bluuebunny/crossref_metadata_2025 huggingface dataset:
Achievements and Challenges in the Prevention of Mother-to-Child Transmission of HIV—A Retrospective Cohort Study from a Rural Hospital in Northern Tanzania
Authors: Nydal Sunniva Marie , Munyaw Yuda , Bruun Johan N. , Brantsæter Arne Broch
Published: March 2021

Despite the goal of eliminating new human immunodeficiency virus (HIV) infections in children, mother-to-child transmission is still common in resource-poor countries. The aims of this study were to assess the occurrence of mother-to-child transmission of HIV (MTCT) by age 18 months, risk factors for transmission, and the implementation of the national prevention of MTCT (PMTCT) program in a rural hospital in Tanzania. Data were collated from various medical registers and records. We included 172 children and 167 HIV-infected mothers. Among 88 children (51%) with adequate information, 9 (10.2%) were infected. Increased risk of MTCT was associated with late testing of the child (>2 months) [OR = 9.5 (95% CI: 1.8–49.4)], absence of antiretroviral therapy during pregnancy [OR = 9.7 (95% CI: 2.1–46.1)], and maternal CD4 cell count <200 cells/mm3 [OR = 15.3 (95% CI: 2.1–111)]. We were unable to determine the occurrence of MTCT transmission in 84 children (49%). The results from this study highlight that there is an urgent need for enhanced efforts to improve follow-up of HIV-exposed children, to improve documentation in registries and records, and to facilitate ease of linkage between these.
Survey of the Knowledge and Use of Antibiotics among Medical and Veterinary Health Professionals and Students in Portugal
Authors: Marta-Costa Ana , Miranda Carla , Silva Vanessa , Silva Adriana , Martins Ângela , Pereira José Eduardo , Maltez Luis , Capita Rosa , Alonso-Calleja Carlos , Igrejas Gilberto , Poeta Patrícia
Published: March 2021

Antimicrobial resistance (AMR) is an urgent and complex problem worldwide, exacerbated by the frequently inappropriate use of antibiotics. The purpose of this study was to survey the levels of knowledge and awareness about antibiotic use and stewardship, among human and veterinary health professionals or students in Portugal, and the associations between antibiotic knowledge factors and socio-professional groups. In cross-sectional survey design, a total of 449 online structured questionnaires were completed in 2018–2019. The statistical analysis was performed dividing the respondents into four groups, A (undergraduate students), B (PhD students and researchers), C (lecturers), and D (technicians and other occupation). Among all respondents, 17% (n = 75) revealed some gap in knowledge about antibiotic resistance and the antibiotics that should be administered for different infection types (bacterial, viral, or fungal). Of the 159 pet owners among the respondents, only half had administered antibiotics to their animal and 64% (n = 102) knew that veterinary prescription is mandatory when administering antibiotics to animals. All groups statistically agreed that the AMR is a major public health problem and the antibiotics should be administrated for bacterial infections and used until the whole pack has been finished (p = 0.00). As expected, only groups B and C demonstrated a higher level of knowledge to recognize the antibiotic name and their active ingredient than undergraduate students (p = 0.00). About the antibiotic use on pets, only group B was statistically significant to no used antibiotics on their pets (p = 0.00). However, groups A, C, and D were statistically significant for the knowledge about the mandatory veterinarian prescription and groups C and D were significantly statistics for fully aware of the transmission of bacteria between animals and humans. In conclusion, in matters related to AMR, the behavior, education, and training of the general public and health professionals, including those who prescribe antibiotics for humans and animals, need to be improved.
Multiple Forms of Sexting and Associations with Psychosocial Health in Early Adolescents
Authors: Lu Yu , Baumler Elizabeth , Temple Jeff R.
Published: March 2021

Despite the recent surge of sexting research, the link between sexting and psychosocial health remains inconclusive. To address this gap in the literature, we examined the link between multiple forms of sexting and a range of psychosocial health problems. Data were from a randomized controlled trial of a school-based dating violence prevention program. Participants were 2199 early adolescents (49.8% female) aged 14 years and under (mean age = 13.53, SD = 0.50) enrolled in middle-schools in southeast Texas. Participants self-reported to be 35.4% Hispanic, 7.9% Non-Hispanic White, 26.2% Non-Hispanic Black, 18.6% Asian, and 11.9% other. Multilevel multivariate regressions found that pressured sexting was associated with hostility and aggressive temperament. Receiving unsolicited sexts was associated with depression, impulsivity, hostility, emotion dysregulation, and aggressive temperament. Forwarding sexts without permission was linked to hostility. Asking someone for sexts was linked to impulsivity and aggressive temperament, while being asked to send a sext was associated with depression, anxiety, impulsivity, hostility, emotion dysregulation, and aggressive temperament. Finally, consensual sexting was not significantly associated with poor psychosocial health of any type. Interventions should focus on preventing pressured sexting and teaching early adolescents on how to respond to being pressured to sext.
Adaptive Health Coaching Technology for Tailored Interventions
Authors: Jimison Holly , Shapiro Michael , Pavel Misha
Published: March 2021

Recent advances in sensor and communications technology have enabled scalable methods for providing continuity of care to the home for patients with chronic conditions and older adults wanting to age in place. In this article we describe our framework for a health coaching platform with a dynamic user model that enables tailored health coaching messages. We have shown that this can improve coach efficiency without a loss of message quality. We also discovered many lessons for coaching technology, most demonstrating the need for more coach input on sample message content, perhaps even requiring that individual coaches be able to modify the message database directly. Overall, coaches felt that the structure of the automated message generation was useful in remembering what to say, easy to edit if necessary and especially helpful for training new health coaches.
Pandemics and Burden of Stroke and Epilepsy in Sub-Saharan Africa: Experience from a Longstanding Health Programme
Authors: Leone Massimo , Ciccacci Fausto , Orlando Stefano , Petrolati Sandro , Guidotti Giovanni , Majid Noorjehan Abdul , Tolno Victor Tamba , Sagno JeanBaptiste , Thole Darlington , Corsi Fabio Massimo , Bartolo Michelangelo , Marazzi Maria Cristina
Published: March 2021

Eighty percent of people with stroke live in low- to middle-income nations, particularly in sub-Saharan Africa (SSA) where stroke has increased by more than 100% in the last decades. More than one-third of all epilepsy−related deaths occur in SSA. HIV infection is a risk factor for neurological disorders, including stroke and epilepsy. The vast majority of the 38 million people living with HIV/AIDS are in SSA, and the burden of neurological disorders in SSA parallels that of HIV/AIDS. Local healthcare systems are weak. Many standalone HIV health centres have become a platform with combined treatment for both HIV and noncommunicable diseases (NCDs), as advised by the United Nations. The COVID-19 pandemic is overwhelming the fragile health systems in SSA, and it is feared it will provoke an upsurge of excess deaths due to the disruption of care for chronic diseases such as HIV, TB, hypertension, diabetes, and cerebrovascular disorders. Disease Relief through Excellent and Advanced Means (DREAM) is a health programme active since 2002 to prevent and treat HIV/AIDS and related disorders in 10 SSA countries. DREAM is scaling up management of NCDs, including neurologic disorders such as stroke and epilepsy. We described challenges and solutions to address disruption and excess deaths from these diseases during the ongoing COVID-19 pandemic.
Structure and Distribution of Health Care Costs across Age Groups of Patients with Multimorbidity in Lithuania
Authors: Nedzinskienė Laura , Jurevičienė Elena , Visockienė Žydrūnė , Ulytė Agnė , Puronaitė Roma , Kasiulevičius Vytautas , Kazėnaitė Edita , Burneikaitė Greta , Navickas Rokas
Published: March 2021

Background. Patients with multimorbidity account for ever-increasing healthcare resource usage and are often summarised as big spenders. Comprehensive analysis of health care resource usage in different age groups in patients with at least two non-communicable diseases is still scarce, limiting the quality of health care management decisions, which are often backed by limited, small-scale database analysis. The health care system in Lithuania is based on mandatory social health insurance and is covered by the National Health Insurance Fund. Based on a national Health Insurance database. The study aimed to explore the distribution, change, and interrelationships of health care costs across the age groups of patients with multimorbidity, suggesting different priorities at different age groups. Method. The study identified all adults with at least one chronic disease when any health care services were used over a three-year period between 2012 and 2014. Further data analysis excluded patients with single chronic conditions and further analysed patients with multimorbidity, accounting for increasing resource usage. The costs of primary, outpatient health care services; hospitalizations; reimbursed and paid out-of-pocket medications were analysed in eight age groups starting at 18 and up to 85 years and over. Results. The study identified a total of 428,430 adults in Lithuania with at least two different chronic diseases from the 32 chronic disease list. Out of the total expenditure within the group, 51.54% of the expenses were consumed for inpatient treatment, 30.90% for reimbursed medications. Across different age groups of patients with multimorbidity in Lithuania, 60% of the total cost is attributed to the age group of 65–84 years. The share in the total spending was the highest in the 75–84 years age group amounting to 29.53% of the overall expenditure, with an increase in hospitalization and a decrease in outpatient services. A decrease in health care expenses per capita in patients with multimorbidity after 85 years of age was observed. Conclusions. The highest proportion of health care expenses in patients with multimorbidity relates to hospitalization and reimbursed medications, increasing with age, but varies through different services. The study identifies the need to personalise the care of patients with multimorbidity in the primary-outpatient setting, aiming to reduce hospitalizations with proactive disease management.
The Story as a Quality Instrument: Developing an Instrument for Quality Improvement Based on Narratives of Older Adults Receiving Long-Term Care
Authors: Scheffelaar Aukelien , Janssen Meriam , Luijkx Katrien
Published: March 2021

The individual experiences of older adults in long-term care are broadly recognized as an important source of information for measuring wellbeing and quality of care. Narrative research is a special type of qualitative research to elicit people’s individual, diverse experiences in the context of their lifeworld. Narratives are potentially useful for long-term care improvement as they can provide a rich description of an older adult’s life from their own point of view, including the provided care. Little is known about how narratives can best be collected and used to stimulate learning and quality improvement in long-term care for older adults. The current study takes a theoretical approach to developing a narrative quality instrument for care practice in order to discover the experiences of older adults receiving long-term care. The new narrative quality instrument is based on the available literature describing narrative research methodology. The instrument is deemed promising for practice, as it allows care professionals to collect narratives among older adults in a thorough manner for team reflection in order to improve the quality of care. In the future, the feasibility and usability of the instrument will have to be empirically tested.
Time Trend of Persistent Organic Pollutants and Metals in Greenlandic Inuit during 1994–2015
Authors: Long Manhai , Wielsøe Maria , Bonefeld-Jørgensen Eva Cecilie
Published: March 2021

Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), organchlorine pesticides and perfluoroalkylated substances (PFASs) and heavy metals bioaccumulate in the marine food chain in the Arctic regions, and thus, the Greenlandic population has a higher body burden due to relatively high intake of marine mammals. We assessed the temporal trend for POPs, including PCB 153; 1,1-dichloro−2,2-bis (p-chlorophenyl)-ethylene (p,p’-DDE); oxychlordane; six PFASs; mercury; lead and selenium in Inuit from Ilulissat, Nuuk, and across Greenland (including thirteen towns/districts), from 1994 to 2015. Data showed a significant annual decrease of 6.85–8.61% for PCB153, 6.67–8.61% for p,p’-DDE, 6.11–9.52% for oxychlordane, 5.92–6.76% for mercury and 6.48–9.43% for lead in Inuit women from Nuuk, Ilulissat, and across thirteen Greenlandic districts. The blood selenium level of all Greenlandic women increased 1.01% annually, while the trend direction was negative for Nuuk women. A similar pattern was seen for men across Greenland, with a yearly decrease of 11.3% for PCB 153, 8.61% for p,p’-DDE, 15.6% for oxychlordane, 13.1% for mercury and 12.2% for lead. Perfluorooctane sulfonate, perfluorohexane sulfonate and perfluorooctanoic acid significantly decreased 5.82–11.7% annually for both women and men across Greenland. For perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid, we observed an increasing trend for women across Greenland. In conclusion, there was a decreasing trend of the regulated POPs and metals but a potential increasing trend of the nonregulated PFASs in the Greenlandic population between 1994 and 2015. The continuing biomonitoring of contaminants of concern is important to protect the Arctic population heath.
Grid-Scale Impact of Climate Change and Human Influence on Soil Erosion within East African Highlands (Kagera Basin)
Authors: Li Chaodong , Li Zhanbin , Yang Mingyi , Ma Bo , Wang Baiqun
Published: March 2021

Under global climate change and pressure from human activities, soil erosion is becoming a major concern in the quest for regional sustainable development in the Kagera basin (KB). However, few studies in this region have comprehensively considered the impact of climate change and human influence on soil erosion, and the associated processes are unclear. Based on the premise of quantifying climate change, human influence, and soil erosion, this study undertook a neighborhood analysis as the theoretical support, for a grey relation analysis which was conducted to realize the qualitative assessment of the influence of climate change and human activities on soil erosion. The results show that 90.32% of the KB saw climate change as having a greater influence on soil erosion than human influence, with the remaining area 9.68% seeing human influence having a greater impact than climate change, mainly as a result of the effect of rangeland and farmland. The average soil erosion rate of the KB shows a very low level (10.54 t ha−1 yr−1), with rangeland and farmland being the main land use/land cover (LULC) types that see soil loss, followed by forest, wetland, and built-up areas. The climate change trends of the KB show the most dramatic changes in the northeast and southwest, gradually decreasing towards the line crossing from the Birunga National Park (Rwanda) to the Keza district (Tanzania). The human influence intensity (HII) shows a high level in the KB (21.93), where it is higher in the west and lower in the east of the basin.
The Impact of Childhood Left-Behind Experience on the Mental Health of Late Adolescents: Evidence from Chinese College Freshmen
Authors: Wu Huajun , Cai Zhiyong , Yan Qing , Yu Yi , Yu Ning Neil
Published: March 2021

A paucity of public service afforded to migrant workers often begets a wide range of social problems. In China, hundreds of millions of migrant worker parents have to leave children behind in their hometowns. This paper investigated the long-term effects of the childhood experience of being left behind on the mental well-being of late adolescents. Mandatory university personality inventory (UPI) surveys (involving psychosomatic problems such as anxiety, depression, and stress) were conducted at a university in Jiangsu, China, during 2014–2017. The study sample consisted of 15,804 first-year college students aged between 15 and 28 years. The PSM method and the OLS regression model were employed. Controlling for the confounding factors (gender, age, single-child status, hometown location, ethnicity, and economic status), our empirical investigation demonstrated that childhood left-behind experience significantly worsened the mental health of the study sample, increasing the measure of mental ill-being by 0.661 standard deviations (p < 0.01). Moreover, the effects were consistently significant in subsamples divided by gender, single-child status, and hometown location; and the effects were greater for females, single-child students, and urban residents.
Reflective Functioning in Patients with Irritable Bowel Syndrome, Non-Affective Psychosis and Affective Disorders—Differences and Similarities
Authors: Dzirlo Larisa , Richter Felix , Steinmair Dagmar , Löffler-Stastka Henriette
Published: March 2021

Irritable bowel syndrome (IBS), as part of the functional somatic syndromes, is frequent in the general population. Medical care and morbidity costs are high, and so is the psychological and somatic strain. The etiopathogenesis of IBS is still poorly understood; it is assumed to be multifactorial and to include biopsychosocial factors. Links between the intestine, psyche, nervous system (e.g., via the hypothalamic–pituitary–adrenal axis (HPA-Axis/neurotransmitters) and with the microbiome, the immune system have lately been investigated. Factors such as personality traits, mentalization, and early attachment strategies (deactivating and hyperactivating) have been suggested to influence IBS with relevance for treatment regimens. At this time, data on reflective functioning (RF) is lacking. Within a cross-sectional, we examined the mentalizing capacity of a clinical sample (n = 90) consisting of patients with IBS (n = 30), affective disorders (AD; n = 28), and non-affective psychosis (NAP; n = 32). The reflective functioning scale was used based on the brief reflective function interview (BRFI). The results revealed severe impairment in patients with IBS concerning their mentalizing ability, which was comparable to patients with affective disorders. Patients with non-affective-psychosis showed the lowest mentalizing ability. Thus, psychotherapeutic treatment with a focus on mentalization could be a promising approach.
Changes in Anthropometric and Performance Parameters in High-Level Endurance Athletes during a Sports Season
Authors: Alves Javier , Barrientos Gema , Toro Víctor , Sánchez Esther , Muñoz Diego , Maynar Marcos
Published: March 2021

Several anthropometric and performance parameters related to aerobic metabolism are associated with performance in endurance runners and are modified according to the training performed. The objective of this study was to investigate the ergospirometric and body composition changes in endurance runners during a sports season in relation to their training. Twenty highly trained men endurance runners performed an incremental test until exhaustion (initial, and at 3, 6, and 9 months) on a treadmill to determine maximal oxygen consumption (VO2 max), second ventilatory threshold (VT2), and their associated running speeds. Skinfolds, perimeters, and weights were measured. No changes were obtained in VO2 max or VT2 during the study, although their associated running speeds increased (p < 0.05) after 3 months of the study. Decreases in fat mass (p < 0.05) and muscle mass (p < 0.05) were observed at the end of the season (9 months). Changes occurred in the different skinfolds according to the characteristics of the training performed during the season. In conclusion, vVO2 max and vVT2 increase with a greater volume of kilometres trained and can be adversely affected by loss of muscle mass.
Healthcare-Associated Laboratory-Confirmed Bloodstream Infections—Species Diversity and Resistance Mechanisms, a Four-Year Retrospective Laboratory-Based Study in the South of Poland
Authors: Chmielarczyk Agnieszka , Pomorska-Wesołowska Monika , Romaniszyn Dorota , Wójkowska-Mach Jadwiga
Published: March 2021

Introduction: Regardless of the country, advancements in medical care and infection prevention and control of bloodstream infections (BSIs) are an enormous burden of modern medicine. Objectives: The aim of our study was to describe the epidemiology and drug-resistance of laboratory-confirmed BSI (LC-BSIs) among adult patients of 16 hospitals in the south of Poland. Patients and methods: Data on 4218 LC-BSIs were collected between 2016–2019. The identification of the strains was performed using MALDI-TOF. Resistance mechanisms were investigated according to European Committee on Antimicrobial Susceptibility Testing, EUCAST recommendations. Results: Blood cultures were collected from 8899 patients, and LC-BSIs were confirmed in 47.4%. The prevalence of Gram-positive bacteria was 70.9%, Gram-negative 27.8% and yeast 1.4%. The most frequently isolated genus was Staphylococcus (50% of all LC-BSIs), with a domination of coagulase-negative staphylococci, while Escherichia coli (13.7%) was the most frequent Gram-negative bacterium. Over 4 years, 108 (2.6%) bacteria were isolated only once, including species from the human microbiota as well as environmental and zoonotic microorganisms. The highest methicillin resistant Staphylococcus aureus (MRSA) prevalence was in intensive care units (ICUs) (55.6%) but S. aureus with resistance to macrolides, lincosamides and streptogramins B (MLSB) in surgery was 66.7%. The highest prevalence of E. faecalis with a high-level aminoglycoside resistance (HLAR) mechanism was in ICUs, (84.6%), while E. faecium-HLAR in surgery was 83.3%. All cocci were fully glycopeptide-sensitive. Carbapenem-resistant Gram-negative bacilli were detected only in non-fermentative bacilli group, with prevalence 70% and more. Conclusions: The BSI microbiology in Polish hospitals was similar to those reported in other studies, but the prevalence of MRSA and enterococci-HLAR was higher than expected, as was the prevalence of carbapenem-resistant non-fermentative bacilli. Modern diagnostic techniques, such as MALDI-TOF, guarantee reliable diagnosis.
Light Quality and Intensity Modulate Cold Acclimation in Arabidopsis
Authors: Prerostova Sylva , Dobrev Petre I. , Knirsch Vojtech , Jarosova Jana , Gaudinova Alena , Zupkova Barbara , Prášil Ilja T. , Janda Tibor , Brzobohatý Břetislav , Skalák Jan , Vankova Radomira
Published: March 2021

Plant survival in temperate zones requires efficient cold acclimation, which is strongly affected by light and temperature signal crosstalk, which converge in modulation of hormonal responses. Cold under low light conditions affected Arabidopsis responses predominantly in apices, possibly because energy supplies were too limited for requirements of these meristematic tissues, despite a relatively high steady-state quantum yield. Comparing cold responses at optimal light intensity and low light, we found activation of similar defence mechanisms—apart from CBF1–3 and CRF3–4 pathways, also transient stimulation of cytokinin type-A response regulators, accompanied by fast transient increase of trans-zeatin in roots. Upregulated expression of components of strigolactone (and karrikin) signalling pathway indicated involvement of these phytohormones in cold responses. Impaired response of phyA, phyB, cry1 and cry2 mutants reflected participation of these photoreceptors in acquiring freezing tolerance (especially cryptochrome CRY1 at optimal light intensity and phytochrome PHYA at low light). Efficient cold acclimation at optimal light was associated with upregulation of trans-zeatin in leaves and roots, while at low light, cytokinin (except cis-zeatin) content remained diminished. Cold stresses induced elevation of jasmonic acid and salicylic acid (in roots). Low light at optimal conditions resulted in strong suppression of cytokinins, jasmonic and salicylic acid.
Identification of Overexpressed Genes in Malignant Pleural Mesothelioma
Authors: Morani Federica , Bisceglia Luisa , Rosini Giulia , Mutti Luciano , Melaiu Ombretta , Landi Stefano , Gemignani Federica
Published: March 2021

Malignant pleural mesothelioma (MPM) is a fatal tumor lacking effective therapies. The characterization of overexpressed genes could constitute a strategy for identifying drivers of tumor progression as targets for novel therapies. Thus, we performed an integrated gene-expression analysis on RNAseq data of 85 MPM patients from TCGA dataset and reference samples from the GEO. The gene list was further refined by using published studies, a functional enrichment analysis, and the correlation between expression and patients’ overall survival. Three molecular signatures defined by 15 genes were detected. Seven genes were involved in cell adhesion and extracellular matrix organization, with the others in control of the mitotic cell division or apoptosis inhibition. Using Western blot analyses, we found that ADAMTS1, PODXL, CIT, KIF23, MAD2L1, TNNT1, and TRAF2 were overexpressed in a limited number of cell lines. On the other hand, interestingly, CTHRC1, E-selectin, SPARC, UHRF1, PRSS23, BAG2, and MDK were abundantly expressed in over 50% of the six MPM cell lines analyzed. Thus, these proteins are candidates as drivers for sustaining the tumorigenic process. More studies with small-molecule inhibitors or silencing RNAs are fully justified and need to be undertaken to better evaluate the cancer-driving role of the targets herewith identified.
Unusually Fast bis-Histidyl Coordination in a Plant Hemoglobin
Authors: Abbruzzetti Stefania , Barker Alex J. , Villar Irene , Pérez-Rontomé Carmen , Bruno Stefano , Cerullo Giulio , Viappiani Cristiano , Becana Manuel
Published: March 2021

The recently identified nonsymbiotic hemoglobin gene MtGlb1-2 of the legume Medicago truncatula possesses unique properties as it generates four alternative splice forms encoding proteins with one or two heme domains. Here we investigate the ligand binding kinetics of MtGlb1-2.1 and MtGlb1-2.4, bearing two hemes and one heme, respectively. Unexpectedly, the overall time-course of ligand rebinding was unusually fast. Thus, we complemented nanosecond laser flash photolysis kinetics with data collected with a hybrid femtosecond–nanosecond pump–probe setup. Most photodissociated ligands are rebound geminately within a few nanoseconds, which leads to rates of the bimolecular rebinding to pentacoordinate species in the 108 M−1s−1 range. Binding of the distal histidine to the heme competes with CO rebinding with extremely high rates (kh ~ 105 s−1). Histidine dissociation from the heme occurs with comparable rates, thus resulting in moderate equilibrium binding constants (KH ~ 1). The rate constants for ligation and deligation of distal histidine to the heme are the highest reported for any plant or vertebrate globin. The combination of microscopic rates results in unusually high overall ligand binding rate constants, a fact that contributes to explaining at the mechanistic level the extremely high reactivity of these proteins toward the physiological ligands oxygen, nitric oxide and nitrite.
Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones
Authors: Horchani Mabrouk , Della Sala Gerardo , Caso Alessia , D’Aria Federica , Esposito Germana , Laurenzana Ilaria , Giancola Concetta , Costantino Valeria , Jannet Hichem Ben , Romdhane Anis
Published: March 2021

Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of hybrid pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones, 5a–h, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide 4 with a series of arylaldehydes in ethanol, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that 5a, 5e, 5g, and 5h were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, 5a, 5e, 5g, and 5h were evaluated for their binding interactions with two well-known anticancer targets, namely the epidermal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of 5a, 5e, 5g, and 5h towards EGFR. Circular dichroism (CD) experiments suggested 5a as a stabilizer agent of the G-quadruplex from the Kirsten ras (KRAS) oncogene promoter. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hydrazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds.
Methamphetamine Blocks Adenosine A2A Receptor Activation via Sigma 1 and Cannabinoid CB1 Receptors
Authors: Casanovas Mireia , Reyes-Resina Irene , Lillo Alejandro , Lillo Jaume , López-Arnau Raul , Camarasa Jorge , Escubedo Elena , Navarro Gemma , Franco Rafael
Published: March 2021

Methamphetamine is, worldwide, one of the most consumed drugs of abuse. One important side effect is neurodegeneration leading to a decrease in life expectancy. The aim of this paper was to check whether the drug affects one of the receptors involved in neurodegeneration/neuroprotection events, namely the adenosine A2A receptor (A2AR). First, we noticed that methamphetamine does not affect A2A functionality if the receptor is expressed in a heterologous system. However, A2AR becomes sensitive to the drug upon complexes formation with the cannabinoid CB1 receptor (CB1R) and the sigma 1 receptor (σ1R). Signaling via both adenosine A2AR and cannabinoid CB1R was affected by methamphetamine in cells co-expressing the two receptors. In striatal primary cultures, the A2AR–CB1R heteromer complex was detected and methamphetamine not only altered its expression but completely blocked the A2AR- and the CB1R-mediated activation of the mitogen activated protein kinase (MAPK) pathway. In conclusion, methamphetamine, with the participation of σ1R, alters the expression and function of two interacting receptors, A2AR, which is a therapeutic target for neuroprotection, and CB1R, which is the most abundant G protein-coupled receptor (GPCR) in the brain.
Exploring the Crosstalk between Hydrostatic Pressure and Adipokines: An In Vitro Study on Human Osteoarthritic Chondrocytes
Authors: Cheleschi Sara , Tenti Sara , Barbarino Marcella , Giannotti Stefano , Bellisai Francesca , Frati Elena , Fioravanti Antonella
Published: March 2021

Obesity is a risk factor for osteoarthritis (OA) development and progression due to an altered biomechanical stress on cartilage and an increased release of inflammatory adipokines from adipose tissue. Evidence suggests an interplay between loading and adipokines in chondrocytes metabolism modulation. We investigated the role of loading, as hydrostatic pressure (HP), in regulating visfatin-induced effects in human OA chondrocytes. Chondrocytes were stimulated with visfatin (24 h) and exposed to high continuous HP (24 MPa, 3 h) in the presence of visfatin inhibitor (FK866, 4 h pre-incubation). Apoptosis and oxidative stress were detected by cytometry, B-cell lymphoma (BCL)2, metalloproteinases (MMPs), type II collagen (Col2a1), antioxidant enzymes, miRNA, cyclin D1 expressions by real-time PCR, and β-catenin protein by western blot. HP exposure or visfatin stimulus significantly induced apoptosis, superoxide anion production, and MMP-3, -13, antioxidant enzymes, and miRNA gene expression, while reducing Col2a1 and BCL2 mRNA. Both stimuli significantly reduced β-catenin protein and increased cyclin D1 gene expression. HP exposure exacerbated visfatin-induced effects, which were counteracted by FK866 pre-treatment. Our data underline the complex interplay between loading and visfatin in controlling chondrocytes’ metabolism, contributing to explaining the role of obesity in OA etiopathogenesis, and confirming the importance of controlling body weight for disease treatment.
Interactions of Meibum and Tears with Mucomimetic Polymers: A Hint towards the Interplay between the Layers of the Tear Film
Authors: Eftimov Petar , Yokoi Norihiko , Melo Ana M. , Daull Philippe , Georgiev Georgi As.
Published: March 2021

Recent clinical findings suggest that mucomimetic polymers (MMP) can alter not only the texture of the aqueous tear but also the spreading and structure of the tear film (TF) lipid layer, thereby allowing for their synchronized performance in vivo. Thus, we aimed to evaluate in vitro (i) the capability of pharmaceutically applicable MMP to ensure the formation of post-evaporative ferning patterns (a characteristic feature of the “healthy” tear colloid) and (ii) the MMP interactions with human meibum films accessed in the course of blink-like deformations via Langmuir surface balance and Brewster angle microscopy (BAM). Four MMP were used- hyaluronic acid (HA), cross-linked hyaluronic acid (CHA), carboxymethyl cellulose (CMC) and gellan gum (GG)- at the concentrations of 0.0001%, 0.001%, 0.01%, 0.05% and 0.1%. Significant differences were observed in the MMP fern formation capability: CHA (≥0.001%) > HA (≥0.01%) = CMC (≥0.01%) > GG (≥0.05%). All MMP affected the spreading of meibum, with BAM micrographs revealing thickening of the films. CHA was particularly efficient, showing concentration-dependent enhancement of tear ferning and of meibomian layer structure, surfactant properties and viscoelasticity. Thus, endogenous and exogenous MMP may play key roles for the concerted action of the TF layers at the ocular surface, revealing novel routes for TF-oriented therapeutic applications.
Auxin and Root Gravitropism: Addressing Basic Cellular Processes by Exploiting a Defined Growth Response
Authors: Konstantinova Nataliia , Korbei Barbara , Luschnig Christian
Published: March 2021

Root architecture and growth are decisive for crop performance and yield, and thus a highly topical research field in plant sciences. The root system of the model plant Arabidopsis thaliana is the ideal system to obtain insights into fundamental key parameters and molecular players involved in underlying regulatory circuits of root growth, particularly in responses to environmental stimuli. Root gravitropism, directional growth along the gravity, in particular represents a highly sensitive readout, suitable to study adjustments in polar auxin transport and to identify molecular determinants involved. This review strives to summarize and give an overview into the function of PIN-FORMED auxin transport proteins, emphasizing on their sorting and polarity control. As there already is an abundance of information, the focus lies in integrating this wealth of information on mechanisms and pathways. This overview of a highly dynamic and complex field highlights recent developments in understanding the role of auxin in higher plants. Specifically, it exemplifies, how analysis of a single, defined growth response contributes to our understanding of basic cellular processes in general.
Specialized Pro-Resolving Mediators and the Lymphatic System
Authors: Kraft Jamie D. , Blomgran Robert , Lundgaard Iben , Quiding-Järbrink Marianne , Bromberg Jonathan S. , Börgeson Emma
Published: March 2021

Diminished lymphatic function and abnormal morphology are common in chronic inflammatory diseases. Recent studies are investigating whether it is possible to target chronic inflammation by promoting resolution of inflammation, in order to enhance lymphatic function and attenuate disease. Resolution of inflammation is an active process regulated by bioactive lipids known as specialized pro-resolving mediators (SPMs). SPMs can modulate leukocyte migration and function, alter cytokine/chemokine release, modify autophagy, among other immune-related activities. Here, we summarize the role of the lymphatics in resolution of inflammation and lymphatic impairment in chronic inflammatory diseases. Furthermore, we discuss the current literature describing the connection between SPMs and the lymphatics, and the possibility of targeting the lymphatics with innovative SPM therapy to promote resolution of inflammation and mitigate disease.
Trans-Cinnamaldehyde Exhibits Synergy with Conventional Antibiotic against Methicillin-Resistant Staphylococcus aureus
Authors: Wang Shu , Kang Ok-Hwa , Kwon Dong-Yeul
Published: March 2021

Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen worldwide and has acquired multiple resistance to a wide range of antibiotics. Hence, there is a pressing need to explore novel strategies to overcome the increase in antimicrobial resistance. The present study aims to investigate the efficacy and mechanism of plant-derived antimicrobials, trans-cinnamaldehyde (TCA) in decreasing MRSA’s resistance to eight conventional antibiotics. A checkerboard dilution test and time–kill curve assay are used to determine the synergistic effects of TCA combined with the antibiotics. The results indicated that TCA increased the antibacterial activity of the antibiotics by 2-16-fold. To study the mechanism of the synergism, we analyzed the mecA transcription gene and the penicillin-binding protein 2a level of MRSA treated with TCA by quantitative RT-PCR or Western blot assay. The gene transcription and the protein level were significantly inhibited. Additionally, it was verified that TCA can significantly inhibit the biofilm, which is highly resistant to antibiotics. The expression of the biofilm regulatory gene hld of MRSA after TCA treatment was also significantly downregulated. These findings suggest that TCA maybe is an exceptionally potent modulator of antibiotics.
Apoptosis Imaging in Oncology by Means of Positron Emission Tomography: A Review
Authors: Van de Wiele Christophe , Ustmert Sezgin , De Spiegeleer Bart , De Jonghe Pieter-Jan , Sathekge Mike , Alex Maes
Published: March 2021

To date, a wide variety of potential PET-apoptosis imaging radiopharmaceuticals targeting apoptosis-induced cell membrane asymmetry and acidification, as well as caspase 3 activation (substrates and inhibitors) have been developed with the purpose of rapidly assessing the response to treatment in cancer patients. Many of these probes were shown to specifically bind to their apoptotic target in vitro and their uptake to be enhanced in the in vivo-xenografted tumours in mice treated by means of chemotherapy, however, to a significantly variable degree. This may, in part, relate to the tumour model used given the fact that different tumour cell lines bear a different sensitivity to a similar chemotherapeutic agent, to differences in the chemotherapeutic concentration and exposure time, as well as to the different timing of imaging performed post-treatment. The best validated cell membrane acidification and caspase 3 targeting radioligands, respectively 18F-ML-10 from the Aposense family and the radiolabelled caspase 3 substrate 18F-CP18, have also been injected in healthy individuals and shown to bear favourable dosimetric and safety characteristics. However, in contrast to, for instance, the 99mTc-HYNIC-Annexin V, neither of both tracers was taken up to a significant degree by the bone marrow in the healthy individuals under study. Removal of white and red blood cells from the bone marrow through apoptosis plays a major role in the maintenance of hematopoietic cell homeostasis. The major apoptotic population in normal bone marrow are immature erythroblasts. While an accurate estimate of the number of immature erythroblasts undergoing apoptosis is not feasible due to their unknown clearance rate, their number is likely substantial given the ineffective quote of the erythropoietic process described in healthy subjects. Thus, the clinical value of both 18F-ML-10 and 18F-CP18 for apoptosis imaging in cancer patients, as suggested by a small number of subsequent clinical phase I/II trials in patients suffering from primary or secondary brain malignancies using 18F-ML-10 and in an ongoing trial in patients suffering from cancer of the ovaries using 18F-CP18, remains to be proven and warrants further investigation.
Assessing Plasmin Generation in Health and Disease
Authors: Miszta Adam , Huskens Dana , Donkervoort Demy , Roberts Molly J. M. , Wolberg Alisa S. , de Laat Bas
Published: March 2021

Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing. Plasmin is a central enzyme in this process via its capacity to cleave fibrin. The kinetics of plasmin generation (PG) and inhibition during fibrinolysis have been poorly understood until the recent development of assays to quantify these metrics. The assessment of plasmin kinetics allows for the identification of fibrinolytic dysfunction and better understanding of the relationships between abnormal fibrin dissolution and disease pathogenesis. Additionally, direct measurement of the inhibition of PG by antifibrinolytic medications, such as tranexamic acid, can be a useful tool to assess the risks and effectiveness of antifibrinolytic therapy in hemorrhagic diseases. This review provides an overview of available PG assays to directly measure the kinetics of plasmin formation and inhibition in human and mouse plasmas and focuses on their applications in defining the role of plasmin in diseases, including angioedema, hemophilia, rare bleeding disorders, COVID-19, or diet-induced obesity. Moreover, this review introduces the PG assay as a promising clinical and research method to monitor antifibrinolytic medications and screen for genetic or acquired fibrinolytic disorders.
Bone Marrow Aspirate Matrix: A Convenient Ally in Regenerative Medicine
Authors: Lana José Fábio , da Fonseca Lucas Furtado , Azzini Gabriel , Santos Gabriel , Braga Marcelo , Cardoso Junior Alvaro Motta , Murrell William D. , Gobbi Alberto , Purita Joseph , Percope de Andrade Marco Antonio
Published: March 2021

The rise in musculoskeletal disorders has prompted medical experts to devise novel effective alternatives to treat complicated orthopedic conditions. The ever-expanding field of regenerative medicine has allowed researchers to appreciate the therapeutic value of bone marrow-derived biological products, such as the bone marrow aspirate (BMA) clot, a potent orthobiologic which has often been dismissed and regarded as a technical complication. Numerous in vitro and in vivo studies have contributed to the expansion of medical knowledge, revealing optimistic results concerning the application of autologous bone marrow towards various impactful disorders. The bone marrow accommodates a diverse family of cell populations and a rich secretome; therefore, autologous BMA-derived products such as the “BMA Matrix”, may represent a safe and viable approach, able to reduce the costs and some drawbacks linked to the expansion of bone marrow. BMA provides —it eliminates many hurdles associated with its preparation, especially in regards to regulatory compliance. The BMA Matrix represents a suitable alternative, indicated for the enhancement of tissue repair mechanisms by modulating inflammation and acting as a natural biological scaffold as well as a reservoir of cytokines and growth factors that support cell activity. Although promising, more clinical studies are warranted in order to further clarify the efficacy of this strategy.
Reduction of Amyloid Burden by Proliferated Homeostatic Microglia in Toxoplasma gondii-Infected Alzheimer’s Disease Model Mice
Authors: Shin Ji-Hun , Hwang Young Sang , Jung Bong-Kwang , Seo Seung-Hwan , Ham Do-Won , Shin Eun-Hee
Published: March 2021

In this study, we confirmed that the number of resident homeostatic microglia increases during chronic Toxoplasma gondii infection. Given that the progression of Alzheimer’s disease (AD) worsens with the accumulation of amyloid β (Aβ) plaques, which are eliminated through microglial phagocytosis, we hypothesized that T. gondii-induced microglial proliferation would reduce AD progression. Therefore, we investigated the association between microglial proliferation and Aβ plaque burden using brain tissues isolated from 5XFAD AD mice (AD group) and T. gondii-infected AD mice (AD + Toxo group). In the AD + Toxo group, amyloid plaque burden significantly decreased compared with the AD group; conversely, homeostatic microglial proliferation, and number of plaque-associated microglia significantly increased. As most plaque-associated microglia shifted to the disease-associated microglia (DAM) phenotype in both AD and AD + Toxo groups and underwent apoptosis after the lysosomal degradation of phagocytosed Aβ plaques, this indicates that a sustained supply of homeostatic microglia is required for alleviating Aβ plaque burden. Thus, chronic T. gondii infection can induce microglial proliferation in the brains of mice with progressed AD; a sustained supply of homeostatic microglia is a promising prospect for AD treatment.
Butyrate Improves Skin/Lung Fibrosis and Intestinal Dysbiosis in Bleomycin-Induced Mouse Models
Authors: Park Hee Jin , Jeong Ok-Yi , Chun Sung Hak , Cheon Yun Hong , Kim Mingyo , Kim Suhee , Lee Sang-Il
Published: March 2021

Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Despite several studies on SSc treatments, effective treatments for SSc are still lacking. Since evidence suggests an association between intestinal microbiota and SSc, we focused on butyrate, which has beneficial effects in autoimmune diseases as a bacterial metabolite. Here, we investigated the therapeutic potential of sodium butyrate (SB) using a bleomycin-induced fibrosis mouse model of SSc and human dermal fibroblasts (HDFs). SB attenuated bleomycin-induced dermal and lung fibrosis in mice. SB influenced fecal microbiota composition (phyla Actinobacteria and Bacteroidetes, genera Bifidobacterium and Ruminococcus_g2). SB controlled macrophage differentiation in mesenteric lymph nodes, spleen, and bronchoalveolar lavage cells of mice with bleomycin-induced skin fibrosis. Profibrotic and proinflammatory gene expression was suppressed by SB administration in skin. Furthermore, SB inhibited transforming growth factor β1-responsive proinflammatory expression with increased acetylation of histone 3 in HDFs. Subcutaneous SB application had antifibrogenic effects on the skin. Butyrate ameliorated skin and lung fibrosis by improving anti-inflammatory activity in a mouse model of SSc. Butyrate may exhibit indirect and direct anti-fibrogenic action on fibroblasts by regulating macrophage differentiation and inhibition of histone deacetylase 3. These findings suggest butyrate as an SSc treatment.