological parameters were evaluated by Cox regression model. The analyses were also performed in patients with different chronic kidney disease (CKD) stages.

RESULTS
In all, 242 (65.4%) patients were anemic before surgery. Those with preoperative anemia had worse CKD stage (P<0.001) and higher pathological tumor stage (P = 0.023). In univariate analysis, metastasis-free and cancer-specific survival rates were not significantly associated with preoperative anemia (HR = 1.51, 95% CI: 0.93-2.44, P = 0.093 and HR = 1.59, 95% CI: 0.93-2.72, PP = 0.094, respectively). However, in patients without stage 5 CKD, those with preoperative anemia had apparently inferior metastasis-free and cancer-specific survival than those without (HR = 1.88, 95% CI: 1.14-3.01, P = 0.014 and HR = 2.03, 95% CI: 1.16-3.56, P = 0.010, respectively). A multivariate Cox proportional hazards model indicated that preoperative anemia was an independent predictor for both metastasis-free (HR = 2.17, 95% CI: 1.21-3.90, P = 0.010) and cancer-specific survival (HR = 2.21, 95% CI: 1.15-4.21, P = 0.017).

CONCLUSIONS
Among patients without stage 5 CKD, preoperative anemia was a significant prognostic factor to predict metastatic progression and cancer-specific death in UTUC following radical nephroureterectomy. It was important to be aware of patients׳ renal function while evaluating the effect of anemia on outcome of UTUC.

Yeh|Hsin-Chih|HC| Chien|Tsu-Ming|TM| Wu|Wen-Jeng|WJ| Li|Ching-Chia|CC| Li|Wei-Ming|WM| Ke|Hung-Lung|HL| Chou|Yii-Her|YH| Wang|Chii-Jye|CJ| Huang|Shu-Pin|SP| Li|Chien-Feng|CF| Liang|Peir-In|PI| Huang|Chun-Nung|CN|

Anemia
Upper tract urothelial carcinoma
Metastasis
Prognosis


Effect of local estrogen therapy (LET) on urinary and sexual symptoms in premenopausal women with interstitial cystitis/bladder pain syndrome (IC/BPS).

Abstract: The association between vulvodynia and interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic, debilitating disease of unknown etiology, may involve sex hormone-dependent mechanisms regulating vulvo-vaginal health. We aimed to prospectively investigate the effects of 12 weeks of local estrogen therapy (LET) on urinary/bladder and sexual symptoms in premenopausal women with IC/BPS. Thirty-four women (mean age: 36.1 ± 8.4) diagnosed with IC/BPS were treated vulvo-vaginally three-times/week with estriol 0.5 mg cream and tested by validated questionnaires (ICSI/ICPI, pain urgency frequency [PUF], female sexual function index [FSFI]) and by cotton swab testing, vaginal health index (VHI) and maturation index (MI) before and after treatment. Vulvodynia was present in 94.1% of IC/BPS women. A significant positive effect of LET was evident on urinary and sexual function (p < 0.001, for both) following 12 weeks, as well as an improvement of the VHI (p < 0.001) and the MI (p < 0.04). The results of this open study indicate that 12 weeks of local estriol cream at vaginal and vestibular level may ameliorate urinary/bladder pain symptoms, as well as may improve domains of sexual function. The association between vulvar pain and bladder pain could, therefore, be related to a vaginal environment carrying signs of hypoestrogenism, but further studies are needed to clarify this issue.

Gardella|Barbara|B|
Iacobone|Anna Daniela|AD|
Porru|Daniele|D|
Musacchi|Valentina|V|
Dominoni|Mattia|M|
Tinelli|Carmine|C|
Spinillo|Arsenio|A|
Nappi|Rossella E|RE|

Estrogens
sexual function
genitourinary syndrome
uro-genital system
vagina


Urinary markers aiding in the detection and risk stratification of prostate cancer.

Abstract: The purpose of this review is to highlight the role of existing and promising urinary biomarkers for the detection and prognostication of prostate cancer (PCa). A number of novel urinary biomarkers have been introduced into the clinical space, which in combination with clinical variables, have demonstrated an increased ability to select patients for biopsy and identify men at risk of harboring clinically significant PCa. Though a number of assays require further validation, initial data is promising and forthcoming results will ultimately determine their clinical utility and commercial availability. For the past 30 years, first-line screening for PCa has relied on measurement of serum prostate-specific antigen (PSA) levels and the results from a digital rectal exam (DRE). A large body of evidence from the last 3 decades indicates that these screening methods are problematic, and often inadequate for detecting clinically significant PCa. Extensive efforts have recently been made to identify and commercialize novel PCa biomarkers for more effective detection of PCa, either alone or in combination with current screening methods. This review article highlights problems with current screening standards, and discusses 6 urinary biomarker assays in terms of their ability to detect and risk-stratify PCa: prostate cancer antigen 3 (PCA3), TMPRSS2-ERG, second chromosome locus associated with prostate-1 (SChLAP1), ExoDx, SelectMDx, and Michigan Prostate Score (MiPS).

Raja|Nicholas|N|
Russell|Christopher M|CM|
George|Arvin K|AK|


Chronic capsiate supplementation increases fat-free mass and upper body strength but not the inflammatory response to resistance exercise in young untrained men: a randomized, placebo-controlled and double-blind study.

Abstract:
BACKGROUND
Acute capsaicinoid and capsinoid supplementation has endurance and resistance exercise benefits; however, if these short-term performance benefits translate into chronic benefits when combined with resistance training is currently unknown. This study investigated changes of chronic Capsiate supplementation on muscular adaptations, inflammatory response and performance in untrained men.

METHODS
Twenty untrained men were randomized to ingest 12 mg Capsiate (CAP) or placebo in a parallel, double-blind design. Body composition and performance were measured at pre-training and after 6 weeks of resistance training. An acute resistance exercise session test was performed pre and post-intervention. Blood samples were collected at rest and post-resistance exercise to analyze Tumor necrosis factor- (TNF-), Soluble TNF- receptor (sTNF-r), Interleukin-6 (IL-6) and Interleukin-10 (IL-10).

RESULTS
Exercise and CAP supplementation increased fat-free mass in comparison to baseline by 1.5 kg (P < 0.001), however, the majority of the increase (1.0 kg) resulted from an increase in total body water. The CAP change scores for fat-free mass were significantly greater in comparison to the placebo (CAP ∆%= 2.1 ± 1.8 %, PLA ∆%= 0.7 ± 1.3 %, P = 0.043) and there was a significant difference between groups in the bench press exercise (P = 0.034) with greater upper body strength change score for CAP (∆%= 13.4 ± 9.1 %) compared to placebo (∆%= 5.8 ± 5.2 %), P = 0.041. CAP had no effect on lower body strength and no supplementation interactions were observed for all cytokines in response to acute resistance exercise (P > 0.05).

CONCLUSION
Chronic Capsiate supplementation combined with resistance training during short period (6 weeks) increased fat-free mass and upper body strength but not inflammatory response and performance in young untrained men.

de Moura E Silva|Vilton Emanoel Lopes|VEL|

D018124:Receptors, Tumor Necrosis Factor

Performance
Hypertrophy
Pre-workout
Strength training


Tolerogenic microenvironment in neonatal period induced by maternal immunization with ovalbumin.

Abstract: Maternal immunization with allergens, such as ovalbumin (OVA), can inhibit the development of an allergic response in offspring. The regulatory mechanisms seem to be mediated by maternal antibodies (MatAbs) and factors generated by the maternal-fetal interface. The aim of this study was to verify the pathways of inhibitory Ab transference after maternal immunization with OVA and the effect of the offspring's dendritic cells (DCs) on the generation of regulatory T (Treg) cells. We verified that preconceptional OVA immunization induces high levels of proinflammatory and regulatory cytokines in the amniotic fluid, allowing the transference of high levels of anti-OVA IgG1 Abs to the offspring. Using an adoptive nursing protocol, we verified that maternal immunization leads to MatAb transference by the placental route and by breastfeeding contribute to the inhibition of anaphylactic IgE and IgG1 Ab responses in immunized offspring. We observed that maternal immunization decreased eosinophil numbers in recovered bronchoalveolar lavage fluid and in the lung tissue, whereas with a lack of control of airway responsiveness to methacholine. Maternal immunization induced in young offspring a decreased percentage of CD11c+ DCs expressing MHC class II and CD40 molecules. Moreover, DCs from both groups of offspring when pulsed with OVA, were able to induce Treg cells in vitro. Similarly, OVA immunization at the neonatal stage increased the frequency of Treg cells, regardless of the mother's immunization status. These findings emphasize that maternal immunization leads to a complex interaction of regulatory factors, with MatAbs, DCs and Treg cells affecting the tolerance of offspring during an allergic response.

Muniz|Bruno Pacola|BP|
Victor|Jefferson Russo|JR|
de Mendonça Oliveira|Luana|L|
de Lima Lira|Aline Aparecida|AA|
Perini|Adenir|A|
Olivo|Clarice Rosa|CR|
Arantes-Costa|Fernanda Magalhães|FM|
Martins|Milton Arruda|MA|
da Silva Duarte|Alberto José|AJ|
Sato|Maria Notomi|MN|

Neonatal
Maternal antibodies
Dendritic cells
Allergy
Regulatory T cells


Effects of Composting Different Types of Organic Fertilizer on the Microbial Community Structure and Antibiotic Resistance Genes.

Abstract: Organic fertilizer is a major carrier that stores and transmits antibiotic resistance genes (ARGs). In the environment, due to the application of organic fertilizers in agriculture, the increasing diversity and abundance of ARGs poses a potential threat to human health and environmental safety. In this paper, the microbial community structure and ARGs in different types of organic fertilizer treated with composting were examined. We found that the abundance and diversity of ARGs in earthworm cast organic fertilizer were the lowest and the highest in chicken manure organic fertilizer. Interestingly, the abundance and diversity of ARGs, especially beta-lactam resistance genes, sulfonamide resistance genes, and macrolide-lincosamide-streptogramin B (MLSB) resistance genes, in organic fertilizers were reduced significantly, while composting caused no significant change in mobile genetic elements (MGEs), where antibiotic deactivation and the use of efflux pumps were the two most dominant mechanisms. It was clear that removal of ARGs became more efficient with increasing reduction in the bacterial abundances and diversity of potential ARG hosts, and integron-mediated horizontal gene transfers (HGTs) played an important role in the proliferation of most ARG types. Therefore, the reduction in ARGs was mainly driven by changes in bacterial community composition caused by composting. Furthermore, rather than HGTs, the diversity and abundance of bacterial communities affected by compost physical and chemical properties were the main drivers shaping and altering the abundance and diversity of ARGs, which was indicated by a correlation analysis of these properties, antibiotic residues, microbial community structure, and ARGs. In general, high-temperature composting effectively removed antibiotic residues and ARGs from these organic fertilizers; however, it cannot prevent the proliferation of MGEs. The insights gained from these results may be of assistance in the safe and rational use of organic fertilizers by indicating the changes in microbial community structure and ARGs in different types of organic fertilizer treated with composting.

composting
organic fertilizer
microbial community structure
antibiotics
ARGs
MGEs


Validation of image analysis techniques to measure skin aging features from facial photographs.

Abstract:
BACKGROUND
Accurate measurement of the extent skin has aged is crucial for skin aging research. Image analysis offers a quick and consistent approach for quantifying skin aging features from photographs, but is prone to technical bias and requires proper validation.

METHODS
Facial photographs of 75 male and 75 female North-European participants, randomly selected from the Rotterdam Study, were graded by two physicians using photonumeric scales for wrinkles (full face, forehead, crow's feet, nasolabial fold and upper lip), pigmented spots and telangiectasia. Image analysis measurements of the same features were optimized using photonumeric grades from 50 participants, then compared to photonumeric grading in the 100 remaining participants stratified by sex.

RESULTS
The inter-rater reliability of the photonumeric grades was good to excellent (intraclass correlation coefficients 0.65-0.93). Correlations between the digital measures and the photonumeric grading were moderate to excellent for all the wrinkle comparisons (Spearman's rho ρ = 0.52-0.89) bar the upper lip wrinkles in the men (fair, ρ = 0.30). Correlations were moderate to good for pigmented spots and telangiectasia (ρ = 0.60-0.75).

CONCLUSION
These comparisons demonstrate that all the image analysis measures, bar the upper lip measure in the men, are suitable for use in skin aging research and highlight areas of improvement for future refinements of the techniques.

Hamer|M A|MA|
Jacobs|L C|LC|
Lall|J S|JS|
Wollstein|A|A|
Hollestein|L M|LM|
Rae|A R|AR|
Gossage|K W|KW|
Hofman|A|A|
Liu|F|F|
Kayser|M|M|
Nijsten|T|T|
Gunn|D A|DA|

Skin aging
Photonumeric
Wrinkles
Pigmented spots
Telangiectasia
Digital
Grading scale


In-vitro and in-vivo measurement of the animal's middle ear acoustical response by partially implantable fiber-optic sensing system.

Abstract: The main obstacle in realization of a totally implantable hearing aid is a lack of reliable implantable microphone. In this paper we have described a potentially miniature fiber-optic vibrometer based on a modified Michelson interferometer, designed to serve as a middle-ear microphone for totally implantable cochlear- or middle-ear hearing aids. A model of the sensing system was used for in-vitro and in-vivo investigation of acoustical response of sheep's middle-ear ossicles. Surgical and implantation procedure of introducing the sensing optical fiber into the middle-ear and its aiming at the incus was investigated and described here in detail. The frequency responses of the incus was measured while a cadaver and living sheep was exposed to the sinusoidal acoustical excitation of 40-90dB SPL, in the frequency range from 100Hz to 10kHz. The amplitude of the incus vibration was found to be in the range between 10pm to 100nm, strongly depending on the frequency, with a lot of resonant peaks, corresponding mainly to the natural outer ear canal gain. The noise floor in the experiments was about 2pm/Hz1/2, but recently we have decreased it to < 0.5pm/Hz1/2, which corresponds to a minimal detectable sound level of 31-35dB(A) SPL for humans. The histological examination of temporal bones of cadaver animals and the intensity of in-vivo optical signal demonstrated that the aiming of the sensing fiber to the target has been preserved for five months after the implantation.

Djinović|Zoran|Z| Pavelka|Robert|R| Tomić|Miloš|M| Sprinzl|Georg|G| Plenk|Hanns|H| Losert|Udo|U| Bergmeister|Helga|H| Plasenzotti|Roberto|R|

Implantable microphone
Fiber-optic sensors
Interferometry
Phase modulation


Sigma 54-Regulated Transcription Is Associated with Membrane Reorganization and Type III Secretion Effectors during Conversion to Infectious Forms of Chlamydia trachomatis.

Abstract: Chlamydia bacteria are obligate intracellular organisms with a phylum-defining biphasic developmental cycle that is intrinsically linked to its ability to cause disease. The progression of the chlamydial developmental cycle is regulated by the temporal expression of genes predominantly controlled by RNA polymerase sigma (σ) factors. Sigma 54 (σ54) is one of three sigma factors encoded by Chlamydia for which the role and regulon are unknown. CtcC is part of a two-component signal transduction system that is requisite for σ54 transcriptional activation. CtcC activation of σ54 requires phosphorylation, which relieves inhibition by the CtcC regulatory domain and enables ATP hydrolysis by the ATPase domain. Prior studies with CtcC homologs in other organisms have shown that expression of the ATPase domain alone can activate σ54 transcription. Biochemical analysis of CtcC ATPase domain supported the idea of ATP hydrolysis occurring in the absence of the regulatory domain, as well as the presence of an active-site residue essential for ATPase activity (E242). Using recently developed genetic approaches in Chlamydia to induce expression of the CtcC ATPase domain, a transcriptional profile was determined that is expected to reflect the σ54 regulon. Computational evaluation revealed that the majority of the differentially expressed genes were preceded by highly conserved σ54 promoter elements. Reporter gene analyses using these putative σ54 promoters reinforced the accuracy of the model of the proposed regulon. Investigation of the gene products included in this regulon supports the idea that σ54 controls expression of genes that are critical for conversion of Chlamydia from replicative reticulate bodies into infectious elementary bodies.IMPORTANCE The factors that control the growth and infectious processes for Chlamydia are still poorly understood. This study used recently developed genetic tools to determine the regulon for one of the key transcription factors encoded by Chlamydia, sigma 54. Surrogate and computational analyses provide additional support for the hypothesis that sigma 54 plays a key role in controlling the expression of many components critical to converting and enabling the infectious capability of Chlamydia These components include those that remodel the membrane for the extracellular environment and incorporation of an arsenal of type III secretion effectors in preparation for infecting new cells.

Soules|Katelyn R|KR|
LaBrie|Scott D|SD|
May|Benjamin H|BH|
Hefty|P Scott|PS|0000-0002-2303-2465

D015964:Gene Expression Regulation, Bacterial

Chlamydia trachomatis
sigma factors
regulon
gene regulation


Feedback activation of NF-KB signaling leads to adaptive resistance to EZH2 inhibitors in prostate cancer cells.

Abstract:
BACKGROUND
Prostate cancer (PCa) is the most common malignant tumor in developed countries, which has seriously threatened men's lifestyle and quality of life. The up-regulation of EZH2 is associated with advanced PCa and poor prognosis, making it a promising therapeutic target. However, the EZH2 inhibitors-based treatment is basically ineffective against PCa, which limits its clinical application.

METHODS
Microarray data (GSE107779) from LNCaP cells treated with either siRNA against EZH2 or a EZH2 inhibitor EPZ6438 was analyzed by Limma R package. Western blot, real-time PCR and luciferase reporter assays were used to determine the EZH2-SOX9-TNFRSF11A axis and the activity of NF-κB signaling in PCa cells. CCK-8 assay was used to determine the viability of PCa cells following various treatments.

RESULTS
Genetic ablation or pharmacological inhibition of EZH2 leads to feedback activation of NF-κB signaling in PCa cells. EZH2-dependent SOX9 expression regulates the activation of NF-κB signaling. TNFRSF11A, also known as receptor activator of NF-κB (RANK), is a downstream target of SOX9 in PCa cells. SOX9 recognizes two putative SOX9 response elements in the promoter region of TNFRSF11A gene to drive TNFRSF11A expression and downstream NF-κB signaling activation. Suppression of the NF-κB signaling by either TNFRSF11A silencing or BAY11-7082 treatment rendered PCa cells to EZH2 inhibitors.

CONCLUSION
Collectively, our finding reveals a EZH2-SOX9-TNFRSF11A axis in the regulation of activity of NF-κB signaling in PCa cells and suggests that a combination of EZH2 inhibitors and BAY11-7082 would be an effective approach for the treatment of PCa patients in the future.