Inflammatory factor receptor Toll-like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell.

Abstract: Toll-like receptor 4 (TLR4) which acts as a receptor for lipopolysaccharide (LPS) has been reported to be involved in carcinogenesis. However, the regulatory mechanism of it has not been elucidated. Herein, we demonstrate that TLR4 promotes the malignant growth of liver cancer stem cells. Mechanistically, TLR4 promotes the expression of histone-lysine N-methyltransferase (SUV39 h2) and increases the formation of trimethyl histone H3 lysine 9-heterochromatin protein 1-telomere repeat binding factor 2 (H3K9me3-HP1-TRF2) complex at the telomeric locus under mediation by long non coding RNA urothelial cancer-associated 1 (CUDR). At the telomeric locus, this complex promotes binding of POT1, pPOT1, Exo1, pExo1, SNM1B and pSNM1B but prevents binding of CST/AAF to telomere, thus controlling telomere and maintaining telomere length. Furthermore, TLR4 enhances interaction between HP1α and DNA methyltransferase (DNMT3b), which limits RNA polymerase II deposition on the telomeric repeat-containing RNA (TERRA) promoter region and its elongation, thus inhibiting transcription of TERRA. Ultimately, TLR4 enhances the telomerase activity by reducing the interplay between telomerase reverse transcriptase catalytic subunit (TERT) and TERRA. More importantly, our results reveal that tri-complexes of HP1 isoforms (α, β and γ) are required for the oncogenic action of TLR4. This study elucidates a novel protection mechanism of TLR4 in liver cancer stem cells and suggests that TLR4 can be used as a novel therapeutic target for liver cancer.

Zheng|Qidi|Q| Xu|Jie|J| Lin|Zhuojia|Z| Lu|Yanan|Y| Xin|Xiaoru|X| Li|Xiaonan|X| Yang|Yuxin|Y| Meng|Qiuyu|Q| Wang|Chen|C| Xiong|Wujun|W| Lu|Dongdong|D|0000-0002-7417-4172

D035341:Telomeric Repeat Binding Protein 2

Toll-like receptor 4
telomeres
heterochromatin protein 1
cancer stem cells


Magnetically Actuated Soft Capsule With the Multimodal Drug Release Function.

Abstract: In this paper, we present a magnetically actuated multimodal drug release mechanism using a tetherless soft capsule endoscope for the treatment of gastric disease. Because the designed capsule has a drug chamber between both magnetic heads, if it is compressed by the external magnetic field, the capsule could release a drug in a specific position locally. The capsule is designed to release a drug in two modes according to the situation. In the first mode, a small amount of drug is continuously released by a series of pulse type magnetic field (0.01-0.03 T). The experimental results show that the drug release can be controlled by the frequency of the external magnetic pulse. In the second mode, about 800 mm3 of drug is released by the external magnetic field of 0.07 T, which induces a stronger magnetic attraction than the critical force for capsule's collapsing. As a result, a polymeric coating is formed around the capsule. The coated area is dependent on the drug viscosity. This paper presents simulations and various experiments to evaluate the magnetically actuated multimodal drug release capability. The proposed soft capsules could be used as minimally invasive tetherless medical devices with therapeutic capability for the next generation capsule endoscopy.

Capsule endoscope
drug delivery
magnetic micro-robot
medical robotics


Changes in MicroRNA Expression during Rabbit Hemorrhagic Disease Virus (RHDV) Infection.

Abstract: Current knowledge on the role of microRNAs (miRNAs) in rabbit hemorrhagic disease virus (RHDV) infection and the pathogenesis of rabbit hemorrhagic disease (RHD) is still limited. RHDV replicates in the liver, causing hepatic necrosis and liver failure. MiRNAs are a class of short RNA molecules, and their expression profiles vary over the course of diseases, both in the tissue environment and in the bloodstream. This paper evaluates the expression of miRNAs in the liver tissue (ocu-miR-122-5p, ocu-miR-155-5p, and ocu-miR-16b-5p) and serum (ocu-miR-122-5p) of rabbits experimentally infected with RHDV. The expression levels of ocu-miR-122-5p, ocu-miR-155-5p, and ocu-miR-16b-5p in liver tissue were determined using reverse transcription quantitative real-time PCR (RT-qPCR), and the expression level of circulating ocu-miR-122-5p was established using droplet digital PCR (ddPCR). The expression levels of ocu-miR-155-5p and ocu-miR-16b-5p were significantly higher in the infected rabbits compared to the healthy rabbits (a fold-change of 5.8 and 2.5, respectively). The expression of ocu-miR-122-5p was not significantly different in the liver tissue from the infected rabbits compared to the healthy rabbits (p = 0.990), while the absolute expression level of the circulating ocu-miR-122-5p was significantly higher in the infected rabbits than in the healthy rabbits (p < 0.0001). Furthermore, a functional analysis showed that ocu-miR-155-5p, ocu-miR-16b-5p, and ocu-miR-122-5p can regulate the expression of genes involved in processes correlated with acute liver failure (ALF) in rabbits. Search tool for the retrieval of interacting genes/proteins (STRING) analysis showed that the potential target genes of the three selected miRNAs may interact with each other in different pathways. The results indicate the roles of these miRNAs in RHDV infection and over the course of RHD and may reflect hepatic inflammation and impairment/dysfunction in RHD.

Hukowska-Szematowicz|Beata|B| Maciejak-Jastrzębska|Agata|A| Blatkiewicz|Małgorzata|M| Maciak|Karolina|K| Góra|Monika|M|0000-0002-8554-663X Janiszewska|Joanna|J| Burzyńska|Beata|B|

D017929:Hemorrhagic Disease Virus, Rabbit

microRNA
rabbit hemorrhagic disease virus (RHDV)
liver, STRING analysis


Obesity as an immune-modifying factor in cancer immunotherapy.

Abstract: Immunotherapy has achieved breakthrough status in many advanced stage malignancies and is rapidly becoming the fourth arm of cancer treatment. Although cancer immunotherapy has generated significant excitement because of the potential for complete and sometimes durable responses, there is also the potential for severe and occasionally life-threatening toxicities, including cytokine release syndrome and severe autoimmunity. A large body of work also points to a "metainflammatory" state in obesity associated with impairment of immune responses. Because immune checkpoint blockade (and other cancer immunotherapies) have altered the landscape of immunotherapy in cancer, it is important to understand how immune responses are shaped by obesity and how obesity may modify both immunotherapy responses and potential toxicities.

Canter|Robert J|RJ|
Le|Catherine T|CT|
Beerthuijzen|Johanna M T|JMT|
Murphy|William J|WJ|

obesity
cancer
immunotherapy
toxicity
cytokines
MDSCs
T cells
T-regs
macrophages


Age-dependent accumulation of dicarbonyls and advanced glycation endproducts (AGEs) associates with mitochondrial stress.

Abstract: Aging is a strong risk factor for brain dementia and cognitive decline. Age-related accumulation of metabolites such as advanced glycation end products (AGEs) could serve as danger signals to initiate and accelerate disease process and neurodegeneration. The underlying causes and consequences of cerebral AGEs accumulation remain largely unknown. Here, we comprehensively investigate age-related accumulation of AGEs and dicarbonyls, including methylglyoxal (MG), glyoxal (GO), and 3-deoxyglucosone (3-DG), and the effects of mitochondrial reactive oxygen species (ROS) on cerebral AGEs accumulation, mitochondrial function, and oxidative stress in the aging human and mouse brain. We demonstrate that AGEs, including arginine and lysine derived N(6)-carboxymethyl lysine (CML), Nε-(1-Carboxyethyl)-l-lysine (CEL), and methylglyoxal-derived hydroimidazolone-1 (MG-H1), were significantly elevated in the cerebral cortex and hippocampus with advanced age in mice. Accordingly, aging mouse and human brains revealed decrease in activities of mitochondrial respiratory chain complexes I & IV and ATP levels, and increased ROS. Notably, administration of mitoTEMPO (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mTEMPO), a scavenger of mitochondrial ROS, not only suppressed ROS production but also reduced aged-induced accumulation of AGEs and dicarbonyls. mTEMPO treatment improved mitochondrial respiratory function and restored ATP levels. Our ﬁndings provide evidence linking age-related accumulation of toxic metabolites (AGEs) to mitochondrial oxidative stress. This highlights a novel mechanism by which AGEs-dependent signaling promotes carbonyl stress and sustained mitochondrial dysfunction. Eliminating formation and accumulation of AGEs may represent a new therapeutic avenue for combating cognitive decline and mitochondrial degeneration relevant to aging and neurodegenerative diseases including Alzheimer's disease.

Akhter|Firoz|F|
Chen|Doris|D|
Akhter|Asma|A|
Yan|Shi Fang|SF|
Yan|Shirley ShiDu|SS|

D017127:Glycation End Products, Advanced

Dicarbonyls
Aging
Advanced glycation end products (AGEs)
Reactive oxygen species (ROS)
Mitochondrial dysfunction


Spinal and bulbar muscular atrophy.

Abstract: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset degenerative disorder of the neuromuscular system resulting in slowly progressive weakness and atrophy of the proximal limb and bulbar muscles. The disease is caused by the expansion of a CAG/glutamine tract in the amino-terminus of the androgen receptor. That SBMA exclusively affects males reflects the fact that critical pathogenic events are hormone-dependent. These include translocation of the polyglutamine androgen receptor from the cytoplasm to the nucleus and unfolding of the mutant protein. Studies of the pathology of SBMA subjects have revealed nuclear aggregates of the mutant androgen receptor, loss of lower motor neurons in the brainstem and spinal cord, and both neurogenic and myopathic changes in skeletal muscle. Mechanisms underlying disease pathogenesis include toxicity in both lower motor neurons and skeletal muscle, where effects on transcription, intracellular transport, and mitochondrial function have been documented. Therapies to treat SBMA patients remain largely supportive, although experimental approaches targeting androgen action or promoting degradation of the mutant androgen receptor protein or the encoding RNA are under active study.

D000818:Animals
D001933:Brain Stem
D004195:Disease Models, Animal
D006801:Humans
D009046:Motor Neurons
D009134:Muscular Atrophy, Spinal
D010455:Peptides
D011944:Receptors, Androgen
D013116:Spinal Cord

spinal and bulbar muscular atrophy
androgen receptor
CAG/polyglutamine expansion
neuromuscular disease
testosterone


Using empirically constructed lexical resources for named entity recognition.

Abstract: Because of privacy concerns and the expense involved in creating an annotated corpus, the existing small-annotated corpora might not have sufficient examples for learning to statistically extract all the named-entities precisely. In this work, we evaluate what value may lie in automatically generated features based on distributional semantics when using machine-learning named entity recognition (NER). The features we generated and experimented with include n-nearest words, support vector machine (SVM)-regions, and term clustering, all of which are considered distributional semantic features. The addition of the n-nearest words feature resulted in a greater increase in F-score than by using a manually constructed lexicon to a baseline system. Although the need for relatively small-annotated corpora for retraining is not obviated, lexicons empirically derived from unannotated text can not only supplement manually created lexicons, but also replace them. This phenomenon is observed in extracting concepts from both biomedical literature and clinical notes.

Jonnalagadda|Siddhartha|S| Cohen|Trevor|T| Wu|Stephen|S| Liu|Hongfang|H| Gonzalez|Graciela|G|

named entity recognition
distributional semantics
concept extraction
empirical lexical resources
natural language processing


Validation of the Hospital Anxiety and Depression Scale in Patients With Acute Low Back Pain.

Abstract:
UNLABELLED
The Hospital Anxiety and Depression Scale (HADS) is a self-report instrument used to evaluate depression and anxiety in clinical research. The HADS has advantages over other assessments of anxiety and depression; it is efficient in assessing both anxiety and depression with a total of 14 items, and it was originally developed on a general medical rather than psychiatric sample. However, the HADS has not been evaluated specifically for use in clinical trials of acute pain. Validation analyses were conducted on data from a randomized, double-blind, parallel-group study of tapentadol immediate release vs oxycodone immediate release for acute low back pain (N = 666). Analyses of psychometric properties, internal consistency, convergent validity, assessments of bias, and confirmatory factor analysis were conducted on pretreatment data. Additional analyses were performed to test the responsiveness and predictive validity of the HADS. Both the Anxiety and Depression subscales (1) showed good psychometric properties, (2) had high internal consistency, (3) displayed good convergent validity, (4) had no unexpected biases, (5) fit the a priori factor structure, and (6) were highly sensitive to changes as a result of analgesic treatment. We conclude that the HADS is a valid instrument for efficient, low-burden assessment of anxiety and depression in clinical trials with an acute low back pain population.

PERSPECTIVE
Considered together with the results of other recent studies, the data suggest that the HADS can provide a valid, responsive, and efficient assessment of anxiety and depression in acute low back pain for clinical trials and other clinical research examining acute pain populations.

Turk|Dennis C|DC|
Dworkin|Robert H|RH|
Trudeau|Jeremiah J|JJ|
Benson|Carmela|C|
Biondi|David M|DM|
Katz|Nathaniel P|NP|
Kim|Myoung|M|

D011569:Psychiatric Status Rating Scales

D016032:Randomized Controlled Trials as Topic

Hospital Anxiety and Depression Scale
Anxiety
depression
low back pain
acute pain


Lupus Nephritis: A Different Disease in European Patients?

Abstract:
BACKGROUND
Lupus nephritis (LN) is still associated with significant mortality and substantial risk of progression to end-stage renal failure. Its outcome is related to the class and severity of LN and response to treatment, and it is poorer in patients with renal relapses. Ethnicity has a relatively well-defined impact on the outcome of the patients and their response to treatment and must always be taken into consideration in treatment decisions.

SUMMARY
In this article, we provide a review of the impact of ethnicity on the prevalence of systemic lupus erythematosus (SLE), the proportion of patients with SLE developing LN, outcomes of SLE and LN and response of LN to treatment. In European patients, the prevalence of SLE and the proportion of SLE patients with LN are lower and the outcome of LN is better than in nonwhite populations. European patients may respond better to some modes of treatment [e.g. cyclophosphamide (CYC) or rituximab] and may be less frequently refractory to treatment compared to black patients with LN. Although these differences may be largely genetically driven, socioeconomic factors (poverty, education, insurance, access to health care and adherence to treatment) may also play a significant role in some disadvantaged patients.

KEY MESSAGE
Treatment of LN may be different in patients with different ethnicity. Less aggressive disease in European patients may better respond to less aggressive treatment. Treatment of LN in nonwhite patients may require newer (more effective) therapeutic approaches, but targeting negative socioeconomic factors might be even more effective.

FACTS FROM EAST AND WEST
(1) The prevalence of SLE is lower among Caucasians than other ethnicities. A higher prevalence is observed among Asians and African Americans, while the highest prevalence is found in Caribbean people. The prevalence of LN in Asian SLE patients is much higher than in Caucasians as well. However, the 10-year renal outcome and renal survival rate appear to be better in Asians. (2) Polymorphisms of genes involved in the immune response, such as Fcγ receptor, integrin alpha M, TNF superfamily 4, myotubularin-related protein 3 and many others, might be partly responsible for the differences in prevalence between the different ethnic groups. European ancestry was shown to be associated with a decrease in the risk of LN even after adjustment for genes most associated with renal disease. (3) Access to health care is a key determinant of disease progression, treatment outcome and the management of complications such as infections, particularly in South Asia, and might also explain disparities between clinical outcomes. (4) The efficacy of low-dose CYC combined with corticosteroids for induction treatment of LN was proved in European Caucasian patients. This treatment is also used in Asia, although no formal evaluation of efficacy and safety in comparison with other treatment regimens exists in this population. The efficacy of mycophenolate mofetil (MMF) is similar to that of CYC, and similar between Asians and Caucasians. MMF may be more effective than CYC in inducing response in high-risk populations such as African American or Hispanic patients. MMF might cause less infection-related events in Asians, but its high cost prevents broader usage at present. (5) For maintenance therapy, corticosteroid combined with azathioprine (AZA) or MMF is used worldwide, with a broadly similar efficacy of both treatments, although there are data suggesting that in high-risk populations (e.g. African Americans) MMF may be more effective in preventing renal flares. AZA is often preferred in Asia due to economic constraints and because of its safety in pregnancy. (6) Alternative therapies under investigation include rituximab, which might be more efficient in Caucasians, as well as belimumab. Recent Japanese and Chinese studies have indicated a potential benefit of tacrolimus as a substitute for or in addition to CYC or MMF (dual or triple immunosuppression). Mizoribine is used in Japan exclusively.

Lupus nephritis
Outcome
Ethnicity
Prevalence
Cyclophosphamide
Mycophenolate mofetil


Modelling audiovisual integration of affect from videos and music.

Abstract: Two experiments examined how affective values from visual and auditory modalities are integrated. Experiment 1 paired music and videos drawn from three levels of valence while holding arousal constant. Experiment 2 included a parallel combination of three levels of arousal while holding valence constant. In each experiment, participants rated their affective states after unimodal and multimodal presentations. Experiment 1 revealed a congruency effect in which stimulus combinations of the same extreme valence resulted in more extreme state ratings than component stimuli presented in isolation. An interaction between music and video valence reflected the greater influence of negative affect. Video valence was found to have a significantly greater effect on combined ratings than music valence. The pattern of data was explained by a five parameter differential weight averaging model that attributed greater weight to the visual modality and increased weight with decreasing values of valence. Experiment 2 revealed a congruency effect only for high arousal combinations and no interaction effects. This pattern was explained by a three parameter constant weight averaging model with greater weight for the auditory modality and a very low arousal value for the initial state. These results demonstrate key differences in audiovisual integration between valence and arousal.

Gao|Chuanji|C|
Wedell|Douglas H|DH|
Kim|Jongwan|J|
Weber|Christine E|CE|
Shinkareva|Svetlana V|SV|

audiovisual integration
Affect
congruency
modality dominance
negativity dominance


Comparison between Colloid Preload and Coload in Bone Cement Implantation Syndrome under Spinal Anesthesia: A Randomized Controlled Trial.

Abstract:
Background
Bone cement implantation syndrome (BCIS) is characterized by hypoxia hypotension cardiac arrest. There is not any research that investigated the hemodynamic effects of colloid use during and before cement implantation regarding BCIS development.

Aims
We aimed to compare the effects of colloid preloading before or coloading simultaneously at cement implantation on BCIS development and hemodynamic parameters in patients who underwent total knee arthroplasty.

Settings and Design
This is a prospective, randomized, clinical trial with the participation of 109 patients over 60 years of age and patients physical status American Society of Anesthesiologists Classes I and II to undergo knee surgery. The patients were administered spinal anesthesia, divided into three groups.

Subjects and Methods
The patients in Group I were infused 8 mL/kg hydroxyethyl starch (130/0.4) 20 min before the cement implantation, those in Group II were infused the same simultaneously during cement implantation. Group III was infused 8 mL/kg/h sodium chloride during the anesthesia management. Hemodynamic parameters of the patients were recorded at before and after cement implantation and once the tourniquet was removed.

Statistical Analysis Used
The descriptive statistics were presented as the mean ± standard deviation for normally distributed variables, as the median for nonnormally distributed variables, and as the number of cases and (%) for nominal variables. Pearson's Chi-square test and Fisher's exact test were used in the analysis of categorical variables.

Results
Compared to the control group, Groups I and II were hemodynamically more stable. The development of moderate hypoxia during cement implantation was significantly different between the study groups (P < 0.05).

Conclusions
We suggest that avoiding intravascular volume depletion by using the colloids, particularly in elderly patients, is important for preventing from the BCIS.

Dumanlı Özcan|Ayça T|AT|
Kesimci|Elvin|E|
Balcı|Cemile Altın|CA|
Kanbak|Orhan|O|
Kaşıkara|Hülya|H|
But|Abdulkadir|A|

colloid
Bone cement
hypoxia
hypotension
hydroxyethyl starch


2D Bismuthene Metal Electron Mediator Engineering Super Interfacial Charge Transfer for Efficient Photocatalytic Reduction of Carbon Dioxide.

Abstract: The interfacial charge transfer still limits the photoactivity of artificial Z-scheme photocatalysts although they showed complementary light absorption and a strong photoredox ability. In this study, layered metallene is designed as an efficient electron mediator for constructing a C3N4/bismuthene/BiOCl 2D/2D/2D Z-scheme system. This bismuthene serves as a bridge processing superior charge conductibility, abundant metal-semiconductor contact sites, and the shortened charge diffusion distance, enhancing the photocatalytic CO2 reduction reaction activity and stability. Density functional theory calculations show that the bismuthene creates a built-in electric field and congregates interfacial electrons, which is confirmed by the stable and consistent emission of the ultrafast transient absorption spectra. This work gives new insight into the interface design of Z-scheme photocatalysts by selecting a novel metallene electron mediator.

bismuthene
Z-scheme
C3N4
BiOCl
photocatalytic CO2RR


Kinetic modelling and meta-analysis of the B. subtilis SigA regulatory network during spore germination and outgrowth.

Abstract: This study describes the meta-analysis and kinetic modelling of gene expression control by sigma factor SigA of Bacillus subtilis during germination and outgrowth based on microarray data from 14 time points. The analysis computationally models the direct interaction among SigA, SigA-controlled sigma factor genes (sigM, sigH, sigD, sigX), and their target genes. Of the >800 known genes in the SigA regulon, as extracted from databases, 311 genes were analysed, and 190 were confirmed by the kinetic model as being controlled by SigA. For the remaining genes, alternative regulators satisfying kinetic constraints were suggested. The kinetic analysis suggested another 214 genes as potential SigA targets. The modelling was able to (i) create a particular SigA-controlled gene expression network that is active under the conditions for which the expression time series was obtained, and where SigA is the dominant regulator, (ii) suggest new potential SigA target genes, and (iii) find other possible regulators of a given gene or suggest a new mechanism of its control by identifying a matching profile of unknown regulator(s). Selected predicted regulatory interactions were experimentally tested, thus validating the model.

Ramaniuk|O|O| Černý|M|M| Krásný|L|L| Vohradský|J|J|

D015964:Gene Expression Regulation, Bacterial

Kinetic modelling
Regulatory network
Gene expression
Bacillus subtilis
Sigma A


Does warfarin-related intracerebral haemorrhage lead to higher costs of management?

Abstract:
BACKGROUND AND PURPOSE
Warfarin-related intracerebral haemorrhage is associated with significant morbidity but long term treatment costs are unknown. Our study aimed to assess the cost of warfarin-related intracerebral haemorrhage.

METHODS
We included all patients with intracerebral haemorrhage between July 2006 and December 2011 at a single centre. We collected data on anticoagulant use, baseline clinical variables, discharge destinations, modified Rankin Scale at discharge and in-hospital costings. First year costings were extracted from previous studies. Multiple linear regression for treatment cost was performed with stratified analysis to assess for effect modification.

RESULTS
There were 694 intracerebral haemorrhage patients, with 108 (15.6%) previously on warfarin. Mean age (SD) of participants was 70.3 (13.6) and 58.5% were male. Patients on warfarin compared to those not on warfarin had significantly lower rates of discharge home (12.0% versus 18.9%, p=0.013). Overall total costs between groups were similar, $AUD 25,767 for warfarin-related intracerebral haemorrhage and $AUD 27,388 for non-warfarin intracerebral haemorrhage (p=0.353). Stratified analysis showed survivors of warfarin-related intracerebral haemorrhage had higher costs compared to those without warfarin ($AUD 33,419 versus $AUD 30,193, p<0.001) as well as increased length of stay (12 days versus 8 days, p<0.001). Inpatient mortality of patients on warfarin was associated with a shorter length of stay (p=0.001) and lower costs.

CONCLUSION
Survival of initial haemorrhage on warfarin was associated with increased treatment cost and length of stay but this was discounted by higher rates and earlier nature of mortality in warfarinised patients.

Kam|Jeremy K|JK|
Chen|Zhibin|Z|
Liew|Danny|D|
Yan|Bernard|B|

Intracerebral haemorrhage
Cost
Warfarin
Mortality
Stroke


Ultrastructure alterations induced by gamma irradiation in spermiogenesis of the ground beetle, Blaps sulcata: reference to environmental radiation protection.

Abstract: Ultrastructure alterations in spermiogenesis of the ground beetle, Blaps sulcata (Coleoptera: Tenebrionidae) were studied in normal adult males and in two male groups irradiated by gamma rays of 3 and 16 μSv/h dose rate. Ultrastructure examination of irradiated sperms revealed many alterations both in the head and in the flagellum regions of mature sperm. Alterations of the head region included nuclei with uncondensed chromatin materials and irregular nuclear envelope. Abnormal flagella contained malformed mitochondrial derivatives and damaged axonemes in addition to the absence of accessory bodies. Bi- and multi-flagellate sperms (with two, three, and four axonemes) were the most common alterations. Sperm cells with residual bodies were also obtained. Agglutinated sperms and sperms with enlarged and/or vacuolated cytoplasm were common. Sperm abnormalities were more pronounced in males irradiated by 16 μSv/h dose rate than those irradiated by 3 μSv/h. Spermiogenesis alterations induced by irradiation of B. sulcata may be used as a monitoring model for predicting the effects of environmental radioactivity.

Kheirallah|Dalia|D| El-Samad|Lamia|L| Fahmi|Naglaa|N| Osman|Wafaa|W|

Ultrastructure alterations
Spermiogenesis
Monitoring model
Radiation effects
Tenebrionid beetles


Micromagnetic simulation of microstructure effect for binary-main-phase Nd-Ce-Fe-B magnets.

Abstract: We investigate the magnetic properties of a chemically heterogeneous binary-main-phase (BMP) Nd-Ce-Fe-B magnet with a core-shell structure via micromagnetic simulation. It is found that the coercivity strongly depends on the shell thickness. The BMP magnet's coercivity initially increases and then decreases with increasing Nd-rich shell thickness, and so there is the optimal shell thickness which shows the maximum coercivity for any given Ce concentration. The simulation shows the significant difference in coercivity and maximum energy product between the BMP and single-main-phase magnets. Notably, the magnetization reversal mechanism of the BMP magnet is revealed in the simulation. Local reversals in the BMP magnet first occur in the Ce-rich shells, followed by the Nd-rich cores. Then, the magnetization in Ce-rich core/Nd-rich shell typed grains is switched after reversed magnetization of all the Nd-rich core/Ce-rich shell typed grains. The BMP magnet represents a further increased coercivity for a larger GB thickness, which can be well explained by a maximum stray field.

micromagnetic simulation
binary-main-phase
coercivity
magnetization reversal
stray field


Maestro, Marguerite, morphine: The last years in the life of Mikhail Bulgakov.

Abstract:
UNLABELLED
The manuscript pages of the final draft of Master i Margarita, the masterpiece by Mikhail Bulgakov, written in the last four years of his life (1936-1940), have been treated with a mixture of chromatographic beads, namely a strong cation exchanger and a C8 resin. Potential substances captured by the beads, after harvesting them, were eluted with a mixture of isopropyl alcohol, dichloromethane and ammonium hydroxide and the eluate subjected to GC-MS analysis in order to detect the presence, if any, of drugs, due to the fact that the writer suffered intense pains caused by an inherited nephrotic syndrome. Indeed all the pages under investigation (a total of ten, taken at random among 127 foils) contained traces of morphine, from as little as 5 up to 100ng/cm(2). In addition to the intact drug, we could detect one of its metabolites, namely 6-O-acetyl morphine. The significance of these findings in terms of a possible improvement of the novel and in terms of drug use (or abuse) in the modern world is discussed and evaluated.

BIOLOGICAL SIGNIFICANCE
The extraction of metabolites/proteins from the surface of the original manuscript pages of Bulgakov masterpiece Master i Margarita has permitted to monitor his health state and intake of medicaments over the last four years of his life. We have ascertained that: (1) he was assuming large doses of morphine as pain killers; (2) he was affected by a nephrotic syndrome, since we could identify three proteins known as biomarkers of this pathology. The double extraction procedure here reported could open up a novel field of investigation of (relatively) ancient manuscripts for metabolome/proteome analysis on the health status of the writer/artist.

Zilberstein|Gleb|G|
Maor|Uriel|U|
Baskin|Emmanuil|E|
Righetti|Pier Giorgio|PG|

Morphine
Master i Margarita
6-O-acetyl morphine
Bulgakov manuscript
Chromatographic resins
Gas chromatography/mass spectrometry


Soil heterotrophic respiration in response to rising temperature and moisture along an altitudinal gradient in a subtropical forest ecosystem, Southwest China.

Abstract: Globally, one-third of the terrestrial carbon (C) is stored in tropical soils. The warming predicted for this century is expected to increase microbial decomposition in soil and escalate climate change potential by releasing more carbon dioxide (CO2) into the atmosphere. Understanding the response of soils to warming is a key challenge in predicting future climate change trajectories. Here we examined the combined effect of soil temperature (Ts) and soil water content (VWC) on soil heterotrophic respiration (Rsh) and its temperature sensitivity across different altitudes (2400, 1900, and 1450 m ASL) in the Ailaoshan subtropical forest ecosystem, Southwest China. Along the elevation gradient, soil C stocks in the top 50 cm soil layer increased significantly from 10.7 g/ kg at 1480 m ASL to 283.1 g/ kg at 2480 m ASL. Soil cores from various elevations were translocated to the same, and lower elevations and Rsh from those cores were measured every month from February 2010 to January 2014. Temperature sensitivity (Q10) of Rsh for the period was highest at the highest (H) elevation (Q10 = 5.3), decreased significantly towards the middle (M, Q10 = 3.1) and low (L, Q10 = 1.2) elevation. Q10 at M and L elevation did not differ between the place of origin and translocated cores. For the cores within each elevation, Q10 did not vary across the years. Our models suggest that Rsh increased significantly in response to an increase in Ts at each elevation under an intermediate VWC. Hence, the rate of emission was higher in lower elevations due to a higher Ts range. Our findings highlight that the predicted warming over the 21st century will have the greatest impact of Ts on Rsh, especially on the soils at the highest elevations, and will lead towards positive feedback to the climate system.

Zeeshan|Mohd|M|
Wenjun|Zhou|Z|
Chuansheng|Wu|W|
Yan|Lin|L|
Azeez|P A|PA|
Qinghai|Song|S|
Yuntong|Liu|L|
Yiping|Zhang|Z|
Zhiyun|Lu|L|
Liqing|Sha|S|

Heterotrophic respiration
Forest ecosystem
Terrestrial carbon
Climate change
Soil temperature
Soil water content


A one-step matrix application method for MALDI mass spectrometry imaging of bacterial colony biofilms.

Abstract: Matrix-assisted laser desorption/ionization imaging of biofilms cultured on agar plates is challenging because of problems related to matrix deposition onto agar. We describe a one-step, spray-based application of a 2,5-dihydroxybenzoic acid solution for direct matrix-assisted laser desorption/ionization imaging of hydrated Bacillus subtilis biofilms on agar. Using both an optimized airbrush and a home-built automatic sprayer, region-specific distributions of signaling metabolites and cannibalistic factors were visualized from B. subtilis cells cultivated on biofilm-promoting medium. The approach provides a homogeneous, relatively dry coating on hydrated samples, improving spot to spot signal repeatability compared with sieved matrix application, and is easily adapted for imaging a range of agar-based biofilms. Copyright © 2016 John Wiley & Sons, Ltd.

Li|Bin|B|
Comi|Troy J|TJ|
Si|Tong|T|
Dunham|Sage J B|SJ|
Sweedler|Jonathan V|JV|

D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

matrix application
biofilms
airbrush
automatic sprayer
MALDI MSI


Electroconvulsive Therapy for Agitation in Schizophrenia: Metaanalysis of Randomized Controlled Trials.

Abstract:
BACKGROUND
Agitation poses a significant challenge in the treatment of schizophrenia. Electroconvulsive therapy (ECT) is a fast, effective and safe treatment for a variety of psychiatric disorders, but no meta-analysis of ECT treatment for agitation in schizophrenia has yet been reported.

AIMS
To systematically evaluate the efficacy and safety of ECT alone or ECT-antipsychotics (APs) combination for agitation in schizophrenia.

METHODS
Systematic literature search of randomized controlled trials (RCTs) was performed. Two independent evaluators selected studies, extracted data about outcomes and safety with available data, conducted quality assessment and data synthesis. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to judge the level of the overall evidence of main outcomes.

RESULTS
Seven RCTs from China, including ECT alone (4 RCTs with 5 treatment arms, n=240) and ECT-APs combination (3 RCTs, n=240), were identified. Participants in the studies were on average 34.3(4.5) years of age and lasted an average of 4.3(3.1) weeks of treatment duration. All 7 RCTs were non-blinded, and were rated as low quality based on Jadad scale. Meta-analysis of the pooled sample found no significant difference in the improvement of the agitation sub-score of the Positive and Negative Syndrome Scale (PANSS) when ECT alone (weighted mean difference=-0.90, (95% confidence interval (CI): -2.91, 1.11), p=0.38) or ECT-APs combination (WMD=-1.34, (95%CI: -4.07, 1.39), p=0.33) compared with APs monotherapy. However, ECT alone was superior to APs monotherapy regarding PANSS total score (WMD=-7.13, I=0.004) and its excitement sub-score (WMD=-1.97, p<0.0001) as well as the PANSS total score at 14 days (WMD=-7.13, I =0%, p=0.004) and its excitement sub-score at 7 and 14 days (WMD=-1.97 to -1.92, p=0.002 to 0.0001) after ECT. The ECT-APs combination was superior to APs monotherapy with respect to the PANSS total score at treatment endpoint (WMD=-10.40, p=0.03) and 7 days (WMD=-5.01, p=0.02). Headache (number-needed-to-harm (NNH)=3, 95%CI=2-4) was more frequent in the ECT alone group compared to AP monotherapy. According to the GRADE approach, the evidence levels of main outcomes were rated as ''very low'' (37.5%) and "low" (50%).

CONCLUSION
Pooling of the data based on 7 RCTs from China found no advantage of ECT alone or ECT-APs combination in the treatment of agitation related outcomes in schizophrenia patients. However, ECT alone or ECT-APs combination were associated with significant reduction in the PANSS total score. High-quality RCTs are needed to confirm the current interpretations.

Gu|Xiaojing|X|
Zheng|Wei|W|
Guo|Tong|T|
Ungvari|Gabor S|GS|
Chiu|Helen F K|HFK|
Cao|Xiaolan|X|
D'Arcy|Carl|C|
Meng|Xiangfei|X|
Ning|Yuping|Y|
Xiang|Yutao|Y|

Electroconvulsive therapy
agitation
schizophrenia
meta-analysis
headache


Very late onset neuromyelitis optica spectrum disorders.

Abstract:
BACKGROUND AND PURPOSE
Neuromyelitis optica spectrum disorder (NMOSD) often presents in the elderly with an insidious onset of symptoms and aggressive progression. There have been anecdotal cases of very late onset (VLO)-NMOSD, but case series reports are rare. The aim of this retrospective study was to clarify the clinical features of VLO-NMOSD.

METHODS
According to the age at onset, we classified patients with NMOSD into three subgroups: ≤49 years, early onset NMOSD (EO-NMOSD); 50-69 years, late onset NMOSD (LO-NMOSD); and ≥70 years, VLO-NMOSD. We evaluated the clinical characteristics, magnetic resonance imaging (MRI) findings, laboratory data, and immunotherapies of the groups.

RESULTS
Overall, 12 men and 64 women with a median (interquartile range) age at onset and duration of disease of 42.0 (29.0-55.8) years and 70.0 (16.3-143.0) months, respectively, were included. Eight (11%) patients had VLO-NMOSD, 22 (29%) had LO-NMOSD, and 46 (61%) had EO-NMOSD. Patients with EO-NMOSD had a significantly longer interval between episodes as well as time between the first symptom and diagnosis of NMOSD than did those with VLO-NMOSD and LO-NMOSD (p = 0.046). Optic neuritis and nerve lesions on MRI were significantly less frequent in patients with VLO-NMOSD than in those with LO-NMOSD and EO-NMOSD (p = 0.002 and p = 0.028, respectively). In contrast, patients with VLO-NMOSD had higher nadir Expanded Disability Status Scale and Nurick scale scores and a significantly longer spinal lesion length than did those with LO-NMOSD and EO-NMOSD (p = 0.029, p = 0.049, and p = 0.032, respectively).

CONCLUSIONS
Patients with VLO-NMOSD tend to develop severe myelitis with long cord lesions but not optic neuritis.

Nakahara|Keiichi|K|0000-0002-8931-8861 Nakane|Shunya|S|0000-0003-1958-095X Nagaishi|Akiko|A| Narita|Tomoko|T| Matsuo|Hidenori|H| Ando|Yukio|Y|

neuromyelitis optica
aging
magnetic resonance imaging
optic neuritis
transverse myelitis


Predictive value of genetic testing for inherited retinal diseases in patients with suspected atypical autoimmune retinopathy.

Abstract:
Purpose
The clinical features of autoimmune retinopathy (AIR) can resemble and be difficult to differentiate from inherited retinal degenerations (IRDs). Misdiagnosis of an IRD as AIR causes unnecessary treatment with immunosuppressive agents. The purpose of this study is to calculate the predictive value of genetic testing for IRDs in patients with suspected AIR and provide clinical examples where genetic testing has been useful.

Methods
We identified patients seen at MEEI between April 2013 and January 2017 for whom the differentiation of AIR vs. IRDs was difficult based on clinical assessment alone. All patients had some atypical features for AIR, but tested positive for anti-retinal antibodies. Within this group, we identified six patients who had genetic testing for IRDs with the Genetic Eye Disease panel for retinal genes (GEDi-R). We calculated the positive predictive value (PPV) and negative predictive value (NPV) of genetic testing in a population with approximately equal numbers of IRD and AIR patients.

Results
Six patients had clinical features that made distinguishing between IRDs and AIR on a clinical basis difficult and were sent for genetic testing: four women and two men with a mean age of 59.5 years. In two of these six patients, genetic diagnoses were made based upon the identification of known pathogenic variants in the common IRD genes USH2A and RHO. Two patients had variants of unknown significance within genes associated with IRDs, and the other two had no relevant genetic findings. Given the 60% sensitivity and 3% false positive rate for GEDi-R testing and assuming a 50% pre-test probability of having an IRD, the PPV for GEDi-R for detecting IRD is 95.2% and the NPV is 70.8%.

Conclusions and Importance
In patients for whom the differential diagnosis of AIR and IRDs is unclear based on clinical information, genetic testing can be a valuable tool when it identifies an IRD, sparing the patient unnecessary immunosuppressive treatment. However, the test has a low NPV so a negative genetic testing result does not confidently exclude IRD as the true diagnosis.

Stanwyck|Lynn K|LK|
Place|Emily M|EM|
Comander|Jason|J|
Huckfeldt|Rachel M|RM|
Sobrin|Lucia|L|

Genetic testing
Autoimmune retinopathy
Inherited retinal degeneration
Cancer associated-retinopathy


Specific cytokines in the inflammatory cytokine storm of patients with COVID-19-associated acute respiratory distress syndrome and extrapulmonary multiple-organ dysfunction.

Abstract:
BACKGROUND
To date, specific cytokines associated with development of acute respiratory distress syndrome (ARDS) and extrapulmonary multiple organ dysfunction (MOD) in COVID-19 patients have not been systematically described. We determined the levels of inflammatory cytokines in patients with COVID-19 and their relationships with ARDS and extrapulmonary MOD.

METHODS
The clinical and laboratory data of 94 COVID-19 patients with and without ARDS were analyzed. The levels of inflammatory cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α [TNF-α]) were measured on days 1, 3, and 5 following admission. Seventeen healthy volunteers were recruited as controls. Correlations in the levels of inflammatory cytokines with clinical and laboratory variables were analyzed, furthermore, we also explored the relationships of different cytokines with ARDS and extrapulmonary MOD.

RESULTS
The ARDS group had higher serum levels of all 4 inflammatory cytokines than the controls, and these levels steadily increased after admission. The ARDS group also had higher levels of IL-6, IL-8, and IL-10 than the non-ARDS group, and the levels of these cytokines correlated significantly with coagulation parameters and disseminated intravascular coagulation (DIC). The levels of IL-6 and TNF-α correlated with the levels of creatinine and urea nitrogen, and were also higher in ARDS patients with acute kidney injury (AKI). All 4 inflammatory cytokines had negative correlations with PaO2/FiO2. IL-6, IL-8, and TNF-α had positive correlations with the APACHE-II score. Relative to survivors, non-survivors had higher levels of IL-6 and IL-10 at admission, and increasing levels over time.

CONCLUSIONS
The cytokine storm apparently contributed to the development of ARDS and extrapulmonary MOD in COVID-19 patients. The levels of IL-6, IL-8, and IL-10 correlated with DIC, and the levels of IL-6 and TNF-α were associated with AKI. Relative to survivors, patients who died within 28 days had increased levels of IL-6 and IL-10.

Wang|Jiajia|J| Yang|Xinjing|X| Li|Yongsheng|Y| Huang|Jian-An|JA| Jiang|Junhong|J| Su|Nan|N|0000-0002-4564-1595

Inflammatory cytokine
Acute respiratory distress syndrome
Multiple-organ dysfunction
COVID-19
Disseminated intravascular coagulation
SARS-CoV-2


Prediction of Gestational Diabetes by Measuring the Levels of Pregnancy Associated Plasma Protein-A (PAPP-A) During Gestation Weeks 11-14.

Abstract:
Background
The present study aimed to determine the association between pregnancy-associated plasma protein A (PAPP-A) and Gestational Diabetes Methods (GDM) to detect a risk factor for predicting GDM at gestational weeks 11-14.

Methods
This analytical prospective study recruited 284 pregnant women presenting to six healthcare centers of Qazvin, Iran from February to December 2016. PAPP-A was measured at gestational weeks 11-14 and glucose tolerance test was conducted at gestational weeks 24-28. The participants were assigned into two groups of exposure (reduced PAPP-A) and non-exposure (normal PAPP-A). The association between GDM and PAPP-A was studied. The number of women in exposure group were 201 and 83 in the non-exposure group. Differences between groups were assessed by the Mann-Whitney, Chi-square, T test, logistic regression analysis and ROC Curve with a significance level of 0.05.

Results
Twenty eight (33.73%) patients of the exposure group and 17 (8.46%) of non-exposure group developed GDM. There was a significant difference between the two groups in terms of GDM (p<0.001) and the risk of GDM was 3.98 fold higher in the exposure group (reduced PAPPA mu/L) than that of the non-exposure group (CI=2.39-6.65, p<0.001). Also, 53.3% of the exposure group and 46.7% of the nonexposure group were diagnosed with GDM (p=0.02). There was a significant difference in GDM between the groups and the risk of GDM was 1.85 times higher in the exposure group (reduced PAPPA MOM) than that in the control group (CI=1.09-3.15, p=0.020). According to the ROC curve results, PAPP-A and MOM are acceptable indicators for predicting GDM.

Conclusion
A low PAPP-A level (MOM, MU/L) as a new risk factor for GDM can help early prediction and prevent maternal and fetal complication by timely treatment.

Ramezani|Somayeh|S|
Doulabi|Mahboubeh Ahmadi|MA|
Saqhafi|Hamid|H|
Alipoor|Mahmood|M|

Gestational diabetes
Pregnancies
Pregnancy associated plasma protein A


The complete mitochondrial genome of Thitarodes sejilaensis (Lepidoptera: Hepialidae), a host insect of Ophiocordyceps sinensis and its implication in taxonomic revision of Hepialus adopted in China.

Abstract: The mitochondrial genome is widely used for phylogenetic analyses and evolutionary biology. The complete mitochondrial genome of Thitarodes sejilaensis (Lepidoptera: Hepialidae) was sequenced and analyzed in this study. This mitogenome is a typical circular molecule of 15,290bp, with the gene content, orientation and order identical to other insects in the family Hepialidae. The genome nucleotide composition is heavily biased towards As and Ts, accounting for 80.87% of total nucleotide content. The major strand shows a positive AT-skew and negative GC-skew. All 13 protein-coding genes (PCG) are initiated by the canonical putative start codons ATN, except for COI and ND1 that use the initiation codons CGA and TTG, respectively. Nine PCGs share the complete termination codons TAA, while the remaining PCGs use an incomplete termination codon T. Additionally, the codon distribution and Relative Synonymous Codon Usage of all PCGs in the T. sejilaensis mitogenome are consistent with other Hepialidae mitogenomes. Among 22 transfer RNAs, 21 have the typical clover-leaf structure, while tRNASer(AGN) does not possess the dihydrouridine (DHU) arm and could not form a stable stem-loop structure. The secondary structures of 2 ribosomal RNA genes broadly conform to the proposed models of these genes documented in other lepidopteran insects. T. sejilaensis AT-rich region exhibits three repetitive sequences of 118bp. Other regions contain 22-bp overlapping nucleotides and 72-bp intergenic nucleotides. The phylogenetic relationships were constructed by two datasets, the amino acid sequence derived from protein-coding genes and the nucleotide sequence of 13 PCGs and 2 rRNAs. Using Maximum Likelihood (ML), we reconstructed a phylogenetic tree which supported a more primitive taxa of Hepialoidea within Lepidoptera. Moreover, according to comparisons based on the CytB sequences and morphological characteristic, Hepialus species reported in China should be revised. Our taxonomic recommendations include assigning these species to the following genera: Thitarodes, Ahamus, Hepialus and Parahepialus.

Zou|Zhiwen|Z| Min|Qiang|Q| Cheng|Shiyu|S| Xin|Tianrong|T| Xia|Bin|B|

Mitochondrial genome
Thitarodes sejilaensis
Taxonomic revision
Hepialus


Interactive effects of ethanol on ulcerative colitis and its associated testicular dysfunction in pubertal BALB/c mice.

Abstract: Available epidemiological reports have indicated an increase in the incidence of ulcerative colitis, as well as alcohol consumption, globally. The present study investigated the possible interactive effects of ethanol consumption on ulcerative colitis and its associated testicular dysfunction using six groups of 12 pubertal mice each. Group I (Control) mice received drinking water alone. Group II mice received ethanol alone at 5 g/kg body weight. Group III mice received 2.5% dextran sulphate sodium (DSS) in drinking water followed by normal drinking water. Groups IV, V, and VI mice received DSS followed by ethanol at 1.25, 2.5, and 5 g/kg, respectively. Administration of ethanol to mice with ulcerative colitis intensified the disease-activity index with marked reduction in colon length, colon mass index, body weight gain, and organo-somatic indices of testes and epididymis when compared with the DSS-alone group. Moreover, ethanol exacerbated colitis-mediated decrease in enzymatic and non-enzymatic antioxidants but increased the oxidative stress and inflammatory biomarkers in the testes and epididymis. The diminution in luteinizing hormone, follicle stimulating hormone, and testosterone levels was intensified following administration of ethanol to mice with ulcerative colitis that were administered 5 g/kg ethanol alone. The decrease in sperm functional parameters and testicular spermatogenic indices as well as histopathological damage in colon, testes, and epididymis was aggravated following administration of ethanol to mice with ulcerative colitis. In conclusion, the exacerbating effects of ethanol on ulcerative colitis-induced testicular dysfunction are related to increased oxidative stress and inflammation in the treated mice.

Adedara|Isaac A|IA|
Ajayi|Babajide O|BO|
Awogbindin|Ifeoluwa O|IO|
Farombi|Ebenezer O|EO|

Ethanol
Colitis
Testicular dysfunction
Mice
Spermatogenesis


White matter changes in chronic and episodic migraine: a diffusion tensor imaging study.

Abstract:
BACKGROUND
White matter alterations have been observed in patients with migraine. However, no microstructural white matter alterations have been found particularly in episodic or chronic migraine patients, and there is limited research focused on the comparison between these two groups of migraine patients.

METHODS
Fifty-one healthy controls, 55 episodic migraine patients and 57 chronic migraine patients were recruited and underwent brain T1-weighted and diffusion-weighted MRI acquisition. Using Tract-Based Spatial Statistics (TBSS), fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity were compared between the different groups. On the one hand, all migraine patients were compared against healthy controls. On the other hand, patients from each migraine group were compared between them and also against healthy controls. Correlation analysis between clinical features (duration of migraine in years, time from onset of chronic migraine in months, where applicable, and headache and migraine frequency, where applicable) and Diffusion Tensor Imaging measures was performed.

RESULTS
Fifty healthy controls, 54 episodic migraine and 56 chronic migraine patients were finally included in the analysis. Significant decreased axial diffusivity (p < .05 false discovery rate and by number of contrasts corrected) was found in chronic migraine compared to episodic migraine in 38 white matter regions from the Johns Hopkins University ICBM-DTI-81 White-Matter Atlas. Significant positive correlation was found between time from onset of chronic migraine and mean fractional anisotropy in the bilateral external capsule, and negative correlation between time from onset of chronic migraine and mean radial diffusivity in the bilateral external capsule.

CONCLUSIONS
These findings suggest global white matter structural differences between episodic migraine and chronic migraine. Patients with chronic migraine could present axonal integrity impairment in the first months of chronic migraine with respect to episodic migraine patients. White matter changes after the onset of chronic migraine might reflect a set of maladaptive plastic changes.

D038524:Diffusion Magnetic Resonance Imaging

Migraine
Diffusion tensor imaging
Chronic migraine
Tract-based spatial statistics
Magnetic resonance imaging (MRI)


Comparing Outcomes Following Endoscopic Ultrasound-Guided Biliary Drainage Versus Percutaneous Transhepatic Biliary Drainage for Malignant Biliary Obstruction: A Systematic Review and Meta-Analysis.

Abstract: The aim of this study was to explore the efficacy and safety of endoscopic ultrasound-guided biliary drainage (EUS-BD) and percutaneous transhepatic biliary drainage (PTCD) in patients with malignant biliary obstruction and failed endoscopic retrograde cholangiopancreatography.  We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov to identify studies reporting outcomes comparing EUS-BD and PTCD.  We identified 9 studies involving 469 patients. Technical success was similar for EUS-BD and PTCD (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.17-3.30; P = .71). EUS-BD was associated with higher clinical success versus PTCD (OR, 2.11; 95% CI, 1.15-3.87; P = .02) in all studies. However, there was no significant difference between groups in studies using self-expandable metal stents (OR, 0.36; 95% CI, 0.06-2.00; P = .24). The reported adverse event rate was significantly lower for EUS-BD compared with PTCD (OR, 0.33; 95% CI, 0.22-0.52; P < .00001).  The available literature suggests that EUS-BD is associated with fewer adverse events, greater clinical success, and comparable technical success compared with PTCD. According to the shortcomings of our study, more large, high-quality, randomized controlled trials are needed to compare these techniques and confirm our findings.

Wang|Yuan|Y| Lyu|Yunxiao|Y|0000-0002-2795-9698 Li|Ting|T| Wang|Bin|B| Cheng|Yunxiao|Y|


Circulating levels of adiponectin, resistin, and visfatin after mud-bath therapy in patients with bilateral knee osteoarthritis.

Abstract: Adipocytokines, including adiponectin, resistin, and visfatin may play an important role in the pathophysiology of osteoarthritis (OA). Spa therapy is one of the most commonly used non-pharmacological approaches for OA, but its mechanisms of action are not completely known. The aim of the present study was to assess whether a cycle of mud-bath therapy (MBT) influences the serum levels of adiponectin, resistin, and visfatin in patients with knee OA. As part of a prospective randomized, single blind-controlled trial evaluating the efficacy of MBT in knee OA, we included in this study 95 outpatients. One group (n = 49) received a cycle of MBT at the spa center of Chianciano Terme (Italy) in addition to the usual treatment, and one group (control group; n = 46) continued their regular care routine alone. Patients were assessed at basal time and at the end of the study (15 days) for clinical and biochemical parameters. Clinical assessments included spontaneous pain on a visual analog scale (VAS) score and the Western Ontario and McMaster Universities index (WOMAC) subscores for knee OA evaluated as total pain score (W-TPS), total stiffness score (W-TSS), and total physical function score (W-TPFS). Adiponectin, resistin and visfatin serum levels were assessed by enzyme immunoassay methods. At the end of the mud-bath therapy, serum adiponectin levels showed a significant decrease (p < 0.001), while no significant modifications were found in the control group at day 15. Serum resistin showed a significant decrease (p < 0.0001) in the MBT group at the end of the study and a significant increase in the control patients (p < 0.001). No significant modifications of visfatin were found in MBT. Furthermore, we tested the relationships between demographic and clinical parameters and adipocytokine concentrations measured in the MBT group at basal and at the end of the study. In conclusion, the present study shows that a cycle of MBT can modify serum levels of adiponectin and resistin but not the circulating levels of visfatin. In view of the recent evidences about the involvement of adiponectin and resistin in the pathogenesis and progression of OA, the decrease of these adipokines after mud-bath therapy may play a protective role in the course of the disease. However, it remains to be clarified which of the mechanisms of action of MBT may have determined the changes in serum levels of adiponectin and resistin that we observed.

Fioravanti|Antonella|A|
Giannitti|Chiara|C|
Cheleschi|Sara|S|
Simpatico|Antonella|A|
Pascarelli|Nicola Antonio|NA|
Galeazzi|Mauro|M|

Adiponectin
Resistin
Visfatin
Mud-bath therapy
Osteoarthritis


Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in high-risk patient groups: cancer and critically ill.

Abstract:
Background
Clinical practice shows that venous thromboembolism (VTE) presents a substantial burden in medical patients, and awareness and advocacy for its primary and secondary prevention remains inadequate. Specific patient populations, such as those with cancer and the critically ill, show elevated risk for VTE, bleeding or both, and significant gaps in VTE prophylaxis and treatment exist in these groups.

Objective
To present novel insights and consolidated evidence collected from experts, clinical practice guidelines and original studies on the unmet needs in thromboprophylaxis, and on the treatment of VTE in two high-risk patient groups: patients with cancer and the critically ill.

Methodology
To identify specific unmet needs in the management of VTE, a methodology was designed and implemented that assessed gaps in prophylaxis and treatment of VTE through interviews with 44 experts in the field of thrombosis and haemostasis, and through a review of current guidelines and seminal studies to substantiate the insights provided by the experts. The research findings were then analysed, discussed and consolidated by a multidisciplinary group of experts.

Results
The gap analysis methodology identified shortcomings in the VTE risk assessment tools, patient stratification approaches for prophylaxis, and the suboptimal use of anticoagulants for primary prophylaxis and treatment.

Conclusions
Specifically, patients with cancer need better VTE risk assessment tools to tailor primary thromboprophylaxis to tumour types and disease stages, and the potential for drug-drug interactions needs to be considered. In critically ill patients, unfractionated heparin is not advised as a first-line treatment option, and the strength of evidence is increasing for direct oral anticoagulants as a treatment option over low-molecular-weight heparins.

Brenner|Benjamin|B| Hull|Russell|R| Arya|Roopen|R| Beyer-Westendorf|Jan|J| Douketis|James|J| Elalamy|Ismail|I| Imberti|Davide|D| Zhai|Zhenguo|Z|

Venous thromboembolism
Cancer
Critically ill
Anticoagulants
Low-molecular-weight heparin


RD or Not RD: Using Experimental Studies to Assess the Performance of the Regression Discontinuity Approach.

Abstract:
BACKGROUND
This article explores the performance of regression discontinuity (RD) designs for measuring program impacts using a synthetic within-study comparison design. We generate synthetic RD data sets from experimental data sets from two recent evaluations of educational interventions-the Educational Technology Study and the Teach for America Study-and compare the RD impact estimates to the experimental estimates of the same intervention.

OBJECTIVES
This article examines the performance of the RD estimator with the design is well implemented and also examines the extent of bias introduced by manipulation of the assignment variable in an RD design.

RESEARCH DESIGN
We simulate RD analysis files by selectively dropping observations from the original experimental data files. We then compare impact estimates based on this RD design with those from the original experimental study. Finally, we simulate a situation in which some students manipulate the value of the assignment variable to receive treatment and compare RD estimates with and without manipulation.

RESULTS AND CONCLUSION
RD and experimental estimators produce impact estimates that are not significantly different from one another and have a similar magnitude, on average. Manipulation of the assignment variable can substantially influence RD impact estimates, particularly if manipulation is related to the outcome and occurs close to the assignment variable's cutoff value.

D000465:Algorithms
D066264:Datasets as Topic
D018961:Educational Technology
D017063:Outcome Assessment, Health Care
D015397:Program Evaluation
D012044:Regression Analysis
D012107:Research Design
D013663:Teaching

design and evaluation of programs and policies

outcome evaluation (other than economic evaluation)


Ecotoxicological and regulatory aspects of environmental sustainability of nanopesticides.

Abstract: Recent years have seen the development of various colloidal formulations of pesticides and other agrochemicals aimed at use in sustainable agriculture. These formulations include inorganic, organic or hybrid particulates, or nanocarriers composed of biodegradable polymers, that can provide a better control of the release of active ingredients. The very small particle sizes and high surface areas of nanopesticides may however also lead to some unintended (eco)toxicological effects due to the way in which they interact with the target and non-target species and the environment. The current level of knowledge on ecotoxicological effects of nanopesticides is scarce, especially in regard to the fate and behaviour of such formulations in the environment. Nanopesticides will however have to cross a stringent regulatory scrutiny before marketing in most countries for health and environmental risks under a range of regulatory frameworks that require pre-market notification, risk assessment and approval, followed by labelling, post-market monitoring and surveillance. This review provides an overview of the key regulatory and ecotoxicological aspects relating to nanopesticides that will need to be considered for environmentally-sustainable use in agriculture.

Grillo|Renato|R|
Fraceto|Leonardo F|LF|
Amorim|Mónica J B|MJB|
Scott-Fordsmand|Janeck James|JJ|
Schoonjans|Reinhilde|R|
Chaudhry|Qasim|Q|

Nanopesticides
Agriculture
Risk assessment
Ecotoxicity
Nanotechnology
Nanotoxicology


Discovering Protein-Protein Interactions Using Nucleic Acid Programmable Protein Arrays.

Abstract: We have developed a protocol enabling the study of protein-protein interactions (PPIs) at the proteome level using in vitro-synthesized proteins. Assay preparation requires molecular cloning of the query gene into a vector that supports in vitro transcription/translation (IVTT) and appends a HaloTag to the query protein of interest. In parallel, protein microarrays are prepared by printing plasmids encoding glutathione S-transferase (GST)-tagged target proteins onto a carrier matrix/glass slide coated with antibody directed against GST. At the time of the experiment, the query protein and the target protein are produced separately through IVTT. The query protein is then applied to nucleic acid programmable protein arrays (NAPPA) that display thousands of freshly produced target proteins captured by anti-GST antibody. Interactions between the query and immobilized target proteins are detected through addition of a fluorophore-labeled HaloTag ligand. Our protocol allows the elucidation of PPIs in a high-throughput fashion using proteins produced in vitro, obviating the scientific challenges, high cost, and laborious work, as well as concerns about protein stability, which are usually present in protocols using conventional protein arrays. © 2017 by John Wiley & Sons, Inc.

Tang|Yanyang|Y| Qiu|Ji|J| Machner|Matthias|M| LaBaer|Joshua|J|

D005822:Genetic Vectors
D006367:HeLa Cells
D006801:Humans
D009696:Nucleic Acids
D040081:Protein Array Analysis
D025941:Protein Interaction Mapping

protein-protein interactions
protein arrays
HaloTag
NAPPA
cell-free gene expression


Antinociception induced by galanin in anterior cingulate cortex in rats with acute inflammation.

Abstract: The present study was performed to explore the role of galanin in nociceptive modulation in anterior cingulate cortex (ACC) of rats with acute inflammation, and the changes in galanin and galanin receptor 2 (Gal R2) expressions in rats with acute inflammation. Intra-ACC injection of galanin induced antinociception in rats with acute inflammation, the antinociceptive effects induced by galanin were attenuated significantly by intra-ACC injection of the Gal R2 antagonist M871, indicating an involvement of Gal R2 in nociceptive modulation in ACC in rats with acute inflammation. Furthermore, we found that both the galanin mRNA expression and galanin content increased significantly in ACC in rats with acute inflammation than that in normal rats. Moreover, both the mRNA levels of Gal R2 and the content of Gal R2 in ACC increased significantly in rats with acute inflammation than that in normal rats. These results demonstrated that galanin induced antinociception in ACC in rats with acute inflammation. And there were changes in the expression of galanin and Gal R2 in rats with acute inflammation.

Antinociception
Galanin
Acute inflammation
Anterior cingulate cortex (ACC)
Galanin receptor 2 (Gal R2)
Hindpaw withdrawal latency


Red cell and platelet transfusions in neonates: a population-based study.

Abstract:
OBJECTIVES
This study aimed to describe the use of red cells, platelets and exchange transfusions among all neonates in a population cohort, to examine trends in transfusion over time and to determine transfusion rates in at-risk neonates.

DESIGN
Linked population-based birth and hospital data from New South Wales (NSW), Australia, were used to determine rates of blood product transfusion in the first 28 days of life. The study included all live births ≥23 weeks' gestation in NSW between 2001 and 2011.

RESULTS
Between 2001 and 2011, 5326 of 989 491 live born neonates received a red cell, platelet or exchange transfusion (5.4/1000 births). Transfusion rates were 4.8 per 1000 for red cells, 1.3 per 1000 for platelets and 0.3 per 1000 for exchange transfusion. Overall transfusion rate remained constant from 2001 to 2011 (p=0.27). Among transfused neonates, 60% were <32 weeks' gestation (n=3210, 331/1000 births), 40% were ≥32 weeks' gestation (n= 2116, 2/1000 births) and 7% received transfusions in a hospital without a neonatal intensive care unit (NICU). Factors other than prematurity associated with higher transfusion rates were prior in utero transfusion (631/1000), congenital anomaly requiring surgery (440/1000) and haemolytic disorder (106/1000).

CONCLUSIONS
In this population-based study, preterm neonates had a higher rate of transfusion than term neonates; however, 40% of those who received a transfusion were born ≥32 weeks' gestation and 7% were transfused in hospitals without an NICU. These findings need to be considered by transfusion services and personnel developing neonatal transfusion guidelines.

Bowen|Jennifer R|JR|
Patterson|Jillian A|JA|
Roberts|Christine L|CL|
Isbister|James P|JP|
Irving|David O|DO|
Ford|Jane B|JB|

D005078:Exchange Transfusion, Whole Blood


Fiber-based polarization-sensitive OCT of the human retina with correction of system polarization distortions.

Abstract: In polarization-sensitive optical coherence tomography (PS-OCT) the use of single-mode fibers causes unpredictable polarization distortions which can result in increased noise levels and erroneous changes in calculated polarization parameters. In the current paper this problem is addressed by a new Jones matrix analysis method that measures and corrects system polarization distortions as a function of wavenumber by spectral analysis of the sample surface polarization state and deeper located birefringent tissue structures. This method was implemented on a passive-component depth-multiplexed swept-source PS-OCT system at 1040 nm which was theoretically modeled using Jones matrix calculus. High-resolution B-scan images are presented of the double-pass phase retardation, diattenuation, and relative optic axis orientation to show the benefits of the new analysis method for in vivo imaging of the human retina. The correction of system polarization distortions yielded reduced phase retardation noise, and better estimates of the diattenuation and the relative optic axis orientation in weakly birefringent tissues. The clinical potential of the system is shown by en face visualization of the phase retardation and optic axis orientation of the retinal nerve fiber layer in a healthy volunteer and a glaucoma patient with nerve fiber loss.

Braaf|Boy|B|
Vermeer|Koenraad A|KA|
de Groot|Mattijs|M|
Vienola|Kari V|KV|
de Boer|Johannes F|JF|

(170.3880) Medical and biological imaging


Of Mice and Women: A Laparoscopic Mouse Model for Endometriosis.

Abstract:
STUDY OBJECTIVE
To demonstrate how a novel laparoscopic approach allows the development of a mouse model for endometriosis after seeding menstrual endometrium from donor mice into the abdominal cavity of syngeneic recipient mice.

DESIGN
A step-by-step video description of the techniques used to adapt the estrous cycle of mice towards a menstrual cycle and to subsequently induce endometriosis via laparoscopic seeding of menstrual endometrium.

SETTING
University research institute.

ETHICS
All animal experiments were ethically approved by KU Leuven, Belgium (ethical approval number: P031/2013).

INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS
Oophorectomized female C57BL/6JRj mice received a series of estrogen injections. Next, a progesterone pellet was administered, together with a second series of estrogen injections. In addition, decidualization of the endometrium was induced with an intrauterine sesame oil stimulus. Four days later the progesterone pellet was removed and menstruation started [1]. Five hours after the progesterone pellet was removal the uterus was harvested, and the menstrual endometrium was dissected and seeded into the abdominal cavity of syngeneic recipient mice to induce endometriosis [2] using a laparoscopic approach [3]. Uterus and lesions were removed from the recipient mice 1 week after induction, and tissues were immunohistochemically stained for H&E, vimentin, and cytokeratin.

CONCLUSION
In this video we show a novel methodology to induce endometriosis in mice using laparoscopic inoculation of syngeneic menstrual endometrium, mimicking Sampson's theory of retrograde menstruation [4]. Compared with currently available rodent models, our model offers a less invasive and more physiologic way for fundamental and preclinical endometriosis research, with a high endometriosis incidence and lesion take rate.

Peterse|Daniëlle|D|
Binda|M Mercedes|MM|
O|Dorien F|DF|
Vanhie|Arne|A|
Fassbender|Amelie|A|
Vriens|Joris|J|
D'Hooghe|Thomas M|TM|

Endometrium Estrogen Progesterone Decidualization Menstruation


The role of inducible costimulatory molecular ligand (ICOSL) in children with neutrophilic asthma.

Abstract:
Background
It has been shown that certain severe and refractory asthma cases are caused by neutrophil and not eosinophil infiltration. Inducible costimulatory molecular ligand (ICOSL) expression is closely associated with tumor and autoimmune diseases, yet a limited amount of data has been published regarding the significance of ICOSL in children with neutrophilic asthma. The present study aimed to explore the clinical significance of abnormal expression of ICOSL in peripheral blood and bronchoalveolar lavage fluid (BALF) samples of children with neutrophilic asthma.

Methods
Selected children from the Children's Hospital of Soochow University who met the diagnostic criteria of asthma and excluded patients with a pathogen-positive etiology. Children who were admitted to the hospital for foreign body inhalation in the same period acted as the control group. Children with more than 50% of neutrophils in BALF samples were assigned to the neutrophilic asthma group (NA group), and the remaining subjects composed the asthma group (A group). The expression levels of ICOSL, IL-4, IL-17, IFN-γ, neutrophil elastase (NE), and matrix metalloproteinase-9 (MMP-9) were detected in plasma and BALF samples by enzyme-linked immunosorbent assays, in order to analyze the differences in the levels of cytokines and clinical characteristics between children with neutrophilic asthma and non-neutrophilic asthma. Moreover, the potential mechanism of ICOSL in neutrophilic asthma was explored.

Results
32 children were enrolled: 12 children in the NA group and 20 children in the A group. The mean hospitalization time of the NA group was longer than that of the A group (P<0.05). The concentration levels of ICOSL, IL-17, NE, and MMP-9 in plasma and BALF samples in the NA group were higher than those in the A group, while the levels of IFN-γ exhibited opposite. A significant correlation was found between ICOSL and IL-17 levels in plasma (r=0.753, P=0.012) and BALF (r=0.774, P=0.009) samples in the NA group.

Conclusions
Children with neutrophilic asthma were more severely affected, experiencing a considerably more difficult clinical treatment and longer hospitalization time. ICOSL may regulate the secretion of IL-17 by Th17 and increase the levels of NE and MMP-9, which are involved in the development of immune inflammation in neutrophils.

Dong|Heting|H| Wang|Ting|T| Wang|Meijuan|M| Yan|Yongdong|Y| Zhang|Xinxing|X| Gu|Wenjing|W| Ji|Wei|W| Huang|Li|L| Chen|Zhengrong|Z|


Endovascular Ischemic Stroke Models in Nonhuman Primates.

Abstract: To bridge the gap between rodent and human studies, the Stroke Therapy Academic Industry Roundtable committee suggests that nonhuman primates (NHPs) be used for preclinical, translational stroke studies. Owing to the fact that vast majority of ischemic strokes are caused by transient or permanent occlusion of a cerebral blood vessel eventually leading to brain infarction, ischemia induced by endovascular methods closely mimics thromboembolic or thrombotic cerebrovascular occlusion in patients. This review will make a thorough summary of transient or permanent occlusions of a cerebral blood vessel in NHPs using endovascular methods. Then, advantages and disadvantages, and potential applications will be analyzed for each kind of models. Additionally, we also make a further analysis based on different kinds of emboli, various occlusion sites, infract size, abnormal hemodynamics, and potential dysfunctions. Experimental models of ischemic stroke in NHPs are valuable tools to analyze specific facets of stroke in patients, especially those induced by endovascular methods.

Wu|Di|D| Chandra|Ankush|A| Chen|Jian|J| Ding|Yuchuan|Y| Ji|Xunming|X|

D020244:Infarction, Middle Cerebral Artery

Ischemic stroke
nonhuman primate
animal model
prognosis
thrombolysis


Nonapeptides mediate trade-offs in parental care strategy.

Abstract: Parental care represents a suite of distinct behaviors performed by parents to maximize fitness. Dynamic shifts in parental care behaviors, such as between nest defense and direct provisioning of the offspring, are required in response to environmental variation. However, the neural mechanisms which mediate such behavioral shifts remain a mystery. The anemonefish, Amphiprion ocellaris, represents an experimentally valuable model in social neuroscience which is conducive to manipulating the environment while simultaneously measuring parental care. The goal of this study was to determine the extent to which arginine vasotocin (AVT) and isotocin (IT) signaling are necessary for males to shift between direct egg care and aggressive nest defense in the presence of intruders, Domino damselfish (Dascyllus trimaculatus). The IT receptor antagonist desGly-NH2-d(CH2)5[D-Tyr2,Thr4]OVT, significantly reduced direct egg care, while at the same time increased levels of aggressive nest defense relative to vehicle. Conversely, blockade of AVT using the antagonist d(CH2)5[Tyr(Me)2]AVP, reduced aggression and tended to increase egg care. Results demonstrate that male anemonefish alter their parental strategy in response to allospecific intruders, and that IT and AVT signaling oppositely regulate parental care displays of aggression versus egg care.

Nonapeptides
Parental care
Anemonefish
Aggression
Parental strategies


Comparison of allele frequencies of Plasmodium falciparum merozoite antigens in malaria infections sampled in different years in a Kenyan population.

Abstract:
BACKGROUND
Plasmodium falciparum merozoite antigens elicit antibody responses in malaria-endemic populations, some of which are clinically protective, which is one of the reasons why merozoite antigens are the focus of malaria vaccine development efforts. Polymorphisms in several merozoite antigen-encoding genes are thought to arise as a result of selection by the human immune system.

METHODS
The allele frequency distribution of 15 merozoite antigens over a two-year period, 2007 and 2008, was examined in parasites obtained from children with uncomplicated malaria. In the same population, allele frequency changes pre- and post-anti-malarial treatment were also examined. Any gene which showed a significant shift in allele frequencies was also assessed longitudinally in asymptomatic and complicated malaria infections.

RESULTS
Fluctuating allele frequencies were identified in codons 147 and 148 of reticulocyte-binding homologue (Rh) 5, with a shift from HD to YH haplotypes over the two-year period in uncomplicated malaria infections. However, in both the asymptomatic and complicated malaria infections YH was the dominant and stable haplotype over the two-year and ten-year periods, respectively. A logistic regression analysis of all three malaria infection populations between 2007 and 2009 revealed, that the chance of being infected with the HD haplotype decreased with time from 2007 to 2009 and increased in the uncomplicated and asymptomatic infections.

CONCLUSION
Rh5 codons 147 and 148 showed heterogeneity at both an individual and population level and may be under some degree of immune selection.

Ochola-Oyier|Lynette Isabella|LI|
Okombo|John|J|
Wagatua|Njoroge|N|
Ochieng|Jacob|J|
Tetteh|Kevin K|KK|
Fegan|Greg|G|
Bejon|Philip|P|
Marsh|Kevin|K|


Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [(11)C]Flumazenil PET.

Abstract: Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABAA receptors. We were interested whether this therapeutic benefit might extend to Parkinson's disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin's mechanism of action. In this work we investigated whether the proposed activity of clarithromycin at the GABAA receptor is associated with the benzodiazepine binding site using in vivo [(11)C]flumazenil positron emission tomography (PET) in primates and ex vivo [(3)H]flumazenil autoradiography in rat brain. While the studies demonstrate that clarithromycin does not change the K d of FMZ, nor does it competitively displace FMZ, there is preliminary evidence from the primate PET imaging studies that clarithromycin delays dissociation and washout of flumazenil from the primate brain in a dose-dependent fashion. These findings would be consistent with the proposed GABAA allosteric modulator function of clarithromycin. While the results are only preliminary, further investigation of the interaction of clarithromycin with GABA receptors and/or GABAergic medications is warranted, and therapeutic applications of clarithromycin alone or in combination with flumazenil, to treat hyper-GABAergic status in PD at minimally effective doses, should also be pursued.

Scott|Peter J H|PJ|
Shao|Xia|X|
Desmond|Timothy J|TJ|
Hockley|Brian G|BG|
Sherman|Phillip|P|
Quesada|Carole A|CA|
Frey|Kirk A|KA|
Koeppe|Robert A|RA|
Kilbourn|Michael R|MR|
Bohnen|Nicolaas I|NI|

Hypersomnia
positron emission tomography
Parkinson’s disease
[11C]FMZ


Protective Effect of Topical Vitamin D3 against Photocarcinogenesis in a Murine Model.

Abstract:
BACKGROUND
Although the incidence of non-melanoma skin cancer is increasing, there are no effective practical preventive measures other than avoiding sun exposure.

OBJECTIVE
To elucidate the protective effect of topical application of biologically active vitamin D3 (calcitriol) on skin cancer development caused by exposure to ultraviolet (UV).

METHODS
Groups of hairless mice were topically treated with either calcitriol or vehicle immediately after exposure to UVB and UVA three times weekly for the initial 20 weeks, and without UV exposure in the following 6 weeks. Tumor number was counted and biopsies were done for histopathologic analysis. The changes of cyclobutane pyrimidine dimer (CPD) were evaluated 1 hour and 11 hours after short term of UV exposure and application of calcitriol. For safety evaluation, blood test and body weights were evaluated at 23rd and 25th week.

RESULTS
Total tumor count and number of tumors less than 3 mm in size tended to be fewer in calcitriol group, and tumors more than 3 mm in size showed significantly lower tumor formation rate in calcitriol group. Single application of calcitriol reduced CPD at 1 hour and 11 hours after UV exposure. Histopathologic analysis showed tumors with lower grade malignancy in calcitriol group which suggested a delay in tumor progression. However, serum levels of calcium and phosphate in calcitriol group were above normal range, and weight loss was found.

CONCLUSION
Topical calcitriol may suppress the formation and progression of UV-induced non-melanoma skin cancer by enhancing the repair mechanism of UV damage.

Kim|Ji Seok|JS|
Jung|Minyoung|M|
Yoo|Jiyeon|J|
Choi|Eung Ho|EH|
Park|Byung Cheol|BC|
Kim|Myung Hwa|MH|
Hong|Seung Phil|SP|

Calcitriol
1,25-dihydroxyvitamin D
Carcinogenesis
Skin neoplasm


Targetability of cervical cancer by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-mediated hyperthermia (HT) for patients receiving radiation therapy.

Abstract:
PURPOSE
To evaluate the targetability of late-stage cervical cancer by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-induced hyperthermia (HT) as an adjuvant to radiation therapy (RT).

METHODS
Seventy-nine cervical cancer patients (stage IIIB-IVA) who received RT with lesions visible on positron emission tomography-computed tomography (PET-CT) were retrospectively analyzed for targetability using a commercially-available HT-capable MRgHIFU system. Targetability was assessed for both primary targets and/or any metastatic lymph nodes using both posterior (supine) and anterior (prone) patient setups relative to the transducer. Thirty-four different angles of rotation along subjects' longitudinal axis were analyzed. Targetability was categorized as: (1) Targetable with/without minimal intervention; (2) Not targetable. To determine if any factors could be used for prospective screening of patients, potential associations between demographic/anatomical factors and targetability were analyzed.

RESULTS
72.15% primary tumors and 33.96% metastatic lymph nodes were targetable from at least one angle. 49.37% and 39.24% of primary tumors could be targeted with patient laying in supine and prone positions, respectively. 25°-30° rotation and 0° rotation had the highest rate of the posterior and anterior targetability, respectively. The ventral depth of the tumor and its distance to the coccyx were statistically correlated with the anterior and posterior targetability, respectively.

CONCLUSION
Most late-stage cervical cancer primaries were targetable by MRgHIFU HT requiring either no/minimal intervention. A rotation of 0° or 25°-30° relative to the transducer might benefit anterior and posterior targetability, respectively. Certain demographic/anatomic parameters might be useful in screening patients for treatability.

Zhu|Lifei|L|
Huang|Yi|Y|
Lam|Dao|D|
Gach|H Michael|HM|
Zoberi|Imran|I|
Hallahan|Dennis E|DE|
Grigsby|Perry W|PW|
Chen|Hong|H|
Altman|Michael B|MB|

D057086:High-Intensity Focused Ultrasound Ablation

D000072078:Positron Emission Tomography Computed Tomography

hyperthermia
MRgHIFU
HIFU
interventional oncology
thermal therapy
treatment planning


What is the impact of rerouting a cancer diagnosis from emergency presentation to GP referral on resource use and survival? Evidence from a population-based study.

Abstract:
BACKGROUND
Studies on alternative routes to diagnosis stimulated successful policy interventions reducing the number of emergency diagnoses and associated mortality risk. A dearth of evidence on the costs of such interventions might prevent new policies from achieving more ambitious targets.

METHODS
We conducted a retrospective cohort study on the population of colorectal (88,051), breast (90,387), prostate (96,219), and lung (97,696) cancer patients diagnosed after a GP referral or an emergency presentation and reported in the Cancer Registry of England. Resource use and survival were compared 1 year before and 5 years after diagnosis (3 years for lung), including the costs of GP referrals not converted into a positive diagnosis. Risk-adjusted statistical models were used to calculate the effect of rerouting patient' diagnoses from emergency presentation to GP referral.

RESULTS
Rerouting a cancer diagnosis results in a relatively small additional costs to the National Health System against additional years of life saved to the patient. The cost per year of life saved is £6456 in colorectal, £1057 in breast, -£662 in prostate (savings), and £819 in lung cancer. Reducing the overall prevalence of emergency presentations to the level achieved by the 20% of Clinical Commissioning Groups with the lowest prevalence would result in £11,481,948 against 1863 years of life saved for Colorectal, £847,750 against 889 years for breast, -£943,434 (cost savings) against 1195 years for prostate, and £609,938 against 1011 years for lung cancer.

CONCLUSION
Redirecting diagnoses from emergency presentation to GP referral appears an achievable target that can produce large benefits to patients against modest additional costs to the National Health System.

Laudicella|Mauro|M|0000-0001-5322-4452
Walsh|Brendan|B|
Burns|Elaine|E|
Li Donni|Paolo|P|
Smith|Peter C|PC|

D004632:Emergency Medical Services
D058005:General Practitioners
D017048:Health Care Costs
D006295:Health Resources
D006801:Humans
D009369:Neoplasms
D011159:Population Surveillance
D011379:Prognosis
D012017:Referral and Consultation

Emergency
Survival
Route to diagnosis
Early diagnosis
Hospital costs
Primary care


In-line solid state prediction during pharmaceutical hot-melt extrusion in a 12 mm twin screw extruder using Raman spectroscopy.

Abstract: The aim of this research was to use Raman spectroscopy for the in-line monitoring of the solid state of materials during pharmaceutical hot-melt extrusion in the die head of a 12 mm (development scale) twin-screw extruder during formulation development. A full factorial (mixed) design was generated to determine the influence of variations in concentration of Celecoxib (CEL) in Eudragit® E PO, three different screw configurations and varying barrel temperature profiles on the solid state, 'melt temperature' and die pressure of continuously produced extrudates in real-time. Off-line XRD and DSC analysis were used to evaluate the suitability of Raman spectroscopy for solid state predictions. First, principal component analysis (PCA) was performed on all in-line collected Raman spectra from the experimental design. The resulting PC 1 versus PC 2 scores plot showed clustering according to solid state of the extrudates, and two classes, one class where crystalline CEL is still present and a second class where no crystalline CEL was detected, were found. Then, a soft independent modelling of class analogy (SIMCA) model was developed, by modelling these two classes separately by disjoint PCA models. These two separate PCA models were then used for the classification of new produced extrudates and allowed distinction between glassy solid solutions of CEL and crystalline dispersions of CEL. All extrudates were classified similarly by Raman spectroscopy, XRD and DSC measurements, with exception of the extrudates with a 30% CEL concentration extruded at 130 °C. The Raman spectra of these experiments showed bands which were sharper than the amorphous spectra, but broader than the crystalline spectra, indicating the presence of CEL that has dissolved into the matrix and CEL in its crystalline state. XRD and DSC measurements did not detect this. Modifications in the screw configuration did not affect the solid state and did not have an effect on the solid state prediction of new produced extrudates. Secondly, the influence of variations in die pressure on the Raman spectra was examined. The applied drug concentration, processing temperature and feeder performance influence the die pressure, which is reflected in the Raman spectra as a change in spectral intensity. When applying PCA on the raw spectra from the experimental design, the first principal component describes the influence of die pressure on the spectra, which was seen as a decrease in Raman intensity of the whole spectrum when the pressure in the sample increased. Clustering according to processing temperature was found, although the temperature in the die remained constant, indicating that a difference in viscosity, resulting in a changed die pressure, was detected. When the feeder was stopped, the score values of the first principal component almost simultaneously decreased, and only stabilized once the die pressure became stable. Since Raman spectra collected in the extrusion die are influenced by changes in die pressure, disturbances upstream of the extrusion process can be observed and identified in the Raman measurements.

Saerens|Lien|L|
Ghanam|Dima|D|
Raemdonck|Cedric|C|
Francois|Kjell|K|
Manz|Jürgen|J|
Krüger|Rainer|R|
Krüger|Susan|S|
Vervaet|Chris|C|
Remon|Jean Paul|JP|
De Beer|Thomas|T|

Solid state prediction
Hot-melt extrusion
Continuous production
Design of experiments
In-line Raman spectroscopy
Multivariate data analysis
PAT


Multiresponsive polymeric microstructures with encoded predetermined and self-regulated deformability.

Abstract: Dynamic functions of biological organisms often rely on arrays of actively deformable microstructures undergoing a nearly unlimited repertoire of predetermined and self-regulated reconfigurations and motions, most of which are difficult or not yet possible to achieve in synthetic systems. Here, we introduce stimuli-responsive microstructures based on liquid-crystalline elastomers (LCEs) that display a broad range of hierarchical, even mechanically unfavored deformation behaviors. By polymerizing molded prepolymer in patterned magnetic fields, we encode any desired uniform mesogen orientation into the resulting LCE microstructures, which is then read out upon heating above the nematic-isotropic transition temperature (TN-I) as a specific prescribed deformation, such as twisting, in- and out-of-plane tilting, stretching, or contraction. By further introducing light-responsive moieties, we demonstrate unique multifunctionality of the LCEs capable of three actuation modes: self-regulated bending toward the light source at T < TN-I, magnetic-field-encoded predetermined deformation at T > TN-I, and direction-dependent self-regulated motion toward the light at T > TN-I We develop approaches to create patterned arrays of microstructures with encoded multiple area-specific deformation modes and show their functions in responsive release of cargo, image concealment, and light-controlled reflectivity. We foresee that this platform can be widely applied in switchable adhesion, information encryption, autonomous antennae, energy harvesting, soft robotics, and smart buildings.

actuators
autonomous materials multifunctionality
liquid-crystal elastomers


Dynamical Strain-Driven Phase Separation in Flexible CoFe2O4/CoO Exchange Coupling System.

Abstract: Epitaxial CoFe2O4(CFO)/CoO bilayers were fabricated by pulsed laser deposition on flexible muscovite mica substrate. Samples with different CFO thicknesses were employed to study the phenomenon of exchange bias involving strongly anisotropic ferromagnet. Magnetic measurements exhibited great enhancement in the features of exchange bias. Raman and X-ray absorption spectroscopies indicated that a new phase emerged within the CFO layer because of the cation charge redistribution in CFO layer under bending, which in turn gave rise to anomalous hysteresis loops exhibited in the bent bilayers. These results provide a fundamental understanding about the mechanisms of exchange bias prevailing in these bilayers and call attention to the implementation of spintronic devices using flexible heterostructures such as the present CFO/CoO bilayers.

phase separation
flexible
exchange bias
cobalt ferrite
magnetic anisotropy


A nationwide population-based study on overall survival after meningioma surgery.

Abstract:
BACKGROUND
There are very few nationwide studies on meningioma outcome, the most common primary intracranial tumour.

METHODS
We processed the French Système National des Données de Santé (SNDS) database using an algorithm combining the type of surgical procedure and the International Classification of Diseases to retrieve all cases of meningiomas operated between 2007 and 2017. A survival analysis was performed.

RESULTS
This nationwide study found 28 773 patients of which 75 % were female. Median age at surgery was 59 years, IQR[49-68]. Cranial convexity (24.4 %) and middle skull base (21.7 %) were the most common locations. 91.3 % of the tumours were benign and 2.6 % malignant.7.5 % of the patients underwent redo surgery, 9.1 % radiotherapy (RT) and 3.2 % stereotactic radiosurgery for recurrence. Median follow-up was 5.3 years 95 % CI [5.24-5.35]. 0.64 % of the patients died within a month of surgery and 2.1 % within a year. Overall survival (OS) rates at 5 and 10 years respectively were: 92.6 %, 95 %CI[92.3, 93] and 85 %, 95 %CI[84.3, 85.8]. In the multivariable analysis, female gender (HR = 0.64, 95 %CI[0.59, 0.69], p < 0.001), older age at surgery (HR= 1.07, 95 %CI[1.06, 1.07], p < 0.001), type 2 neurofibromatosis (HR= 3.89, 95 %CI[2.62, 5.76], p < 0.001), parasagittal (HR= 1.2, 95 %CI[1.05, 1.37], p = 0.00944) or falx cerebri location (HR= 1.18, 95 %CI[1.01, 1.37], p = 0.0343), atypical or (HR= 1.34, 95 %CI[1.15, 1.56], p < 0.001) malignant histology (HR= 2.34, 95 %CI[2.01, 2.73], p < 0.001), redo surgery (HR=1.81, 95 %CI[1.6, 2.04], p < 0.001), progressing meningioma (HR=1.34, 95 %CI[1.05, 1.71], p = 0.0175) or RT for recurrence (HR=2.17, 95 %CI[1.95, 2.4], p < 0.001) were established as independent prognostic factors of the OS.

CONCLUSION
In this registry-based study, OS after meningioma surgery is good and is even better in women, younger adults and those with convexity and benign tumour. We also found that NF2 patients and those required redo surgery or additional treatment for uncontrolled meningioma disease are further at risk of death.

Champeaux-Depond|Charles|C| Weller|Joconde|J| Froelich|Sebastien|S| Resche-Rigon|Matthieu|M|

Survival Meningioma Outcome SNDS Database Predictors


Solid-State Characterization and Biological Activity of Betulonic Acid Derivatives.

Abstract: Betulonic acid belongs to the pentacyclic triterpenic derivative class and can be obtained through the selective oxidation of betulin. In this study we set obtaining several functionalized derivatives of this compound by its condensation with several amino compounds such as aminoguanidine, hydroxylamine, n-butylamine and thiosemicarbazide as our goal. The functionalization of the parent compound led to several molecules with antiproliferative potential, the most promising being 3-2-carbamothioylhydrazonolup-20(29)-en-28-oic acid.

Ledeţi|Ionuţ|I| Avram|Ştefana|Ş| Bercean|Vasile|V| Vlase|Gabriela|G| Vlase|Titus|T| Ledeţi|Adriana|A| Zupko|Istvan|I| Mioc|Marius|M| Şuta|Lenuţa-Maria|LM| Şoica|Codruţa|C| Dehelean|Cristina|C|

D017550:Spectroscopy, Fourier Transform Infrared

biological activity
betulonic acid derivatives
triterpene
MTT assay
synthesis
thermal analysis


Histone H2AX and the small RNA pathway modulate both non-homologous end-joining and homologous recombination in plants.

Abstract: Using a zinc finger nuclease (ZFN) that creates a site-specific DNA double-strand break (DSB) at the endogenous ADH1 locus, we provide genetic evidence that histone H2AX and DSB-induced small RNAs modulate DNA repair by both non-homologous end-joining (NHEJ) and homologous recombination (HR) in the model plant Arabidopsis thaliana.

Qi|Yiping|Y|
Zhang|Yong|Y|
Baller|Joshua A|JA|
Voytas|Daniel F|DF|

H2AX
Small RNA
Zinc finger nuclease (ZFN)
Arabidopsis thaliana
DNA double-strand break (DSB) repair