Direct crosstalk between cancer and osteoblast lineage cells fuels metastatic growth in bone via auto-amplification of IL-6 and RANKL signaling pathways.

Abstract: The bone microenvironment and its modification by cancer and host cell interactions is a key driver of skeletal metastatic growth. Interleukin-6 (IL-6) stimulates receptor activator of NF-κB ligand (RANKL) expression in bone cells, and serum IL-6 levels are associated with poor clinical outcomes in cancer patients. We investigated the effects of RANKL on cancer cells and the role of tumor-derived IL-6 within the bone microenvironment. Using human breast cancer cell lines to induce tumors in the bone of immune-deficient mice, we first determined whether RANKL released by cells of the osteoblast lineage directly promotes IL-6 expression by cancer cells in vitro and in vivo. We then disrupted of IL-6 signaling in vivo either via knockdown of IL-6 in tumor cells or through treatment with specific anti-human or anti-mouse IL-6 receptor antibodies to investigate the tumor effect. Finally, we tested the effect of RANK knockdown in cancer cells on cancer growth. We demonstrate that osteoblast lineage-derived RANKL upregulates secretion of IL-6 by breast cancers in vivo and in vitro. IL-6, in turn, induces expression of RANK by cancer cells, which sensitizes the tumor to RANKL and significantly enhances cancer IL-6 release. Disruption in vivo of this auto-amplifying crosstalk by knockdown of IL-6 or RANK in cancer cells, or via treatment with anti-IL-6 receptor antibodies, significantly reduces tumor growth in bone but not in soft tissues. RANKL and IL-6 mediate direct paracrine-autocrine signaling between cells of the osteoblast lineage and cancer cells, significantly enhancing the growth of metastatic breast cancers within bone.

Zheng|Yu|Y|
Chow|Shu-Oi|SO|
Boernert|Katja|K|
Basel|Dennis|D|
Mikuscheva|Anastasia|A|
Kim|Sarah|S|
Fong-Yee|Colette|C|
Trivedi|Trupti|T|
Buttgereit|Frank|F|
Sutherland|Robert L|RL|
Dunstan|Colin R|CR|
Zhou|Hong|H|
Seibel|Markus J|MJ|

D053246:Receptor Activator of Nuclear Factor-kappa B

D023041:Xenograft Model Antitumor Assays

OSTEOBLAST
RANKL
INTERLEUKIN-6
BREAST CANCER
BONE METASTASIS


Education for prevention of STIs to young people (2021 version) Standardized slides in youth education for the prevention of sexually transmitted infections-for high school students and for junior high school students.

Abstract: The best strategy for preventing the spread of sexually transmitted infections (STIs) is by educating the young. It is considered effective to provide such education by the age of 15-16 years (at the beginning of high school age), ideally before teenagers become sexually active. This guideline describes the framework and discusses the educational points for standard educational slides created by the Japanese Society for Sexually Transmitted Infections and the Japan Society of Adolescentology. A discussion of sexuality is also a discussion of human life, and the prevention of STIs is an important part of sex education. The Japanese Society for Sexually Transmitted Infections has a certification system for doctors and experts, and considers prevention education to be one of its key programs. In this revised version additional slides which are more easy to understand for junior high school students are shown.

D007722:Health Knowledge, Attitudes, Practice

Standard slides
Sexually transmitted infections
Teenagers
Certification system
Prevention education


Diabetic ketoacidosis: A consensus statement of the Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology and Pediatric Diabetoloy (SIEDP).

Abstract:
BACKGROUND AND AIM
Diabetic ketoacidosis (DKA) is a serious medical emergency once considered typical of type 1 diabetes (T1DM), but now reported to occur in type 2 and GDM patients as well. DKA can cause severe complications and even prove fatal. The aim of our study was to review recent international and national guidelines on diagnosis, clinical presentation and treatment of diabetic ketoacidosis, to provide practical clinical recommendations.

METHODS AND RESULTS
Electronic databases (MEDLINE (via PUB Med), Scopus, Cochrane library were searched for relevant literature. Most international and national guidelines indicate the same accurate flow chart to diagnose, to evaluate from clinical and laboratory point of view, and treat diabetic ketoacidosis.

CONCLUSION
Prompt diagnosis, rapid execution of laboratory analysis and correct treatment are imperative to reduce the mortality related to diabetic ketoacidosis. These recommendations are designed to help healthcare professionals reduce the frequency and burden of DKA.

Lapolla|Annunziata|A|
Amaro|Flavia|F|
Bruttomesso|Daniela|D|
Di Bartolo|Paolo|P|
Grassi|Giorgio|G|
Maffeis|Claudio|C|
Purrello|Francesco|F|
Tumini|Stefano|S|

Diabetic ketoacidosis
Euglycemic ketoacidosis
Ketoacidosis complications
Ketoacidosis management


Protein crosslinking improves the thermal resistance of plastocyanin immobilized on a modified gold electrode.

Abstract: Increasing the thermal stability of immobilized proteins is a motivating goal for improving the performance of electrochemical biodevices. In this work, we propose the immobilization of crosslinked plastocyanin from the thermophilic cyanobacterium Phormidium laminosum by simultaneous incubation of a mixture of plastocyanin and the coupling reagents. The thermal stability of the so built covalently immobilized protein films has been assessed by cyclic voltammetry in the 0-90 °C temperature range and has been compared to that of physisorbed films. It is shown that the protein loss along a thermal cycle is significantly reduced in the case of the crosslinked films, whose redox properties remain unaltered along a cyclic heating-cooling thermal scan, and can withstand the contact with 70 °C solutions for four hours. Comparison of thermal unfolding curves obtained by circular dichroism spectroscopy of both free and crosslinked protein confirms the improved thermic resistance of the crosslinked plastocyanin. Notably, the electron transfer thermodynamics of physisorbed and crosslinked plastocyanin films are quite similar, suggesting that the formation of intra- and inter-protein amide bonds do not affect the integrity and functionality of the copper redox centers. UV-Vis absorption and circular dichroism measurements corroborate that protein crosslinking does not alter the coordination geometry of the metal center.

Olloqui-Sariego|José Luis|JL|
Díaz-Quintana|Antonio|A|
De la Rosa|Miguel Ángel|MÁ|
Calvente|Juan José|JJ|
Márquez|Inmaculada|I|
Díaz-Moreno|Irene|I|
Andreu|Rafael|R|

Covalent crosslinking
Multilayered protein film
Protein thermostability
Temperature variable voltammetry
Thermophilic plastocyanin


Metazoan tsRNAs: Biogenesis, Evolution and Regulatory Functions.

Abstract: Transfer RNA-derived small RNAs (tsRNAs) are an emerging class of regulatory non-coding RNAs that play important roles in post-transcriptional regulation across a variety of biological processes. Here, we review the recent advances in tsRNA biogenesis and regulatory functions from the perspectives of functional and evolutionary genomics, with a focus on the tsRNA biology of Drosophila. We first summarize our current understanding of the biogenesis mechanisms of different categories of tsRNAs that are generated under physiological or stressed conditions. Next, we review the conservation patterns of tsRNAs in all domains of life, with an emphasis on the conservation of tsRNAs between two Drosophila species. Then, we elaborate the currently known regulatory functions of tsRNAs in mRNA translation that are independent of, or dependent on, Argonaute (AGO) proteins. We also highlight some issues related to the fundamental biology of tsRNAs that deserve further study.

tsRNAs
Argonaute
stress response
tRNA-derived small RNAs
translational regulation


Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis.

Abstract: An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% conﬁdence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for paediatric-onset and 6.3 (4.9-8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9-4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.

Amato|Maria Pia|MP|
Fonderico|Mattia|M|
Portaccio|Emilio|E|
Pastò|Luisa|L|
Razzolini|Lorenzo|L|
Prestipino|Elio|E|
Bellinvia|Angelo|A|
Tudisco|Laura|L|
Fratangelo|Roberto|R|
Comi|Giancarlo|G|
Patti|Francesco|F|
De Luca|Giovanna|G|
Brescia Morra|Vincenzo|V|
Cocco|Eleonora|E|
Pozzilli|Carlo|C|
Sola|Patrizia|P|
Bergamaschi|Roberto|R|
Salemi|Giuseppe|G|
Inglese|Matilde|M|
Millefiorini|Enrico|E|
Galgani|Simonetta|S|
Zaffaroni|Mauro|M|
Ghezzi|Angelo|A|
Salvetti|Marco|M|
Lus|Giacomo|G|
Florio|Ciro|C|
Totaro|Rocco|R|
Granella|Franco|F|
Vianello|Marika|M|
Gatto|Maurizia|M|
Di Battista|Giancarlo|G|
Aguglia|Umberto|U|
Logullo|Francesco Ottavio|FO|
Simone|Marta|M|
Lucisano|Giuseppe|G|
Iaffaldano|Pietro|P|
Trojano|Maria|M|

clinical trials
demyelination
clinically isolated syndrome
multiple sclerosis epidemiology
neuroinflammation


Long-Term Outcomes of Radial Osteotomy for the Treatment of Kienböck Disease.

Abstract: Background Kienböck disease is an aseptic necrosis of the lunate of unknown etiology, prevalent in young adults. Treatment aims to lower forces on the lunate, decrease pain and improve function. We conducted a retrospective evaluation of the 10-year clinical and radiological outcomes of radial osteotomy as a treatment for Kienböck disease. Materials and Methods We analyzed pain, grip strength, wrist range of motion (ROM), radiological carpal geometry, and staging of osteoarthritic changes over a 10-year period, postosteotomy, for 18 patients. The Mayo wrist score was used as an overall measure of outcome. Technique Outcomes for two types of osteotomies were included, a step-cut osteotomy with fixed screws and an updated technique of two linear transverse osteotomies with volar locking plates. For cases with negative ulnar variance, resection of the radius was included to obtain a final ulnar variance of -1 to 0 mm. For positive ulnar variance, the goal was to obtain a correction of radial inclination of 10 to 15 degrees. Results Improvements in pain, ROM, and grip strength were maintained over the 10-year follow-up, without radiological improvement in geometry (carpal height ratio and Stahl index). Mild osteoarthritic changes were identified in 33% of patients, with no effect on clinical results. Degree of cartilage damage determined postoperative grip strength improvement. The Mayo wrist score at the final follow-up was excellent in one patient, good in nine, and fair in eight. Conclusions Radial osteotomy provides reasonable and long-term clinical benefits. Preoperative arthroscopic evaluation of cartilage damage can inform treatment decisions.

long-term outcome
radial osteotomy
Kienböck disease
lunate
arthroscopy


Detection of miR-122 by fluorescence real-time PCR in blood from patients with chronic hepatitis B and C infections.

Abstract:
BACKGROUND
This study aims to determine whether relative miR-122 levels in peripheral blood are correlated with chronic hepatitis B (CHB) and chronic hepatitis C (CHC) virus infection and viral replication to determine whether miR-122 can be a new marker for liver injury.

METHODS
MicroRNA (miRNA) was extracted from the peripheral blood of 20 CHB patients, 20 CHC patients, and 20 healthy controls. The levels of miR-122 were determined using fluorescence real-time reverse transcription PCR. Then, the associations of miR-122 with CHB and CHC were analyzed, and its correlation with other markers of liver function and viral replication were determined.

RESULTS
The expression level of miR-122 in patients with CHB was significantly higher when compared to subjects in the control group (P = 0.007) or CHC patients (P = 0.005). Furthermore, the miR-122 level in patients with CHC was somewhat higher when compared to healthy controls (66% higher), but the difference was not statistically significant (P = 0.229). MiR-122 levels were significantly correlated with ALT (correlation coefficient [R] = 0.7, P < 0.001), AST (R = 0.71, P < 0.001), and HBV NA (R = 0.9, P < 0.001). The regression analysis indicated that the AUC of miR-122 levels in the diagnosis of CHB was 0.87, with a sensitivity of 0.8 and a specificity of 0.8.

CONCLUSION
MiR-122 can be used to distinguish healthy persons and patients with CHB infection with high sensitivity and specificity. These present findings presented that the complex and context-specific associations of miR-122 with liver diseases, suggesting that this may be a promising marker for liver injury.

Ma|Zhen-Hua|ZH| Sun|Cheng-Xue|CX| Shi|Hong|H| Fan|Jian-Hua|JH| Song|Yu-Guo|YG| Cong|Pei-Jun|PJ| Kong|Xiang-Min|XM| Hao|Da-Lin|DL|

D060888:Real-Time Polymerase Chain Reaction

miR-122
Fluorescence real-time PCR
Chronic hepatitis B
Chronic hepatitis C


Promoter-Targeted Small Activating RNAs Alter Nucleosome Positioning.

Abstract: Epigenetic modification of target promoters has been identified as a mechanism underlying RNA activation (RNAa) induced by promoter-targeting small activating RNAs (saRNAs), but it is unclear how the chromosomal environment influences gene expression. In a study of the activation of the OCT4, SOX2, and NANOG genes by saRNAs, we found that saRNA targeting induced nucleosome-depleted region (NDRs) and the accumulation of RNA polymerase II (RNAPII) near or at the saRNA target sites. Additionally, promoters containing certain cis-regulatory elements such as the TATA box and CpG islands (CGIs) appeared to be more susceptible to RNAa. These results provide novel insight into the mechanism underlying RNAa in that saRNAs induce NDRs in the target promoter to remove nucleosome barriers between RNAPII-binding sites and the transcription start site (TSS), resulting in rapid assembly of transcription preinitiation complex (PIC) and subsequent activation of transcription.

D042002:Chromatin Assembly and Disassembly

Nucleosome
RNAa
saRNA
Nucleosome barrier
Open chromatin structure


Conflicts Experienced by Caregivers of Older Adults With the Health-Care System.

Abstract:
Background
Family caregivers of older adults frequently navigate the health system for their loved ones. As older adults experience more medical issues, the interactions between caregivers and the health system can be fraught with conflicts.

Objective
To characterize the conflicts that caregivers of older adults experience with the health-care system.

Methods
A cross-sectional national online survey with open-ended questions was conducted among family caregivers ascertaining experiences with the health-care system. Qualitative thematic analysis was completed using constant comparative analysis and review by a third author.

Results
Over a 2-month period, 97 caregivers completed the survey. Common themes where caregivers experienced conflicts were Difficulty With Accessing/Communicating With Providers, Delivery of Emergency Care, Disjointed Transitional Care, Unaddressed Clinical Concerns, and Financial. Caregivers reported needing to act as patient advocates in the conflicts with the health-care system.

Conclusion
Understanding the conflicts that family caregivers encounter with the health system provides potential targets for future interventions to combat the challenges faced by caregivers of older adults and ultimately improve delivery of geriatric care.

conflicts
caregivers
older adults
health care


Teaching Tradition: Diverse Perspectives on the Pilot Urban American Indian Traditional Spirituality Program.

Abstract: Many urban American Indian community members lack access to knowledgeable participation in indigenous spiritual practices. And yet, these sacred traditional activities remain vitally important to their reservation-based kin. In response, our research team partnered with an urban American Indian health center in Detroit for purposes of developing a structured program to facilitate more ready access to participation in indigenous spiritual knowledge and practices centered on the sweat lodge ceremony. Following years of preparation and consultation, we implemented a pilot version of the Urban American Indian Traditional Spirituality Program in the spring of 2016 for 10 urban AI community participants. Drawing on six first-person accounts about this program, we reflect on its success as a function of participant meaningfulness, staff support, mitigated sensitivities, and program structure. We believe that these observations will enable other community psychologists to undertake similar program development in service to innovative and beneficial impacts on behalf of their community partners.

Gone|Joseph P|JP|
Blumstein|Katherine P|KP|
Dominic|David|D|
Fox|Nickole|N|
Jacobs|Joan|J|
Lynn|Rebecca S|RS|
Martinez|Michelle|M|
Tuomi|Ashley|A|

D003466:Cultural Characteristics
D006801:Humans
D007198:Indians, North American
D007398:Interpersonal Relations
D008519:Medicine, Traditional
D008824:Michigan
D010865:Pilot Projects
D016730:Program Development
D012069:Religion and Psychology
D012933:Social Identification
D012944:Social Support
D029181:Spirituality
D014505:Urban Population

American Indians
Traditional spirituality
Sweat lodge ceremony
Program development
Community psychology


Advances in Perfusion Techniques: Minimally Invasive Procedures.

Abstract: There is a growing demand from patients and referring physicians for minimally invasive cardiac surgery. Minimally invasive cardiac procedures are technically unique from conventional cardiac procedures and require a thorough understanding of the surgical, anesthetic, and perfusion strategies. Strategies include routine use of augmented venous drainage, alternative arterial and venous cannulation sites, and special cannulas designed for minimally invasive procedures. The following review describes the strategies and safety systems that should be considered when performing minimally invasive cardiac surgery.

D019060:Minimally Invasive Surgical Procedures

cardiac surgery
aortic valve replacement
cardiopulmonary bypass
minimally invasive surgery
mitral valve


Knowing Ourselves Together: The Cultural Origins of Metacognition.

Abstract: Metacognition - the ability to represent, monitor and control ongoing cognitive processes - helps us perform many tasks, both when acting alone and when working with others. While metacognition is adaptive, and found in other animals, we should not assume that all human forms of metacognition are gene-based adaptations. Instead, some forms may have a social origin, including the discrimination, interpretation, and broadcasting of metacognitive representations. There is evidence that each of these abilities depends on cultural learning and therefore that cultural selection might shape human metacognition. The cultural origins hypothesis is a plausible and testable alternative that directs us towards a substantial new programme of research.

Heyes|Cecilia|C|
Bang|Dan|D|
Shea|Nicholas|N|
Frith|Christopher D|CD|
Fleming|Stephen M|SM|

metacognition
cultural learning
confidence
cultural evolution


Prospective comparison of conventional radiography, low-dose computed tomography and magnetic resonance imaging in monoclonal gammopathies.

Abstract:
AIMS
We carried out a prospective study in order to identify the best imaging approach for patients with newly diagnosed multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).

METHODS
We assessed the extent of myeloma bone disease (MBD) in 112 individuals - 84 patients with MM and 28 individuals with MGUS. For the detection of osteolytic involvement we used whole-body magnetic resonance imaging (WB-MRI), low-dose computed tomography (LD-CT) and conventional radiography (CR). Each method assessed the presence of osteolytic involvement, compressive fractures and extramedullary involvement in the following regions: skull, spine and chest, pelvis and humerus and femur. We compared the difference in the number and extent of osteolytic involvement, especially the findings in CR negative patients.

RESULTS
Conventional radiography showed no superiority in any of the evaluated regions, and failed in the detection of extramedullary massess and spine involvement. WB-MRI was best at imaging the spine including extramedullary involvement, however, detection of osteolytic lesions of the skull was limited in comparison with both CR and LD-CT. Both WB-MRI and LD-CT were comparable in imaging of lesions of pelvis, humerus, femur and the presence of extramedullary masses. LD-CT showed superiority in detection of skull lesions but lower sensitivity in spine compared to WB-MRI.

CONCLUSIONS
Our results confirm that relying solely on CR in the diagnostics of MM is insufficient. We suggest that the most suitable method for primary assessment of osteolytic involvement in monoclonal gammopathies should include either whole-body MRI together with CR of the skull or, with an equivalent sensitivity, whole body LD-CT.

Minarik|Jiri|J| Krhovska|Petra|P| Hrbek|Jan|J| Pika|Tomas|T| Bacovsky|Jaroslav|J| Herman|Miroslav|M| Scudla|Vlastimil|V|


Gastrointestinal Digestion Model Assessment of Peptide Diversity and Microbial Fermentation Products of Collagen Hydrolysates.

Abstract: Osteoarthritis (OA), the most common form of arthritis, is associated with metabolic diseases and gut microbiome dysbiosis. OA patients often take supplements of collagen hydrolysates (CHs) with a high peptide content. Following digestion, some peptides escape absorption to induce prebiotic effects via their colonic fermentation to generate short-chain fatty acids (SCFAs), branched-chain fatty acids (BCFAs) and colonic gases (NH4 and H2S). The capacity of CHs to generate microbial metabolites is unknown. Proteomic analysis of two CHs (CH-GL and CH-OPT) demonstrated different native peptide profiles with increased peptide diversity after in vitro gastric and small intestinal digestion. Subsequent 24 h fermentation of the CH digests in a dynamic gastrointestinal (GI) digestion model containing human fecal matter showed that CH-OPT increased (p < 0.05) H2S, SCFAs (propionic, butyric and valeric acids), BCFAs, and decreased NH4 in the ascending colon reactor with no major changes seen with CH-GL. No major effects were observed in the transverse and descending vessels for either CH. These findings signify that CHs can induce prebiotic effects in the ascending colon that are CH dependent. More studies are needed to determine the physiological significance of CH-derived colonic metabolites, in view of emerging evidence connecting the gut to OA and metabolic diseases.

collagen hydrolysate
osteoarthritis
short-chain fatty acids
branched-chain fatty acids
ammonium
antioxidant
hydrogen sulfide
in vitro digestion
nutraceutical
peptide sequencing


A Hippo-like Signaling Pathway Controls Tracheal Morphogenesis in Drosophila melanogaster.

Abstract: Hippo-like pathways are ancient signaling modules first identified in yeasts. The best-defined metazoan module forms the core of the Hippo pathway, which regulates organ size and cell fate. Hippo-like kinase modules consist of a Sterile 20-like kinase, an NDR kinase, and non-catalytic protein scaffolds. In the Hippo pathway, the upstream kinase Hippo can be activated by another kinase, Tao-1. Here, we delineate a related Hippo-like signaling module that Tao-1 regulates to control tracheal morphogenesis in Drosophila melanogaster. Tao-1 activates the Sterile 20-like kinase GckIII by phosphorylating its activation loop, a mode of regulation that is conserved in humans. Tao-1 and GckIII act upstream of the NDR kinase Tricornered to ensure proper tube formation in trachea. Our study reveals that Tao-1 activates two related kinase modules to control both growth and morphogenesis. The Hippo-like signaling pathway we have delineated has a potential role in the human vascular disease cerebral cavernous malformation.

Poon|Carole L C|CLC|
Liu|Weijie|W|
Song|Yanjun|Y|
Gomez|Marta|M|
Kulaberoglu|Yavuz|Y|
Zhang|Xiaomeng|X|
Xu|Wenjian|W|
Veraksa|Alexey|A|
Hergovich|Alexander|A|
Ghabrial|Amin|A|
Harvey|Kieran F|KF|

signaling
morphogenesis
Hippo-like pathways
kinases
trachea
tubular networks


Pharmacovigilance in developing countries (part I): importance and challenges.

Abstract: The thalidomide disaster was the significant historical event that acted as a catalyst for pharmacovigilance activity. Following this event developed countries initiated drug monitoring systems that evolved and now extend their scope to broader drug-related safety issues; however, this was not the case in developing countries. Pharmacovigilance is still a relatively new concept with low priority in developing countries although various issues are raising concerns that magnify the need for systems to monitor post marketing drug safety in these countries. This article analyzes the barriers to introducing robust pharmacovigilance systems in developing countries.

D016907:Adverse Drug Reaction Reporting Systems

D064420:Drug-Related Side Effects and Adverse Reactions

Pharmacovigilance
Developing countries
Drug safety
Adverse drug reactions
Post marketing monitoring


Detection and Prioritization of Developmentally Neurotoxic and/or Neurotoxic Compounds Using Zebrafish.

Abstract: The standard methods for toxicity testing using rodent models cannot keep pace with the increasing number of chemicals in our environment due to time and resource limitations. Hence, there is an unmet need for fast, sensitive, and cost-effective alternate models to reliably predict toxicity. As part of Tox21 Phase III's effort, a 90-compound library was created and made available to researchers to screen for neurotoxicants using novel technology and models. The chemical library was evaluated in zebrafish in a dose-range finding test for embryo-toxicity (ie, mortality or morphological alterations induced by each chemical). In addition, embryos exposed to the lowest effect level and nonobservable effect level were used to measure the internal concentration of the chemicals within the embryos by bioanalysis. Finally, considering the lowest effect level as the highest testing concentration, a functional assay was performed based on locomotor activity alteration in response to light-dark changes. The quality control chemicals included in the library, ie, negative controls and replicated chemicals, indicate that the assays performed were reliable. The use of analytical chemistry pointed out the importance of measuring chemical concentration inside embryos, and in particular, in the case of negative chemicals to avoid false negative classification. Overall, the proposed approach presented a good sensitivity and supports the inclusion of zebrafish assays as a reliable, relevant, and efficient screening tool to identify, prioritize, and evaluate chemical toxicity.

Quevedo|Celia|C|
Behl|Mamta|M|
Ryan|Kristen|K|
Paules|Richard S|RS|
Alday|Aintzane|A|
Muriana|Arantza|A|
Alzualde|Ainhoa|A|

prioritization
neurotoxicity
zebrafish
internal concentration
malformations
toxicity screening


Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy.

Abstract: Mutations in valosin-containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in 90%, 42% and 30% of the patients, respectively, beginning at an average age of 43, 41, and 56 years, respectively. Approximately 9% of patients with VCP mutations had an amyotrophic lateral sclerosis (ALS) phenotype, 4% had been diagnosed with Parkinson's disease (PD), and 2% had been diagnosed with Alzheimer's disease (AD). Large interfamilial and intrafamilial variation made establishing correlations difficult. We did not find a correlation between the mutation type and the incidence of any of the clinical features associated with VCP disease, except for the absence of PDB with the R159C mutation in our cohort and R159C having a later age of onset of myopathy compared with other molecular subtypes.

D020022:Genetic Predisposition to Disease

genotype-phenotype
valosin-containing protein
VCP
IBMPFD
multisystem proteinopathy (MSP)


Probing the effectiveness of spectroscopic reporter unnatural amino acids: a structural study.

Abstract: The X-ray crystal structures of superfolder green fluorescent protein (sfGFP) containing the spectroscopic reporter unnatural amino acids (UAAs) 4-cyano-L-phenylalanine (pCNF) or 4-ethynyl-L-phenylalanine (pCCF) at two unique sites in the protein have been determined. These UAAs were genetically incorporated into sfGFP in a solvent-exposed loop region and/or a partially buried site on the β-barrel of the protein. The crystal structures containing the UAAs at these two sites permit the structural implications of UAA incorporation for the native protein structure to be assessed with high resolution and permit a direct correlation between the structure and spectroscopic data to be made. The structural implications were quantified by comparing the root-mean-square deviation (r.m.s.d.) between the crystal structure of wild-type sfGFP and the protein constructs containing either pCNF or pCCF in the local environment around the UAAs and in the overall protein structure. The results suggest that the selective placement of these spectroscopic reporter UAAs permits local protein environments to be studied in a relatively nonperturbative fashion with site-specificity.

Dippel|Andrew B|AB|
Olenginski|Gregory M|GM|
Maurici|Nicole|N|
Liskov|Melanie T|MT|
Brewer|Scott H|SH|
Phillips-Piro|Christine M|CM|


Attachment as a framework to facilitate empowerment for people with severe mental illness.

Abstract:
OBJECTIVES
Recovery and empowerment have evolved into key objectives in the treatment and care of people with severe mental illness (SMI), and interest has grown in the role of social relationships in recovery. This study is the first to explore whether attachment styles are related to levels of empowerment, and secondly, whether attachment anxiety and attachment avoidance are associated with lower empowerment levels, independently of quality and frequency of social contact.

DESIGN
We used a cross-sectional design.

METHODS
In a sample of 157 participants with SMI in outpatient care, associations between attachment (Revised Adult Attachment Scale), self-reported social functioning, and empowerment (Netherlands Empowerment List) were assessed.

RESULTS
Attachment anxiety and attachment avoidance were both associated with lower levels of empowerment. A stepwise multiple regression analysis showed that the prediction of empowerment was significantly improved by adding attachment anxiety and attachment avoidance to quality and frequency of social contact. Attachment anxiety, attachment avoidance, and quality of social contact were significant predictors; frequency of social contact was not.

CONCLUSIONS
Although our design does not allow causal conclusions, our results highlight the importance of interpersonal processes and behaviours as routes to improving empowerment for people with SMI. A promising approach might thus consist of securing attachment bonds with significant others so that the self and the other are perceived as reliable resources. Our findings also feature the importance of reciprocity and equality in social relationships. Taken together, our study emphasizes the value of social, contextualized interventions in recovery work for people with SMI.

PRACTITIONER POINTS
Working towards attachment safety in interpersonal relations may be important in recovery-oriented treatment and care for people with severe mental illness (SMI). Helping people with SMI to recognize and change how they tend to relate themselves to others may promote engagement and effectiveness of recovery-oriented treatment and care. Reciprocity and equality in social relationships as vital complements to the more one-sided nature of 'standing alongside' and offering support may be important requisites for empowerment.

Delespaul|Philippe A E G|PAEG|0000-0001-7420-0898

attachment
empowerment
severe mental illness
recovery
interpersonal relationships


Improving healthcare performance through Activity-Based Costing and Time-Driven Activity-Based Costing.

Abstract: Improving healthcare performance has become a need for resource optimisation in a field where they are scarce. Activity-Based Costing (ABC) has been applied for more than 30 years to allocate costs and provide information for decision-making. This paper seeks to review previous literature in the health field that analysed this cost system and its new version, TDABC (Time-Driven Activity-Based Costing). Five hundred ninety articles published from 1989 to 2019 were retrieved from Scopus and Medline. The review includes descriptive, relational and content analyses. Results show that the interest in applying these cost systems is growing, especially in journals focusing on the financial aspects of health, policy and planning, and radiology. However, there is a difference in the application of ABC and TDABC. ABC is more related to efficiency and more used in laboratories. In contrast, TDABC is primarily used in hospitals and addressing the value of health rather than cost-effectiveness. On the other hand, the findings suggest that TDABC present greater opportunities for publication compared with ABC. Its progression is higher and gets more citations. The current article contributes to broadening the field's vision and encourages authors for further research.

D003362:Cost-Benefit Analysis
D003695:Delivery of Health Care
D006761:Hospitals
D013997:Time Factors

Activity-Based Costing
Time-Driven Activity-Based Costing
health
cost determination
value-based health care


Stylohyoid complex syndrome: A report of two cases and review of the literature.

Abstract: This article reports two patients with stylohyoid complex syndrome. Cone beam computed tomography examination of the 37-year-old Caucasian woman with hemifacial pain, radiating to the left ear which intensified in response to opening the mouth revealed the ossified distal part of the left stylohyoid ligament, 23.85 mm long, which had a contact with the lesser horn of the hyoid. A 43-year-old man with a 5-month history of pain in the anterolateral surface of the neck and temporomandibular joint on the right side when swallowing and yawning had the styloid process elongation with a "bayonet-like" deformity on the same side. Ossification of the stylohyoid ligament, elongation and bending of the slyloid process, as a reason of the lateral neck and/or facial pain is not commonly suspected in clinical practice where diagnosis is often first made radiologically.

Kabak|Sergey|S| Savrasova|Nina|N| Melnichenko|Yuliya|Y| Vysotski|Andrei|A| Mashchanka|Iryna|I|

Cone beam computed tomography
Styloid process
Anatomy
Clinical research
Eye-ear-nose-throat
Face pain
Medical imaging
Musculoskeletal system
Neck pain


Stress, cortisol, and obesity: a role for cortisol responsiveness in identifying individuals prone to obesity.

Abstract: There is a strong inter-relationship between activation of the hypothalamo-pituitary-adrenal axis and energy homeostasis. Patients with abdominal obesity have elevated cortisol levels. Furthermore, stress and glucocorticoids act to control both food intake and energy expenditure. In particular, glucocorticoids are known to increase the consumption of foods enriched in fat and sugar. It is well-known that, in all species, the cortisol response to stress or adrenocorticotropin is highly variable. It has now emerged that cortisol responsiveness is an important determinant in the metabolic sequelae to stress. Sheep that are characterized as high-cortisol responders (HRs) have greater propensity to weight gain and obesity than low-cortisol responders (LRs). This difference in susceptibility to become obese is associated with a distinct metabolic, neuroendocrine, and behavioral phenotype. In women and ewes, HR individuals eat more in response to stress than LR. Furthermore, HR sheep have impaired melanocortin signaling and reduced skeletal muscle thermogenesis. High-cortisol responder sheep exhibit reactive coping strategies, whereas LRs exhibit proactive coping strategies. This complex set of traits leads to increased food intake and reduced energy expenditure in HR and thus, predisposition to obesity. We predict that cortisol responsiveness may be used as a marker to identify individuals who are at risk of weight gain and subsequent obesity.

Hewagalamulage|S D|SD|
Lee|T K|TK|
Clarke|I J|IJ|
Henry|B A|BA|

Cortisol responsiveness
Hypothalamo-pituitary-adrenal axis
Food intake
Energy expenditure
Stress and obesity


Hypothyroidism: morphological and metabolic changes in the testis of adult albino rat and the amelioration by alpha-lipoic acid.

Abstract:
BACKGROUND
The objective of this study is to evaluate the influence of carbimazole- induced hypothyroidism on the testes of adult albino rats and the probable protective effect of alpha-lipoic acid (ALA).

MATERIALS AND METHODS
The rats were divided into four groups; control group, ALA group, carbimazole, and carbimazole + ALA groups. Rats were exposed to ALA (60 mg/kg body weight) or carbimazole (1.35 mg/kg body weight), or both, administered via gavages for 30 days.

RESULTS
Morphometric analysis revealed a significant decrease in tubular diameter, germinal epithelium thickness, and interstitial space as compared to the controls. Also, rats exposed to carbimazole showed a significant decline in testicular weight, sperm motility, and count. Additionally, deterioration of the testicular architecture was observed. ALA supplementation resulted in a significant improvement in the tubular diameter and germinal epithelium thickness, but no significant improvement regarding interstitial space was observed. Another observation was the significant decline in serum testosterone and follicle-stimulating hormone (FSH) in the carbimazole group, indicating reduced steroidogenesis. A significant reduction in reduced glutathione content was detected in the testes of the carbimazole group compared with the controls, while malonaldehyde concentration significantly increased. Conversely, ALA supplementation ameliorated the toxicity induced by hypothyroidism as illustrated by enhanced reproductive organ weights, testosterone, luteinizing hormone, and FSH levels, testicular steroidogenesis, and oxidative stress parameters.

CONCLUSIONS
Hypothyroidism altered testicular antioxidant balance and negatively affected spermatogenesis. On the other hand, ALA through its antioxidant properties alleviated testicular toxicity in carbimazole-exposed rats.

hypothyroidism
testis
rat
alpha-lipoic acid
carbimazole


Povidone-iodine 1% is the most effective vaginal antiseptic for preventing post-cesarean endometritis: a systematic review and network meta-analysis.

Abstract:
BACKGROUND
Direct comparison metaanalyses have reported benefits with presurgical vaginal preparation before cesarean delivery for the reduction of endometritis. These reports did not perform a multitreatment comparison of the various antiseptic solutions assessed in previous studies.

OBJECTIVE
The purpose of this study was to review the literature systematically and quantitate and summarize indirectly the comparative efficacy of antiseptic formulations and their concentrations that are used for the preparation of the vagina before cesarean delivery in the prevention of endometritis and other infectious complications.

STUDY DESIGN
We used MEDLINE, EMBASE (from their inception to November 2018) and Cochrane databases, biographies, and conference proceedings. We used randomized clinical trials of patients who underwent surgical preparation of the vagina with antiseptic formulations before cesarean delivery with the aim of reducing the risk of infectious morbidity. Our systematic review was registered and followed the Preferred Reporting Items for Systematic Review and Meta-analysis Extension for network meta-analysis guidelines. Network meta-analysis was performed with computerized software and used user-written programs to assess consistency, inconsistency, ranking probabilities, and graphing results. Direct and indirect pairwise comparisons of the various formulations and their concentrations were performed with the use of multivariate random-effects models and metaregression. A frequentist inference method was employed for the fitted model to estimate the ranking probabilities. Subgroup analyses for patients in labor, not in labor, and with ruptured membranes were conducted.

RESULTS
For the prevention of endometritis, we identified 23 studies that comprised 7097 women who were allocated to the following treatments: povidone-iodine (1%, 5%, 10%), chlorhexidine (0.2%, 0.4%), metronidazole gel, cetrimide, or normal saline solution/no treatment. Direct and indirect pairwise comparisons indicated that, when compared with saline solution or no treatment, all antiseptic formulations decreased rates of endometritis (5.2% vs 9.1%; odds ratio, 0.48; 95% confidence interval, 0.35-0.65; 22 studies/6994 women). Individually, povidone-iodine (odds ratio, 0.43; 95% confidence interval, 0.28-0.64; 16 studies/5968 women), cetrimide (odds ratio, 0.34; 95% confidence interval, 0.13-0.90; 1 study/200 women), and metronidazole (odds ratio, 0.38; 95% confidence interval, 0.16-0.90; 1 study/224 women) significantly reduced the risk of endometritis. Rankings of vaginal preparations indicated that povidone-iodine 1% had the highest probability (72.7%) of being the most effective treatment for the prevention of endometritis. For the secondary outcomes of postoperative wound infection and fever, a significant reduction was found only with povidone-iodine (odds ratio, 0.61; 95% confidence interval, 0.48-0.78; 16 studies/5968 women; and odds ratio, 0.58; 95% confidence interval, 0.40-0.83; 12 studies/4667 women). Subgroup analyses also found that povidone-iodine significantly reduced risk of endometritis for women in labor (odds ratio, 0.42; 95% confidence interval, 0.20-0.88; 5 studies/1211 women), with ruptured membranes(odds ratio, 0.21; 95% confidence interval, 0.10-0.44; 4 studies/476 women), and undergoing planned cesarean delivery (odds ratio, 0.39; 95% confidence interval, 0.27-0.57; 8 studies/1825 women).

CONCLUSION
Among patients who underwent cesarean delivery, presurgical vaginal irrigation with povidone-iodine had the highest probability of reducing the risk of endometritis, postoperative wound infections, and fever.

Roeckner|Jared T|JT|
Sanchez-Ramos|Luis|L|
Mitta|Melanie|M|
Kovacs|Andrew|A|
Kaunitz|Andrew M|AM|

antiseptic
endometritis
network meta-analysis
vaginal preparation
cesarean delivery


Assessment of expected breeding values for fertility traits of Murrah buffaloes under subtropical climate.

Abstract:
AIM
The aim of the present study was to assess the influence of temperature and humidity prevalent under subtropical climate on the breeding values for fertility traits viz. service period (SP), pregnancy rate (PR) and conception rate (CR) of Murrah buffaloes in National Dairy Research Institute (NDRI) herd.

MATERIALS AND METHODS
Fertility data on 1379 records of 581 Murrah buffaloes spread over four lactations and climatic parameters viz. dry bulb temperature and relative humidity (RH) spanned over 20 years (1993-2012) were collected from NDRI and Central Soil and Salinity Research Institute, Karnal, India. Monthly average temperature humidity index (THI) values were estimated. Threshold THI value affecting fertility traits was identified by fixed least-squares model analysis. Three zones of non-heat stress, heat stress and critical heat stress zones were developed in a year. The genetic parameters heritability (h(2)) and repeatability (r) of each fertility trait were estimated. Genetic evaluation of Murrah buffaloes was performed in each zone with respect to their expected breeding values (EBV) for fertility traits.

RESULTS
Effect of THI was found significant (p<0.001) on all fertility traits with threshold THI value identified as 75. Based on THI values, a year was classified into three zones: Non heat stress zone(THI 56.71-73.21), HSZ (THI 75.39-81.60) and critical HSZ (THI 80.27-81.60). The EBVfor SP, PR, CR were estimated as 138.57 days, 0.362 and 69.02% in non-HSZ while in HSZ EBV were found as 139.62 days, 0.358 and 68.81%, respectively. EBV for SP was increased to 140.92 days and for PR and CR, it was declined to 0.357 and 68.71% in critical HSZ.

CONCLUSION
The negative effect of THI was observed on EBV of fertility traits under the non-HSZ and critical HSZ Thus, the influence of THI should be adjusted before estimating the breeding values for fertility traits in Murrah buffaloes.

Dash|Soumya|S|
Chakravarty|A K|AK|
Singh|Avtar|A|
Shivahre|Pushp Raj|PR|
Upadhyay|Arpan|A|
Sah|Vaishali|V|
Singh|K Mahesh|KM|

expected breeding value
murrah buffaloes
temperature humidity index
critical heat stress zone


Research as usual in humanitarian settings? Equalising power in academic-NGO research partnerships through co-production.

Abstract:
BACKGROUND
Research partnerships in conflict-affected and humanitarian settings can reveal complex power hierarchies between academics and NGOs. During the process of research, decision-making may skew in favour of more powerful actors, who often direct the scope of the research, hold the budget and lead the analysis. Co-production is increasingly emerging as a helpful approach that attempts to equalise power dynamics during research. The aim of this paper is to draw attention to the main challenges associated with a "research as usual" approach to research partnerships in humanitarian settings, as power hierarchies may be particularly magnified in these settings.

METHODS
This paper is based on a comprehensive literature review and 32 semi-structured interviews with academics and practitioners from non-government organisations. Participants were selected purposively based on their experience in co-producing research or working within research partnerships. Some participants had worked in humanitarian settings while others had experience co-producing research in non-humanitarian contexts. We used Nvivo to thematically code data.

RESULTS
This paper documents the problems with "research as usual" partnerships in humanitarian settings, specifically: the burden on communities as merely sources of data, certain forms of knowledge being valued over others, lack of reflection on the power hierarchies structuring research partnerships, top-down decision-making and lack of transparency, one-way "capacity-building", lack of mutual benefit, and rigid research processes and timeframes.

CONCLUSION
This paper highlights key challenges with standard research practices in humanitarian settings and identifies seven key principles of co-production that can be helpful in attempting to equalise power dynamics within research partnerships, specifically in conflict-affected and humanitarian settings.


Applications of the Linear Mass-Sectional Breakage Population Balance to Various Milling Process Configurations.

Abstract: After an initial grounding discussion, in which the linear mass-sectional population balance is described, and models for reducing the number of its parameters are discussed, this modeling approach is applied to a wide range of processes including batch mills, single-pass continuous mills, mills in series, mills with recycle, milling circuits including classification, and recycled-batch milling. The linearity of the model allows its straightforward inclusion in calculations for all of these processes. The sensitivity of the model to its inputs (order of rate kernel in size, fragment distribution) is explored for batch operations. Then, the effects of key continuous process design variables are explored including the (a) number of mill passes in pendulum milling (mills in series), (b) classifier properties in circuits with classification, and (c) ratio of feed tank-to-mill residence time in recycled-batch operations.

D002626:Chemistry, Pharmaceutical
D010316:Particle Size

Population balances
Milling
Particle breakage


Comparative cytotoxicity of dolomite nanoparticles in human larynx HEp2 and liver HepG2 cells.

Abstract: Dolomite is a natural mineral of great industrial and commercial importance. With the advent of nanotechnology, natural minerals including dolomite in the form of nanoparticles (NPs) are being utilized in various applications to improve the quality of products. However, safety or toxicity information of dolomite NPs is largely lacking. This study evaluated the cytotoxicity of dolomite NPs in two widely used in vitro cell culture models: human airway epithelial (HEp2) and human liver (HepG2) cells. Concentration-dependent decreased cell viability and damaged cell membrane integrity revealed the cytotoxicity of dolomite NPs. We further observed that dolomite NPs induce oxidative stress in a concentration-dependent manner, as indicated by depletion of glutathione and induction of reactive oxygen species (ROS) and lipid peroxidation. Quantitative real-time PCR data demonstrated that the mRNA level of tumor suppressor gene p53 and apoptotic genes (bax, CASP3 and CASP9) were up-regulated whereas the anti-apoptotic gene bcl-2 was down-regulated in HEp2 and HepG2 cells exposed to dolomite NPs. Moreover, the activity of apoptotic enzymes (caspase-3 and caspase-9) was also higher in both kinds of cells treated with dolomite NPs. It is also worth mentioning that HEp2 cells seem to be marginally more susceptible to dolomite NPs exposure than HepG2 cells. Cytotoxicity induced by dolomite NPs was efficiently prevented by N-acetyl cysteine treatment, which suggests that oxidative stress is primarily responsible for the cytotoxicity of dolomite NPs in both HEp2 and HepG2 cells. Toxicity mechanisms of dolomite NPs warrant further investigations at the in vivo level.

Ahamed|Maqusood|M|
Alhadlaq|Hisham A|HA|
Ahmad|Javed|J|
Siddiqui|Maqsood A|MA|
Khan|Shams T|ST|
Musarrat|Javed|J|
Al-Khedhairy|Abdulaziz A|AA|

cytotoxicity
dolomite nanoparticles
oxidative stress
apoptosis
human health


Vertebral compression fracture with intravertebral vacuum cleft sign: pathogenesis, image, and surgical intervention.

Abstract: The intravertebral vacuum cleft (IVC) sign in vertebral compression fracture patients has obtained much attention. The pathogenesis, image character and efficacy of surgical intervention were disputed. Many pathogenesis theories were proposed, and its image characters are distinct from malignancy and infection. Percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) have been the main therapeutic methods for these patients in recent years. Avascular necrosis theory is the most supported; PVP could relieve back pain, restore vertebral body height and correct the kyphotic angulation (KA), and is recommended for these patients. PKP seems to be more effective for the correction of KA and lower cement leakage. The Kümmell's disease with IVC sign reported by modern authors was incomplete consistent with syndrome reported by Dr. Hermann Kümmell.

Intravertebral vacuum cleft
Pathogenesis
Vertebroplasty
Kyphoplasty
Kümmell's disease


UV-induced transformation of 2,3-dibromo-5,6-dimethyl-1,4-benzoquinone in water and treated wastewater.

Abstract: In this work, we investigate the photolysis behavior of 2,3-dibromo-5,6-dimethyl-1,4-benzoquinone (DDBQ), the only dibrominated benzoquinone detected in treated water so far. DDBQ solutions prepared in ultra-pure water were exposed to UV radiation centered at 254 nm (UV254), and the photolysis of the parent compound was monitored together with by-product formation. The DDBQ pseudo-first order photolysis rate constants decreased when increasing the initial DDBQ concentration, and this behavior was caused by saturation of absorption. The photodegradation kinetics was found not to depend on pH and 1-butanol addition, but was affected by humic acids and components that occur in both natural waters and treated wastewater. For the first time with this class of compounds, photolysis studies were also performed using natural and treated wastewater matrices, where photodegradation was always found to proceed significantly slower than in ultra-pure water. The implications for the radiation dose that is required to reach a given treatment target are discussed, and a numerical approach by which to foresee the extent of degradation inhibition is provided that should be taken into account when planning the UV254 treatment of DDBQ. The phototransformation of DDBQ yielded hydroxyderivatives, most likely via a debromination-hydroxylation pathway. In-silico toxicity screening suggested that the transformation of DDBQ into the detected hydroxyderivatives would not eliminate toxicity. Although the monohydroxylated derivative underwent relatively fast transformation, the dihydroxylated compound was found to accumulate during irradiation. As a compromise, the irradiation conditions that produce over 90% degradation of DDBQ in the studied samples, and at the same time keep by-product formation low are discussed.

Treated wastewater
Photolysis
Dibrominated benzoquinone
Natural water
Disinfection by-products
In-silico toxicity estimates


Facile access to cytocompatible multicompartment micelles with adjustable Janus-cores from A-block-B-graft-C terpolymers prepared by combination of ROP and ATRP.

Abstract: The architecture of hydrophobic segments can determine the specific morphology of multicompartment micelles (MCMs) that are generated from aqueous assembly of amphiphilic terpolymers. In this study, we aimed to design and generate poly(ɛ-caprolactone)-based multicompartment micelles with adjustable Janus-cores. Well-defined terpolymers with a novel A-block-B-graft-C architecture composed of biologically compatible polymers, methoxy poly(ethylene glycol) (PEG), poly(ɛ-caprolactone) (PCL) and poly(2-(perfluorobutyl)ethyl methacrylate) (PPFEMA), were prepared by the stepwise use of ring-opening polymerization and atom transfer radical polymerization. Characterization of the obtained terpolymers was carried out by (1)H NMR and gel permeation chromatography. Results from differential scanning calorimetry and X-ray diffraction studies indicated that within the terpolymer structure, the PCL segments are in the crystalline state, while fluorocarbon segments belong to the amorphous domains. Due to the thermodynamic incompatibility of PCL and PPFEMA, MCMs could be obtained upon aqueous self-assembly of the terpolymer. The well-segregated Janus-cores with adjustable compartment balance were revealed by transmission electron microscopy. In vitro cell viability assays further demonstrated an excellent cytocompatibility of the MCMs both in mouse embryonic fibroblasts (3T3) and human acute monocytic leukemia (THP-1) cells.

Wang|Weiwei|W| Zhang|Ju|J| Li|Chen|C| Huang|Pingsheng|P| Gao|Shan|S| Han|Shangcong|S| Dong|Anjie|A| Kong|Deling|D|

Multicompartment micelles
Janus-core
Amphiphilic terpolymers
Graft architecture
Microphase separation


Targeting Angiotensin II Type-1 Receptor (AT1R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8+ T Cells during Blood-Stage Malaria.

Abstract: CD8+ T-cell response is critical in the pathogenesis of cerebral malaria during blood-stage. Our group and other have been shown that angiotensin II (Ang II) and its receptor AT1 (AT1R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT1R signaling protects mice against the lethal disease induced by Plasmodium berghei ANKA infection However, most of the Ang II/AT1R actions were characterized by using only pharmacological approaches, the effects of which may not always be due to a specific receptor blockade. In addition, the mechanisms of action of the AT1R in inducing the pathogenic activity of Plasmodium-specific CD8+ T cells during blood-stage were not determined. Here, we examined how angiotensin II/AT1R axis promotes the harmful response of Plasmodium-specific CD8+ T-cell during blood-stage by using genetic and pharmacological approaches. We evaluated the response of wild-type (WT) and AT1R-/-Plasmodium-specific CD8+ T cells in mice infected with a transgenic PbA lineage expressing ovalbumin; and in parallel infected mice receiving WT Plasmodium-specific CD8+ T cells were treated with losartan (AT1R antagonist) or captopril (ACE inhibitor). Both, AT1R-/- OT-I cells and WT OT-I cells from losartan- or captopril-treated mice showed lower expansion, reduced IL-2 production and IL-2Rα expression, lower activation (lower expression of CD69, CD44 and CD160) and lower exhaustion profiles. AT1R-/- OT-I cells also exhibit lower expression of the integrin LFA-1 and the chemokine receptors CCR5 and CXCR3, known to play a key role in the development of cerebral malaria. Moreover, AT1R-/- OT-I cells produce lower amounts of IFN-γ and TNF-α and show lower degranulation upon restimulation. In conclusion, our results show the pivotal mechanisms of AT1R-induced harmful phenotype of Plasmodium-specific CD8+ T cells during blood-stage malaria.

Silva-Filho|João L|JL|
Caruso-Neves|Celso|C|
Pinheiro|Ana A S|AA|

D053645:Interleukin-2 Receptor alpha Subunit

angiotensin
CD8+ T cells
blood-stage
malaria
AT1 receptor


Endovascular repair during complex thoracic aortic dissection using a micropore stent graft: Midterm follow-up clinical outcomes.

Abstract:
OBJECTIVE
This study explored the clinical efficacy and hemodynamic effects of the micropore stent graft (MSG) that could promote aortic remodeling and preserve important organ branches.

METHODS
We conducted a retrospective analysis of 26 patients who underwent endovascular repair using an MSG for DeBakey types I and III TAD at our center between December 2014 and December 2017. The main efficacy parameters were rupture of the false lumen or dissection-related death, conversion to open repair, secondary reintervention, branch vessel patency, and the hemodynamic effects of TAD at 12 months.

RESULTS
Dissection rupture, dissection-related mortality, conversion to open repair, and secondary reintervention rates at 12 months were 0, 3.9, 0, and 0%, respectively. In the 24 patients with more than 6 months of follow-up, micropore stents were implanted to cover 39 openings in aortic arch branches, 91.7% (22/24) presented with complete thrombosis in the false lumen, 8.3% (2/24) presented with partial thrombosis in the false lumen, 35.2% (6/17) presented with a thrombus in the false lumen that was completely absorbed, and all 39 branches were patent. After surgery, pressure peak value and fluctuation along with the degree and range of unstable blood flow in the aortic lumen decreased.

CONCLUSIONS
For type I and type III thoracic artic dissection, endovascular treatment with an MSG may be a safe and effective treatment option with a good midterm outcome.

Wang|Zhe|Z| Wang|Cheng|C| Li|Fenghe|F| Zhao|Yu|Y|0000-0003-4035-0825

D019917:Blood Vessel Prosthesis Implantation

endovascular repair
thoracic aortic dissection
micropore stent graft
hemodynamics
patency rate


Important interactional strategies for everyday public health nursing practice.

Abstract: This Clinical Concepts article concerns the relational tools required by public health nurses to establish relationships with single mothers living on public assistance, mothers who are vulnerable and often stigmatized. The implications of stigmatization for relationship building are highlighted based on previous research investigating how public health nurses working in Canadian jurisdictions establish professional caring relationships with this cohort of mothers. Public health nurses employed interactional strategies including engaging in a positive manner and offering verbal commendations which served as effective relational tools to break through mothers' walls of defensiveness and to resume the dynamic process of relationship building. Building Relationship is a key practice standard for public health nurses and is instrumental to their work at both individual and community levels to improve social determinants of health. The author concludes with recommendations to facilitate building relationships during everyday public health nursing practice.

health promotion
professional-client relations
special populations
stigma


Learning a Foreign Language: A New Path to Enhancement of Cognitive Functions.

Abstract: The complicated cognitive processes involved in natural (primary) bilingualism lead to significant cognitive development. Executive functions as a fundamental component of human cognition are deemed to be affected by language learning. To date, a large number of studies have investigated how natural (primary) bilingualism influences executive functions; however, the way acquired (secondary) bilingualism manipulates executive functions is poorly understood. To fill this gap, controlling for age, gender, IQ, and socio-economic status, the researchers compared 60 advanced learners of English as a foreign language (EFL) to 60 beginners on measures of executive functions involving Stroop, Wisconsin Card Sorting Task (WCST) and Wechsler's digit span tasks. The results suggested that mastering English as a foreign language causes considerable enhancement in two components of executive functions, namely cognitive flexibility and working memory. However, no significant difference was observed in inhibitory control between the advanced EFL learners and beginners.

Executive functions
Cognitive flexibility
Working memory
Inhibitory control
Acquired bilingualism
Natural bilingualism


CD73 expression identifies a subset of IgM+ antigen-experienced cells with memory attributes that is T cell and CD40 signalling dependent.

Abstract: B-cell memory was long characterized as isotype-switched, somatically mutated and germinal centre (GC)-derived. However, it is now clear that the memory pool is a complex mixture that includes unswitched and unmutated cells. Further, expression of CD73, CD80 and CD273 has allowed the categorization of B-cell memory into multiple subsets, with combinatorial expression of the markers increasing with GC progression, isotype-switching and acquisition of somatic mutations. We have extended these findings to determine whether these markers can be used to identify IgM memory phenotypically as arising from T-dependent versus T-independent responses. We report that CD73 expression identifies a subset of antigen-experienced IgM+ cells that share attributes of functional B-cell memory. This subset is reduced in the spleens of T-cell-deficient and CD40-deficient mice and in mixed marrow chimeras made with mutant and wild-type marrow, the proportion of CD73+ IgM memory is restored in the T-cell-deficient donor compartment but not in the CD40-deficient donor compartment, indicating that CD40 ligation is involved in its generation. We also report that CD40 signalling supports optimal expression of CD73 on splenic T cells and age-associated B cells (ABCs), but not on other immune cells such as neutrophils, marginal zone B cells, peritoneal cavity B-1 B cells and regulatory T and B cells. Our data indicate that in addition to promoting GC-associated memory generation during B-cell differentiation, CD40-signalling can influence the composition of the unswitched memory B-cell pool. They also raise the possibility that a fraction of ABCs may represent T-cell-dependent IgM memory.

D'Souza|Lucas|L|
Gupta|Sneh Lata|SL|
Bal|Vineeta|V|
Rath|Satyajit|S|
George|Anna|A|0000-0001-9401-0944

CD73
memory
T cells
CD40
IgM
age-associated B cells


Vertebral Venous Collaterals with Underlying Agenesis of the Inferior Vena Cava: Implications for Spinal Surgery.

Abstract:
BACKGROUND
Congenital agenesis of the inferior vena cava (IVC) can lead to the development of a prominent venous collateral system within and around the spine due to the development of venous collaterals. In such patients, surgery can carry a risk of catastrophic bleeding or decompensation of a delicate venous drainage pattern during spinal manipulation or even epidural exploration.

CASE DESCRIPTION
A 49-year-old man with a congenital agenesis of the IVC presented with signs and symptoms of an L5 radiculopathy. A computed tomography scan of the lumbar spine showed the characteristic finding of fenestrated or "holey" pedicles within the lumbar spine, due to chronic venous engorgement within the pedicles.

CONCLUSIONS
To our knowledge, this is the first report to describe the characteristic sign of "holey" pedicles on radiographic imaging in a patient with an underdeveloped IVC. This finding may be useful for the detection of abnormal spinal venous anatomy. In such patients, spinal surgery may carry greater risks and requires special consideration.

Yoon|Jang W|JW|
Ganaha|Sara|S|
Watridge|Clarence|C|

Agenesis of the inferior vena cava
Collateral venous circulation
Spinal epidural venous plexus


Genetic analysis of the rates of conception using a longitudinal threshold model with random regression in dairy crossbreeding within a tropical environment.

Abstract: This study was designed to: (i) estimate genetic parameters and breeding values for conception rates (CR) using the repeatability threshold model (RP-THM) and random regression threshold models (RR-THM); and (ii) compare covariance functions for modeling the additive genetic (AG) and permanent environmental (PE) effects in the RR-THM. The CR was defined as the outcome of an insemination. A data set of 130 592 first-lactation insemination records of 55 789 Thai dairy cows, calving between 1996 and 2011, was used in the analyses. All models included fixed effects of year × month of insemination, breed × day in milk to insemination class and age at calving. The random effects consisted of herd × year interaction, service sire, PE, AG and residual. Variance components were estimated using a Bayesian method via Gibbs sampling. Heritability estimates of CR ranged from 0.032 to 0.067, 0.037 to 0.165 and 0.045 to 0.218 for RR-THM with the second, third and fourth-order of Legendre polynomials, respectively. The heritability estimated from RP-THM was 0.056. Model comparisons based on goodness of fit, predictive abilities, predicted service results of animal, and pattern of genetic parameter estimates, indicated that the model which fit the desired outcome of insemination was the RR-THM with two regression coefficients.

Buaban|Sayan|S| Kuchida|Keigo|K| Suzuki|Mitsuyoshi|M| Masuda|Yutaka|Y| Boonkum|Wuttigrai|W| Duangjinda|Monchai|M|

threshold model
random regression
conception rate
crossbred dairy cattle


Data presentation options to manage variability in physical activity research.

Abstract: This paper presents seven tactics for managing the variability evident in some physical activity data. High levels of variability in daily step-count data from pedometers or accelerometers can make typical visual inspection difficult. Therefore, the purpose of the current paper is to discuss several strategies that might facilitate the visual interpretation of highly variable data. The seven strategies discussed in this paper are phase mean and median lines, daily average per week, weekly cumulative, proportion of baseline, 7-day moving average, change point detection, and confidence intervals. We apply each strategy to a data set and discuss the advantages and disadvantages.

Valbuena|Diego|D|
Miller|Bryon G|BG|
Samaha|Andrew L|AL|
Miltenberger|Raymond G|RG|

variability
physical activity
visual inspection
data analysis


Effects of traffic-related air pollution on exercise endurance, dyspnea and cardiorespiratory physiology in health and COPD - A randomized, placebo-controlled crossover trial.

Abstract:
BACKGROUND
Individuals with COPD have increased sensitivity to traffic-related air pollution (TRAP) such as diesel exhaust (DE), but little is known about the acute effects of TRAP on exercise responses in COPD.

RESEARCH QUESTION
Does pre-exercise exposure to TRAP (DE300, PM2.5=300 μg/m3) have greater adverse effects on exercise endurance, exertional dyspnea, and cardiorespiratory responses to exercise in participants with mild-to-moderate COPD compared to former smokers with normal spirometry and healthy controls?

STUDY DESIGN AND METHODS
In this double-blind, randomized, placebo-controlled, crossover study, 11 healthy never-smokers, 9 ex-smokers without COPD and 9 ex-smokers with COPD were separately exposed to filtered air (FA) and DE300 for 2 hours separated by a minimum of 4 weeks. Participants performed symptom limited constant load cycling tests within 2.5 hours of exposure with detailed cardiorespiratory and exertional symptom measurements.

RESULTS
There was a significant negative effect of TRAP on exercise endurance time in healthy controls (DE300 vs. FA: 10.2±8.2 vs. 12.9±9.5 min, respectively; p=0.03), but not in ex-smokers without COPD (10.1±6.9 vs. 12.2±8.0 min; respectively, p=0.57) or ex-smokers with COPD (9.8±6.4 vs. 8.4±6.6 min, respectively, p=0.31). Furthermore, significant increases in inspiratory duty cycle and absolute end-expiratory and end-inspiratory lung volumes were observed, and dyspnea ratings were elevated at select submaximal measurement times only in healthy controls. INTERPRETATION: Contrary to our hypothesis, it was the healthy controls rather than the ex-smokers with and without COPD that were negatively impacted by TRAP during exercise.

Syed|Nafeez|N|
Ryu|Min Hyung|MH|
Dhillon|Satvir|S|
Schaeffer|Michele R|MR|
Ramsook|Andrew H|AH|
Leung|Janice M|JM|
Ryerson|Christopher J|CJ|
Carlsten|Christopher|C|
Guenette|Jordan A|JA|
|||

Air pollution
exercise
COPD
diesel exhaust
controlled exposure


The sociology of the antivaccine movement.

Abstract: Skepticism and misinformation relating to vaccines is not new. The benefits of all our present routinely used vaccines outweigh any risks. In relatively recent times there has been a 'war on science' and relating to this, is the present antivaccine movement. Today, social media is a major contributor to vaccine misinformation. A recent Gallup poll noted that public support for vaccines today is significantly lower than it was in 2001. Social scientists have presented the problem of the antivaccine movement quite well; but mechanisms for addressing it are far from clear. We suggest that physicians and other health care workers should not use social media for vaccine messages. A long-term approach would be to introduce science/epidemiological education in grade school and high school as well as in college.

antivaccine
vaccines
social media
vaccine misinformation
immunization


Neuroprotective Roles of the Adenosine A3 Receptor Agonist AST-004 in Mouse Model of Traumatic Brain Injury.

Abstract: Traumatic brain injury (TBI) remains one of the greatest public health concerns with increasing morbidity and mortality rates worldwide. Our group reported that stimulation of astrocyte mitochondrial metabolism by P2Y1 receptor agonists significantly reduced cerebral edema and reactive gliosis in a TBI model. Subsequent data on the pharmacokinetics (PK) and rapid metabolism of these compounds suggested that neuroprotection was likely mediated by a metabolite, AST-004, which binding data indicated was an adenosine A3 receptor (A3R) agonist. The neuroprotective efficacy of AST-004 was tested in a control closed cortical injury (CCCI) model of TBI in mice. Twenty-four (24) hours post-injury, mice subjected to CCCI and treated with AST-004 (0.22 mg/kg, injected 30 min post-trauma) exhibited significantly less secondary brain injury. These effects were quantified with less cell death (PSVue794 fluorescence) and loss of blood brain barrier breakdown (Evans blue extravasation assay), compared to vehicle-treated TBI mice. TBI-treated mice also exhibited significantly reduced neuroinflammatory markers, glial-fibrillary acidic protein (GFAP, astrogliosis) and ionized Ca2+-binding adaptor molecule 1 (Iba1, microgliosis), both at the mRNA (qRT-PCR) and protein (Western blot and immunofluorescence) levels, respectively. Four (4) weeks post-injury, both male and female TBI mice presented a significant reduction in freezing behavior during contextual fear conditioning (after foot shock). AST-004 treatment prevented this TBI-induced impairment in male mice, but did not significantly affect impairment in female mice. Impairment of spatial memory, assessed 24 and 48 h after the initial fear conditioning, was also reduced in AST-004-treated TBI-male mice. Female TBI mice did not exhibit memory impairment 24 and 48 h after contextual fear conditioning and similarly, AST-004-treated female TBI mice were comparable to sham mice. Finally, AST-004 treatments were found to increase in vivo ATP production in astrocytes (GFAP-targeted luciferase activity), consistent with the proposed mechanism of action. These data reveal AST-004 as a novel A3R agonist that increases astrocyte energy production and enhances their neuroprotective efficacy after brain injury.

Astrocytes
Mitochondrial metabolism
ATP
ADORA3
Concussion treatment


Phytosterol Supplementation Could Improve Atherogenic and Anti-Atherogenic Apolipoproteins: A Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials.

Abstract: Phytosterol and phytostanol (PS) supplementation is reported to improve atherogenic and anti-atherogenic apolipoproteins (Apo). The purpose of the present study is to critically investigate the effectiveness of PS supplementation on Apo in adults.A comprehensive search was conducted of all randomized controlled trials (RCTs) conducted up to September 2018 in the following databases: PubMed, Web of Science, Cochrane Library, and Scopus. Mean difference with 95% confidence intervals (CIs) were pooled using a random-effects model (DerSimonian-Laird method).Fifty-one arms from 37 RCTs were included in the present meta-analysis. Findings showed that PS supplementation and fortification increased Apo-AI (weighted mean difference [WMD]: 0.014 mg/dl, 95% CI: 0.001, 0.028, p = 0.042) and Apo-CII (WMD: 0.303 mg/dl, 95% CI: 0.084, 0.523, p = 0.007) and lowered Apo-B (WMD: -0.063 mg/dl, 95% CI: -0.075, -0.051, p < 0.001), Apo-B/Apo-A-I ratio (WMD: -0.044 mg/dl, 95% CI: -0.062, -0.025, p < 0.001), and Apo-E (WMD: -0.255 mg/dl, 95% CI: -0.474, -0.036, p = 0.023). However, PS supplementation did not have significant effects on Apo-AII and Apo-CIII. PS supplementation or fortification significantly changes Apo-E (r = -0.137, p nonlinearity = 0.006) and Apo-CIII (r = 1.26, p nonlinearity = 0.028) based on PS dosage (mg/d) and Apo-CIII (r = 3.34, p nonlinearity = 0.013) and Apo-CII (r = 1.09, p nonlinearity = 0.017) based on trial duration (weeks) in a nonlinear fashion.Based on our findings, supplements or fortified foods containing PS might have a considerable favorite effect in achieving Apo profile target; however, due to high heterogeneity among included studies, results must be interpreted with caution.KEY TEACHING POINTSCardiovascular diseases (CVDs) recognized as main public health concern worldwide with considerable mortality of all global deaths.Apo-lipoproteins are amphipathic molecules involved in the lipoprotein metabolism which introduced as biomarkers in the evaluation of CVD risk.Phytosterols bioactive components of plants have important biological functions in cholesterol metabolism in humans.Here we showed that phytosterols and phytostanols improve apo-lipoproteins profile of humans; finding from meta-analysis of randomized controlled trials.Phytosterols supplementation lowered atherogenic apo-lipoproteins (Apo-B and Apo-E) and increased anti-atherogenic apo-lipoproteins (Apo-AI, Apo-CII).

Ghaedi|Ehsan|E| Kord-Varkaneh|Hamed|H| Mohammadi|Hamed|H| Askarpour|Moein|M| Miraghajani|Maryam|M|

D016032:Randomized Controlled Trials as Topic

Phytosterol apolipoproteins meta-analysis phytostanol


Chloride-Bridged Dinuclear Rhodium(III) Complexes Bearing Chiral Diphosphine Ligands: Catalyst Precursors for Asymmetric Hydrogenation of Simple Olefins.

Abstract: Efficient rhodium(III) catalysts were developed for asymmetric hydrogenation of simple olefins. A new series of chloride-bridged dinuclear rhodium(III) complexes 1 were synthesized from the rhodium(I) precursor [RhCl(cod)]2 , chiral diphosphine ligands, and hydrochloric acid. Complexes from the series acted as efficient catalysts for asymmetric hydrogenation of (E)-prop-1-ene-1,2-diyldibenzene and its derivatives without any directing groups, in sharp contrast to widely used rhodium(I) catalytic systems that require a directing group for high enantioselectivity. The catalytic system was applied to asymmetric hydrogenation of allylic alcohols, alkenylboranes, and unsaturated cyclic sulfones. Control experiments support the superiority of dinuclear rhodium(III) complexes 1 over typical rhodium(I) catalytic systems.

Kita|Yusuke|Y|
Hida|Shoji|S|
Higashihara|Kenya|K|
Jena|Himanshu Sekhar|HS|
Higashida|Kosuke|K|
Mashima|Kazushi|K|

hydrogenation
asymmetric catalysis
reaction mechanisms
rhodium


Muscle weakness and functional limitations in an ethnically diverse sample of older adults.

Abstract: Objectives: Muscle weakness is often linked to functional limitations in older adults. However, certain demographic characteristics, such as ethnicity, may differentially impact the association between weakness and functional limitations. This investigation sought to (1) identify sex- and ethnically-specific muscle weakness thresholds associated with functional limitations among older adults, and (2) determine the odds of functional limitations for each ethnicity by sex after identifying older adults below the weakness thresholds.Design: Persons aged ≥60 years from the 2011-2012 to 2013-2014 waves of the National Health and Nutrition Examination Survey identifying as non-Hispanic white, non-Hispanic black, Hispanic, or non-Hispanic Asian were included. Handgrip strength was normalized to each participant's body weight (normalized grip strength (NGS)). Participants responded to 19-items asking them about their ability to perform certain activities of daily living, instrumental activities of daily living, leisure and social activities, lower extremity mobility functions, and general physical activities. Receiver operating characteristic curves identified the optimal NGS thresholds associated with functional limitations. Covariate-adjusted multiple logistic regression models were performed to determine the odds of functional limitations for weak vs. not-weak participants.Results: Of the 3,027 participants, the highest NGS thresholds for functional limitations were in non-Hispanic Asian males (0.41; p < 0.001) and Hispanic females (0.36; p < 0.001); whereas, the lowest NGS thresholds were in Hispanic males (0.25; p < 0.001) and non-Hispanic black females (0.23; p < 0.001). Weak non-Hispanic Asian males (odds ratio (OR): 10.42; 95% confidence interval (CI): 10.24, 10.61) and females (OR: 11.95; CI: 11.71, 12.19) had the highest odds for functional limitations compared to their non-weak counterparts.Conclusion: Preserving muscle strength, especially for certain older adult populations, may help reduce the odds of developing functional limitations. Interventions designed to increase muscle strength to preserve or improve function should consider the role of ethnicity when designing such interventions and identifying at risk populations.

McGrath|Ryan P|RP|
Ottenbacher|Kenneth J|KJ|
Vincent|Brenda M|BM|
Kraemer|William J|WJ|
Peterson|Mark D|MD|

Aging
health
ethnology
geriatrics
hand strength
nutrition surveys


Digoxin use and following risk of psoriasis: A population-based cohort study in Taiwan.

Abstract: This study examined the association between digoxin use and subsequent psoriasis risk using a population-based database in Taiwan. This cohort study enrolled 15 545 digoxin users and 15 545 propensity score-matched non-users from the Taiwan National Health Insurance Research Database. Each patient was independently followed up for 5 years to confirm whether they had been diagnosed with psoriasis. Cox proportional hazard regression was used to estimate psoriasis risk among digoxin users. Subgroup and sensitivity analyses were also performed. The psoriasis incidence rates were 3.02 and 2.27 per 1000 person-years among digoxin users and non-users, respectively. After adjustment for confounders, psoriasis risk was significantly higher among digoxin users than among non-users. Notably, in most subgroup analyses, digoxin use tended to increase psoriasis risk, particularly among patients with heart failure, diabetes, hypertension and hyperlipidaemia. Moreover, significantly increased psoriasis risk was noted over 2, 3, 4 and 5 years of digoxin use. In conclusion, our findings confirm that digoxin use increases subsequent psoriasis risk. Thus, physicians should be aware of this association and accordingly estimate the risks and benefits of digoxin use. Nevertheless, some patient variables, such as body mass index and obesity, were unavailable in this study. The findings in this study should be elucidated carefully because the potential effects of these factors could not be considered.

digoxin
psoriasis
drug safety
drug-induced psoriasis
risk factor


Novel GALC Mutations Cause Adult-Onset Krabbe Disease With Myelopathy in Two Chinese Families: Case Reports and Literature Review.

Abstract: Krabbe disease (KD), also referred to as globoid cell leukodystrophy, is a rare autosomal recessive lysosomal storage disorder caused by β-galactocerebrosidase (GALC) deficiency. Most patients affected by this disease are infants, and <10% of cases suffer from adult-onset KD. In this study, two Chinese males presented with long-term progressive weakness in their limbs. Magnetic resonance imaging of the brain and spinal cord of these patients revealed lesions with abnormally high signal intensity on T2-weighted (T2W) and T2W fluid-attenuated inversion recovery images. Whole-exome sequencing was performed for both patients, and four GALC mutations were identified. Case 1 carried a novel deletion mutation (p.T633Tfs*2) and a known missense mutation (p.T529M), while case 2 carried a novel missense mutation (p.W355C) and a known missense mutation (p.P154H). Previous literature has rarely reported myelopathy in patients with KD; in this study, we report two cases of adult-onset KD who both experienced myelopathy. We also conducted a literature review of KD and its association with myelopathy. Our findings provide a better understanding of the phenotypic and genotypic profiles associated with adult-onset KD. We recommend that physicians consider KD as a possible diagnosis in cases showing progressive motor dysfunction or gait disorder in association with typical myelopathy.

Zhong|Junfei|J| Jiang|Fei|F| Yang|Huan|H| Li|Jing|J| Cheng|Jian|J| Zeng|Qiuming|Q| Xu|Qian|Q|

novel GALC mutations
Krabbe disease
myelopathy
literature review
adult onset


Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy.

Abstract:
BACKGROUND
Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities.

METHODS AND RESULTS
Using hyperpolarized carbon-13 ((13)C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs cycle activity was impaired, with decreased (13)C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates.

CONCLUSIONS
The in vivo decrease in Krebs cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment.

Dodd|Michael S|MS|
Atherton|Helen J|HJ|
Carr|Carolyn A|CA|
Stuckey|Daniel J|DJ|
West|James A|JA|
Griffin|Julian L|JL|
Radda|George K|GK|
Clarke|Kieran|K|
Heather|Lisa C|LC|
Tyler|Damian J|DJ|

D019028:Magnetic Resonance Imaging, Cine

myocardial infarction
magnetic resonance spectroscopy
heart
metabolism
citric acid cycle


Genetic analysis for cognitive flexibility in the trail-making test in attention deficit hyperactivity disorder patients from single nucleotide polymorphism, gene to pathway level.

Abstract: Objectives: Investigation of the genetic basis of endophenotype and analysis the pathways with multiple genes of small effects might increase the understanding of the genetic basis of attention deficit hyperactivity disorder (ADHD). Here we aimed to explore the genetic basis of cognitive flexibility in ADHD at the single nucleotide polymorphism (SNP), gene and pathway levels. Methods: The trail-making test was used to test the cognitive flexibility of 788 ADHD patients. A genome-wide association analysis of cognitive flexibility was conducted for 644,166 SNPs. Results: The top SNP rs2049161 (P = 5.08e-7) involved gene DLGAP1 and the top gene CADPS2 in the gene-based analysis resulted in much literature evidence of associations with psychiatric disorders. Gene expression and network analysis showed their contribution to cognition function. The interval-enrichment analysis highlighted a potential contribution of 'adenylate cyclase activity' and ADCY2 to cognitive flexibility. Candidate pathway-based analysis for all SNPs found that glutamate system-, neurite outgrowth- and noradrenergic system-related pathways were significantly associated with cognitive flexibility (FDR <0.05), among which the neurite outgrowth pathway was also associated with ADHD symptoms. Conclusions: This study provides evidence for the genes and pathways associated with cognitive flexibility and facilitate the uncovering of the genetic basis of ADHD.

Zhang|Kunlin|K|
Fan|Zili|Z|
Wang|Yufeng|Y|
Faraone|Stephen V|SV|
Yang|Li|L|
Chang|Suhua|S|

D001289:Attention Deficit Disorder with Hyperactivity

Attention deficit hyperactivity disorder


Therapeutic Targeting of PDEs and PI3K in Heart Failure with Preserved Ejection Fraction (HFpEF).

Abstract:
PURPOSE OF REVIEW
Heart Failure with preserved Ejection Fraction (HFpEF) is a prevalent disease with considerable individual and societal burden. HFpEF patients often suffer from multiple pathological conditions thatcomplicate management and adversely affect outcome, including pulmonary hypertension and chronic obstructive pulmonary disease (COPD). To date, no treatment proved to be fully effective in reducing morbidity and mortality in HFpEF, possibly due to an incomplete understanding of the underlying molecular mechanisms.

RECENT FINDINGS
The emerging view proposes chronic systemic inflammation, leading to endothelial dysfunction and interstitial fibrosis, as a prominent cause of HFpEF, rather than a mere co-existent disease. In the last decade, efforts from pharmaceutical companies attempted to target pharmacologically enzymes which play key roles in systemic and lung inflammation, such as the cyclic nucleotide-degrading enzymes phosphodiesterases (PDEs) and phosphoinositide-3 phosphate kinases (PI3Ks), especially to limit COPD. In this review, we will summarize major successes and drawbacks of hitting these enzymes to tackle inflammation in HFpEF-associated co-morbidities, with a major focus on the results of completed and ongoing clinical trials. Finally, we will discuss the potential of repurposing and/or developing new PDE and PI3K inhibitors for HFpEF therapy.

Sala|Valentina|V|
Margaria|Jean Piero|JP|
Murabito|Alessandra|A|
Morello|Fulvio|F|
Ghigo|Alessandra|A|
Hirsch|Emilio|E|

D029424:Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease
PDE inhibitors
Phosphodieserases
Phosphoinositide-3 kinase inhibitors


Combination therapy with botulinum toxin and bulking agent-An efficient, sustainable, and safe method to treat elderly women with mixed urinary incontinence.

Abstract:
AIMS
To evaluate the efficacy, sustainability and safety of combined botulinum toxin and polyacrylamide hydrogel (PAHG) therapy to treat urgency and stress components of therapy-refractory mixed urinary incontinence (MUI) in an elderly study population.

METHODS
Fifty-five women with therapy-refractory MUI were treated with botulinum toxin and PAHG in one surgical procedure. Urgency urinary incontinence (UUI) and stress urinary incontinence (SUI) outcomes were separately assessed after 4 and 12 months by objective UUI episodes/24 h and cough test, subjective impact of UUI and SUI on quality of life, and subjective International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF). MUI outcome was calculated by combining UUI and SUI outcomes. Complications were monitored throughout the study.

RESULTS
At 4 months, objective cure rates were 73%, 53%, and 42%, and subjective cure rates were 71%, 52%, and 50% for SUI, UUI, and MUI. At 12 months, objective cure rates were 73%, 56%, 50% and subjective cure rates were 78%, 42%, and 40% for SUI, UUI, and MUI. The ICIQ-UI SF score decreased by 9.0 and 8.7 points after 4 and 12 months. All complications were transient and included 22% clean intermittent catheterization immediately after surgery, 33% postvoid residual volumes >100 ml at 14 days, and 13% symptomatic urinary tract infection within the first postoperative month.

CONCLUSIONS
The combination of botulinum toxin and PAHG is effective, sustainable and safe to treat therapy-refractory MUI, even in an elderly and frail study population. Patients benefit from the short surgical procedure without the need for general anaesthesia or discontinuation of anticoagulation.

Viereck|Volker|V|0000-0002-1116-8912 Gamper|Marianne|M|0000-0002-8235-1239 Walser|Claudia|C| Fesslmeier|Debra|D| Münst|Julia|J| Zivanovic|Irena|I|

D000368:Aged
D001905:Botulinum Toxins
D005260:Female
D006801:Humans
D011788:Quality of Life
D016896:Treatment Outcome
D014549:Urinary Incontinence
D014550:Urinary Incontinence, Stress
D053202:Urinary Incontinence, Urge

polyacrylamide hydrogel
urgency urinary incontinence
stress urinary incontinence
1-year follow-up
Botox
Bulkamid
therapy-refractory urinary incontinence


Production and transepithelial transportation of angiotensin-I-converting enzyme (ACE)-inhibitory peptides from whey protein hydrolyzed by immobilized Lactobacillus helveticus proteinase.

Abstract: Lactobacillus helveticus LB 10 proteinases immobilized with sodium alginate were used to hydrolyze whey protein to produce angiotensin-I-converting enzyme (ACE)-inhibitory peptides. The generated hydrolysates were tested for ACE-inhibitory activity and for their ability to be transported across Caco-2 cell monolayers. Using a response surface method, we determined that a proteinase concentration of 7.55 mg/mL, sodium alginate concentration of 2.03 g/100 mL, and glutaraldehyde concentration of 0.39% were found to be the optimal immobilization conditions. Compared with free proteinase, the immobilized proteinase had significantly higher pH, thermal and storage stability, and reusability. Whey protein hydrolysates were fractionated by gel filtration chromatography and ACE-inhibitory peptide mixtures were transported across Caco-2 cell monolayers in a human intestinal-absorption model. The di- and tripeptides KA, EN, DIS, EVD, LF, AIV, and VFK (half-maximal inhibitory concentrations (mean ± standard deviation) of 1.24 ± 0.01, 1.43 ± 0.04, 1.59 ± 0.27, 1.32 ± 0.05, 1.60 ± 0.39, 2.66 ± 0.02, and 1.76 ± 0.09 mmol/L, respectively) were detected on the basolateral side of the Caco-2 cell monolayer using ultra-performance liquid chromatography-tandem mass spectrometry. These results highlight that ACE-inhibitory peptides are present on the basolateral side of the Caco-2 cell model after transportation of whey protein hydrolysate across the Caco-2 cell membrane.

Guo|Yuxing|Y| Jiang|Xiaoxiao|X| Xiong|Binyi|B| Zhang|Tao|T| Zeng|Xiaoqun|X| Wu|Zhen|Z| Sun|Yangying|Y| Pan|Daodong|D|


Relevance of low viral load in haemodialysed patients with chronic hepatitis C virus infection.

Abstract:
AIM
To identify predictors of sustained virological response in hemodialysed patients treated by PEGinterferon α for chronic hepatitis C, genotype 1.

METHODS
The sustained virological response (SVR) rate, IL28B genotype, IFNL4 genotype, initial viral load (IVL) and other pretreatment variables in 39 end-stage renal disease patients (ESRD) on maintenance haemodialysis (HD) infected with hepatitis C virus (HCV), genotype 1b, were compared with a control group of 109 patients with normal kidney function treated within the same period. All the patients were treatment naïve and had well compensated liver disease. The ESRD patients received 135 μg of PEGylated interferon α-2a (PegIFN-α) weekly and a reduced dose of ribavirin (RBV) was administered to 23/39 patients with an initial haemoglobin level > 10 g/dL. Control group patients were given standard doses of PegIFN-α and RBV. SVR was assessed as HCV RNA negativity 24 wk post-treatment. A t-test or ANOVA were used for comparisons of the means and a χ(2) test compared the frequencies. Logistic regression was used to determine significant predictors of SVR. Cutoff values for continuous variables were obtained from Receiver Operating Characteristic analysis.

RESULTS
The distribution of IL28B rs12979860 CC, CT and TT genotypes in the ESRD group was 28.2%, 64.1% and 7.7%, respectively, and 19.3%, 62.4% and 18.3% in the controls. The IFNL4 genotype was in almost absolute linkage disequlibrium with IL28B. The proportion of patients with a low IVL (< 600000 IU/mL) was significantly higher in the ESRD group than in the controls (28/39, 71.8% vs 51/109, 46.8%, P = 0.009), as was the proportion of patients with low IVL in IL28B CC carriers compared with non-CC carriers in the ESRD group (10/11, 90.9% vs 18/28, 64.3%, P = 0.0035). This difference was not found in the controls (7/22, 31.8% vs 44/87, 50.6%, P = 0.9). The overall SVR rate was 64.1% (25/39) in the ESRD group and 50.5% (55/109) in the control group (P = 0.19). 11/11 (100%) and 19/22 (86.4%) IL28B CC patients achieved SVR in the ESRD and control groups, respectively. A statistically significant association between SVR and IL28B and IFNL4 variants was found in both groups. The ESRD patients who achieved SVR showed the lowest IVL [median 21000, interquartile range (IQR): 6000-23000 IU/mL], compared with ESRD individuals without SVR (1680000, IQR: 481000-6880000, P = 0.001), controls with SVR (387000, IQR: 111000-1253000) and controls without SVR (905000, IQR: 451000-3020000). In ESRD, an IVL < 600000 IU/mL was strongly associated with SVR: 24/28 (85.7%) patients who achieved SVR had viraemia below this threshold.

CONCLUSION
Haemodialysis decreases the viral load, especially in IL28B CC genotype carriers. A low IVL was the strongest predictor of SVR in ESRD patients identified in multivariate analysis.

Sperl|Jan|J| Frankova|Sona|S| Senkerikova|Renata|R| Neroldova|Magdalena|M| Hejda|Vaclav|V| Volfova|Miroslava|M| Merta|Dusan|D| Viklicky|Ondrej|O| Spicak|Julius|J| Jirsa|Milan|M|

IFNL4
End-stage renal disease
Ribavirin
Hepatitis C virus genotype 1
Interferon alpha