bluuebunny/crossref_metadata_2025 huggingface dataset:
Antimicrobial Resistance Profiles and Macrolide Resistance Mechanisms of Campylobacter coli Isolated from Pigs and Chickens
Authors: Choi Ji-Hyun , Moon Dong Chan , Mechesso Abraham Fikru , Kang Hee Young , Kim Su-Jeong , Song Hyun-Ju , Yoon Soon-Seek , Lim Suk-Kyung
Published: May 2021

We identified 1218 Campylobacter coli isolates from fecal and carcass samples of pigs (n = 643) and chickens (n = 575) between 2010 and 2018. About 99% of the isolates were resistant to at least one antimicrobial agent. The isolates exhibited high resistance rates (>75%) to ciprofloxacin, nalidixic acid, and tetracycline. Azithromycin and erythromycin resistance rates were the highest in isolates from pigs (39.7% and 39.2%, respectively) compared to those of chickens (15.8% and 16.3%, respectively). Additionally, a low-to-moderate proportion of the isolates were resistant to florfenicol, gentamicin, clindamycin, and telithromycin. Multidrug resistance (MDR) was found in 83.1% of the isolates, and profiles of MDR usually included ciprofloxacin, nalidixic acid, and tetracycline. We found point mutation (A2075G) in domain V of the 23S rRNA gene in the majority of erythromycin-resistant isolates. Multilocus sequence typing of 137 erythromycin-resistant C. coli isolates revealed 37 previously reported sequence types (STs) and 8 novel STs. M192I, A103VI, and G74A substitutions were frequently noted in the ribosomal proteins L4 or L22. Further, we identified a considerable proportion (>90%) of erythromycin-resistant isolates carrying virulence factor genes: flaA, cadF, ceuE, and VirB. The prudent use of antimicrobials and regular microbiological investigation in food animals will be vital in limiting the public health hazards of C. coli in Korea.
Differences in Adolescents’ Food Habits Checklist (AFHC) Scores before and during Pandemic in a Population-Based Sample: Polish Adolescents’ COVID-19 Experience (PLACE-19) Study
Authors: Skolmowska Dominika , Głąbska Dominika , Guzek Dominika
Published: May 2021

The COVID-19 pandemic is known to influence the dietary habits of adults, but results for adolescents in studies are ambiguous. The present work aimed to analyze the differences in the scores of the Adolescents’ Food Habits Checklist (AFHC) before and during the pandemic in the Polish Adolescents’ COVID-19 Experience (PLACE-19) Study population. The PLACE-19 Study was conducted during the pandemic among a population of 2448 students recruited from secondary schools in all regions of Poland using a random quota sampling. The participants were required to complete an AFHC consisting of 23 items pertaining to food purchase, preparation, and consumption habits. Current habits (during the pandemic) and previous habits were assessed and scored separately. The total (p = 0.001), purchase (p < 0.001), and consumption scores (p = 0.014) indicated that the AFHC scores during the pandemic were higher than before. For questions on purchase habits, a lower number of respondents reported eating in a restaurant, eating takeaway meals, having lunch away from home, or buying pastries, cakes or crisps. For questions on preparation habits, an greater number of respondents reported that they usually avoided eating fried food and tried to keep their overall sugar intake down, but fewer respondents said they tried to have low-fat desserts. For questions on consumption habits, a lower number of respondents reported that they usually ate a dessert or pudding if one were available and a larger number said they made sure to eat at least one serving of vegetables or salad a day and at least three servings of fruit most days. Based on the obtained results, it may be stated that although there was an increase in the AFHC scores during the pandemic, a similar share of respondents showed improved or worsened food habits, and a similar share changed their food habits from healthy to unhealthy and from unhealthy to healthy. At the same time, a majority of changes were associated with purchase habits, which were probably forced by lockdowns and the resultant restrictions in eating out or grocery shopping.
Advances in NAD-Lowering Agents for Cancer Treatment
Authors: Ghanem Moustafa S. , Monacelli Fiammetta , Nencioni Alessio
Published: May 2021

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor, but it also acts as a substrate for NAD-consuming enzymes, regulating cellular events such as DNA repair and gene expression. Since such processes are fundamental to support cancer cell survival and proliferation, sustained NAD production is a hallmark of many types of neoplasms. Depleting intratumor NAD levels, mainly through interference with the NAD-biosynthetic machinery, has emerged as a promising anti-cancer strategy. NAD can be generated from tryptophan or nicotinic acid. In addition, the “salvage pathway” of NAD production, which uses nicotinamide, a byproduct of NAD degradation, as a substrate, is also widely active in mammalian cells and appears to be highly exploited by a subset of human cancers. In fact, research has mainly focused on inhibiting the key enzyme of the latter NAD production route, nicotinamide phosphoribosyltransferase (NAMPT), leading to the identification of numerous inhibitors, including FK866 and CHS-828. Unfortunately, the clinical activity of these agents proved limited, suggesting that the approaches for targeting NAD production in tumors need to be refined. In this contribution, we highlight the recent advancements in this field, including an overview of the NAD-lowering compounds that have been reported so far and the related in vitro and in vivo studies. We also describe the key NAD-producing pathways and their regulation in cancer cells. Finally, we summarize the approaches that have been explored to optimize the therapeutic response to NAMPT inhibitors in cancer.
Distinct Effects of a High Fat Diet on Bone in Skeletally Mature and Developing Male C57BL/6J Mice
Authors: Ross Dean , Yeh Tzu-Hsuan , King Shalinie , Mathers Julia , Rybchyn Mark , Neist Elysia , Cameron Melissa , Tacey Alexander , Girgis Christian , Levinger Itamar , Mason Rebecca , Brennan-Speranza Tara
Published: May 2021

Increased risks of skeletal fractures are common in patients with impaired glucose handling and type 2 diabetes mellitus (T2DM). The pathogenesis of skeletal fragility in these patients remains ill-defined as patients present with normal to high bone mineral density. With increasing cases of glucose intolerance and T2DM it is imperative that we develop an accurate rodent model for further investigation. We hypothesized that a high fat diet (60%) administered to developing male C57BL/6J mice that had not reached skeletal maturity would over represent bone microarchitectural implications, and that skeletally mature mice would better represent adult-onset glucose intolerance and the pre-diabetes phenotype. Two groups of developing (8 week) and mature (12 week) male C57BL/6J mice were placed onto either a normal chow (NC) or high fat diet (HFD) for 10 weeks. Oral glucose tolerance tests were performed throughout the study period. Long bones were excised and analysed for ex vivo biomechanical testing, micro-computed tomography, 2D histomorphometry and gene/protein expression analyses. The HFD increased fasting blood glucose and significantly reduced glucose tolerance in both age groups by week 7 of the diets. The HFD reduced biomechanical strength, both cortical and trabecular indices in the developing mice, but only affected cortical outcomes in the mature mice. Similar results were reflected in the 2D histomorphometry. Tibial gene expression revealed decreased bone formation in the HFD mice of both age groups, i.e., decreased osteocalcin expression and increased sclerostin RNA expression. In the mature mice only, while the HFD led to a non-significant reduction in runt-related transcription factor 2 (Runx2) RNA expression, this decrease became significant at the protein level in the femora. Our mature HFD mouse model more accurately represents late-onset impaired glucose tolerance/pre-T2DM cases in humans and can be used to uncover potential insights into reduced bone formation as a mechanism of skeletal fragility in these patients.
Horse Placental Extract Enhances Neurogenesis in the Presence of Amyloid β
Authors: de Toledo Andreia , Nomoto Kaori , Hirano Eiichi , Tohda Chihiro
Published: May 2021

Human placental extract and animal-derived placental extracts from pigs and horses host a wide range of biological activities. Several placental products are used as medicines, cosmetics, and healthcare substances worldwide. However, the use of placental extracts for neuronal functioning is currently not established because the number of relevant studies is limited. A few previous reports suggested the neuroprotective effect and dendrite genesis effect of placental extract. However, no studies have reported on neurogenesis in placental extracts. Therefore, we aimed to investigate the effects of horse placental extract on neurogenesis, and we examined the protective effect of the extract on the onset of memory disorder. A horse placental extract, JBP-F-02, was used in this study. JBP-F-02 treatment dose-dependently increased the number of neural stem cells and dendrite length under Aβ treatment in primary cultured cortical cells. The oral administration of JBP-F-02 to a 5XFAD mouse model of Alzheimer’s disease at a young age significantly prevented the onset of memory dysfunction. This study suggests that the extract has the potential to prevent dementia.
A Combined Analysis of Gut and Skin Microbiota in Infants with Food Allergy and Atopic Dermatitis: A Pilot Study
Authors: Łoś-Rycharska Ewa , Gołębiewski Marcin , Sikora Marcin , Grzybowski Tomasz , Gorzkiewicz Marta , Popielarz Maria , Gawryjołek Julia , Krogulska Aneta
Published: May 2021

The gut microbiota in patients with food allergy, and the skin microbiota in atopic dermatitis patients differ from those of healthy people. We hypothesize that relationships may exist between gut and skin microbiota in patients with allergies. The aim of this study was to determine the possible relationship between gut and skin microbiota in patients with allergies, hence simultaneous analysis of the two compartments of microbiota was performed in infants with and without allergic symptoms. Fifty-nine infants with food allergy and/or atopic dermatitis and 28 healthy children were enrolled in the study. The skin and gut microbiota were evaluated using 16S rRNA gene amplicon sequencing. No significant differences in the α-diversity of dermal or fecal microbiota were observed between allergic and non-allergic infants; however, a significant relationship was found between bacterial community structure and allergy phenotypes, especially in the fecal samples. Certain clinical conditions were associated with characteristic bacterial taxa in the skin and gut microbiota. Positive correlations were found between skin and fecal samples in the abundance of Gemella among allergic infants, and Lactobacillus and Bacteroides among healthy infants. Although infants with allergies and healthy infants demonstrate microbiota with similar α-diversity, some differences in β-diversity and bacterial species abundance can be seen, which may depend on the phenotype of the allergy. For some organisms, their abundance in skin and feces samples may be correlated, and these correlations might serve as indicators of the host’s allergic state.
Vitamin C Deficiency in the Young Brain—Findings from Experimental Animal Models
Authors: Tveden-Nyborg Pernille
Published: May 2021

Severe and long-term vitamin C deficiency can lead to fatal scurvy, which is fortunately considered rare today. However, a moderate state of vitamin C (vitC) deficiency (hypovitaminosis C)—defined as a plasma concentration below 23 μM—is estimated to affect up to 10% of the population in the Western world, albeit clinical hallmarks in addition to scurvy have not been linked to vitC deficiency. The brain maintains a high vitC content and uniquely high levels during deficiency, supporting vitC’s importance in the brain. Actions include both antioxidant and co-factor functions, rendering vitamin C deficiency likely to affect several targets in the brain, and it could be particularly significant during development where a high cellular metabolism and an immature antioxidant system might increase sensitivity. However, investigations of a non-scorbutic state of vitC deficiency and effects on the developing young brain are scarce. This narrative review provides a comprehensive overview of the complex mechanisms that regulate vitC homeostasis in vivo and in the brain in particular. Functions of vitC in the brain and the potential consequences of deficiency during brain development are highlighted, based primarily on findings from experimental animal models. Perspectives for future investigations of vitC are outlined.
Boosting the Photoaged Skin: The Potential Role of Dietary Components
Authors: Geng Ruixuan , Kang Seong-Gook , Huang Kunlun , Tong Tao
Published: May 2021

Skin photoaging is mainly induced by ultraviolet (UV) irradiation and its manifestations include dry skin, coarse wrinkle, irregular pigmentation, and loss of skin elasticity. Dietary supplementation of nutraceuticals with therapeutic and preventive effects against skin photoaging has recently received increasing attention. This article aims to review the research progress in the cellular and molecular mechanisms of UV-induced skin photoaging. Subsequently, the beneficial effects of dietary components on skin photoaging are discussed. The photoaging process and the underlying mechanisms are complex. Matrix metalloproteinases, transforming growth factors, skin adipose tissue, inflammation, oxidative stress, nuclear and mitochondrial DNA, telomeres, microRNA, advanced glycation end products, the hypothalamic–pituitary–adrenal axis, and transient receptor potential cation channel V are key regulators that drive the photoaging-associated changes in skin. Meanwhile, mounting evidence from animal models and clinical trials suggests that various food-derived components attenuate the development and symptoms of skin photoaging. The major mechanisms of these dietary components to alleviate skin photoaging include the maintenance of skin moisture and extracellular matrix content, regulation of specific signaling pathways involved in the synthesis and degradation of the extracellular matrix, and antioxidant capacity. Taken together, the ingestion of food-derived functional components could be an attractive strategy to prevent skin photoaging damage.
Efficacy of Bilberry and Grape Seed Extract Supplement Interventions to Improve Glucose and Cholesterol Metabolism and Blood Pressure in Different Populations—A Systematic Review of the Literature
Authors: Grohmann Teresa , Litts Caroline , Horgan Graham , Zhang Xuguang , Hoggard Nigel , Russell Wendy , de Roos Baukje
Published: May 2021

Intervention with fruit extracts may lower glucose and lipid levels, as well as blood pressure. We reviewed the efficacy of bilberry and grape seed extracts to affect these outcomes across populations with varying health status, age and ethnicity, across intervention doses and durations, in 24 intervention studies with bilberry and blackcurrant (n = 4) and grape seed extract (n = 20). Bilberry and blackcurrant extract lowered average levels of glycated hemoglobin (HbA1c), at least in Chinese subjects, especially in those who were older, who were diagnosed with Type 2 Diabetes Mellitus (T2DM) and who were participating in longer-term studies. We also found good evidence that across studies and in subjects with hypercholesterolemia, T2DM or metabolic syndrome, intervention with bilberry and blackcurrant extract, and to some extent grape seed extract, significantly lowered total and low density lipoprotein (LDL) cholesterol levels after four weeks. Intervention with grape seed extract may reduce systolic and diastolic blood pressure in subjects with hypertension or metabolic syndrome. Differential responsiveness in cholesterol and blood pressure outcomes between stratified populations could not be explained by age, dose or study duration. In conclusion, bilberry and blackcurrant extract appears effective in lowering HbA1c and total and LDL cholesterol, whereas grape seed extract may lower total and LDL cholesterol, and blood pressure, in specific population groups.
Taste Sensitivity of Elderly People Is Associated with Quality of Life and Inadequate Dietary Intake
Authors: Jeon Soyeon , Kim Yeonhee , Min Sohyun , Song Mina , Son Sungtaek , Lee Seungmin
Published: May 2021

Aging has been implicated in the alteration of taste acuity. Diet can affect taste sensitivity. We aimed to investigate the types of tastes altered in elderly Korean people and factors associated with taste alteration in relation to dietary intake and other factors. Elderly participants (≥65 years) and young adults were assessed to determine their recognition thresholds (RT) for sweet, salty, bitter, sour, and umami tastes. Elderly participants were further surveyed for dietary intake and non-nutritional factors. Five taste RTs were correlated with age, but only four taste RTs, except sweetness, differed between the elderly participants and young adults. Inadequate intake of iron, thiamin, folic acid, zinc, and phosphorus among the elderly participants was related to elevated taste RT levels, except for bitter taste. In both correlation and regression analyses, only salty and sour RTs were associated with energy, iron, thiamin, fiber, vitamin C, and riboflavin levels in the elderly participants. The elderly participants’ taste RTs exhibited strong associations with quality of life (QOL) but showed partial relationships with physical activity, number of medicine intakes, social gatherings, and education. Taste sensitivity may decrease with age, which is further influenced by insufficient dietary intake, especially iron and thiamin, and QOL.
Effects of a Self-Prepared Carbohydrate-Reduced High-Protein Diet on Cardiovascular Disease Risk Markers in Patients with Type 2 Diabetes
Authors: Alzahrani Ahmad H. , Skytte Mads J. , Samkani Amirsalar , Thomsen Mads N. , Astrup Arne , Ritz Christian , Frystyk Jan , Holst Jens J. , Madsbad Sten , Haugaard Steen B. , Krarup Thure , Larsen Thomas M. , Magkos Faidon
Published: May 2021

We previously observed beneficial effects of a carbohydrate-reduced, high-protein (CRHP) diet on cardiovascular risk markers in patients with type 2 diabetes mellitus (T2DM) in a crossover 2 × 6-week trial, when all food was provided to subjects as ready-to-eat meals. Here, we report the results from a 6-month open label extension: 28 patients with T2DM were instructed to self-prepare the CRHP diet with dietetic guidance. At weeks 0, 6, 12, and 36, fasting and postprandial (4-h meal test) blood samples were collected for measurements of total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triacylglycerol (TG), apolipoproteins A1 and B, non-esterified fatty acids (NEFA), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6. Diurnal blood pressure and heart rate were also assessed. At the end of the study (week 36), concentrations of fasting total and LDL-cholesterol, fasting and postprandial NEFA and TG, and fasting apolipoprotein-B, CRP and TNF-α concentrations were significantly lower compared with week 0 (p < 0.05). A significant decrease in diurnal heart rate was also observed. From week 12 to 36, an increase in HDL-cholesterol and apolipoprotein-A1 concentrations and a further reduction in fasting and postprandial NEFA (p < 0.05) were found. These changes were independent of minor fluctuations in body weight. We conclude that the substitution of dietary carbohydrate for protein and fat has beneficial effects on several cardiovascular risk markers in patients with T2DM, which are maintained or augmented over the next 6 months when patients select and prepare the CRHP diet on their own in a dietitian-supported setting.
Iron Deficiency Anemia in Celiac Disease
Authors: Talarico Valentina , Giancotti Laura , Mazza Giuseppe Antonio , Miniero Roberto , Bertini Marco
Published: May 2021

The iron absorption process developsmainly in the proximal duodenum. This portion of the intestine is typically destroyed in celiac disease (CD), resulting in a reduction in absorption of iron and subsequent iron deficiency anemia (IDA). In fact, the most frequent extra-intestinal manifestation (EIM) of CD is IDA, with a prevalence between 12 and 82% (in relation with the various reports) in patients with new CD diagnosis. The primary treatment of CD is the gluten-free diet (GFD), which is associated with adequate management of IDA, if present. Iron replacement treatment historically has been based on oral products containing ferrous sulphate (FS). However, the absorption of FS is limited in patients with active CD and unpredictable in patients on a GFD. Furthermore, a poor tolerability of this kind of ferrous is particularly frequent in patients with CD or with other inflammatory bowel diseases. Normalization from anemic state typically occurs after at least 6 months of GFD, but the process can take up to 2 years for iron stores to replenish.
Coenzyme Q10: Clinical Applications beyond Cardiovascular Diseases
Authors: Testai Lara , Martelli Alma , Flori Lorenzo , Cicero Arrigo , Colletti Alessandro
Published: May 2021

Coenzyme Q10 (CoQ10) is an essential cofactor in oxidative phosphorylation (OXPHOS), present in mitochondria and cell membranes in reduced and oxidized forms. Acting as an energy transfer molecule, it occurs in particularly high levels in the liver, heart, and kidneys. CoQ10 is also an anti-inflammatory and antioxidant agent able to prevent the damage induced by free radicals and the activation of inflammatory signaling pathways. In this context, several studies have shown the possible inverse correlation between the blood levels of CoQ10 and some disease conditions. Interestingly, beyond cardiovascular diseases, CoQ10 is involved also in neuronal and muscular degenerative diseases, in migraine and in cancer; therefore, the supplementation with CoQ10 could represent a viable option to prevent these and in some cases might be used as an adjuvant to conventional treatments. This review is aimed to summarize the clinical applications regarding the use of CoQ10 in migraine, neurodegenerative diseases (including Parkinson and Alzheimer diseases), cancer, or degenerative muscle disorders (such as multiple sclerosis and chronic fatigue syndrome), analyzing its effect on patients’ health and quality of life.
Influence of Gender on Occurrence of Aseptic Loosening and Recurrent PJI after Revision Total Knee Arthroplasty
Authors: Kienzle Arne , Walter Sandy , Palmowski Yannick , Kirschbaum Stephanie , Biedermann Lara , von Roth Philipp , Perka Carsten , Müller Michael
Published: May 2021

Background: Periprosthetic joint infection (PJI) is a common yet severe complication after total knee arthroplasty (TKA). Surgical intervention and antibiotic therapy are obligatory to achieve successful, infection-free outcome. Compared to the outcomes after primary TKA, prosthesis failure rates are drastically increased after PJI-dependent revision surgery. Recurrent PJI and aseptic loosening are the most common reasons for prosthesis failure after revision TKA. An open question is the influence of the patients’ gender on long-term prosthesis survival after revision surgery. Additionally, it is unknown whether gender-related parameters and risk factors or differences in treatment are responsible for potential differences in outcome after revision arthroplasty. Patients and Methods: In this report, 109 patients that received TKA revision surgery due to PJI were retrospectively analyzed. We used clinical, paraclinical and radiological examinations to study the influence of gender on the long-term complications aseptic loosening and recurrent PJI after PJI-dependent revision arthroplasty. Results: While overall prosthesis failure rates and risk of recurrent PJI did not differ between genders, the long-term risk of aseptic loosening was significantly elevated in female patients. Postoperative coronal alignment was significantly more varus for women later diagnosed with aseptic loosening. Besides coronal alignment, no gender-dependent differences in clinical presentation or treatment were observed. Conclusions: Female patients displayed a significantly increased risk for aseptic loosening after PJI-dependent revision TKA. The observed gender-dependent differences in long-term outcome in our study support theories surrounding the role of bone metabolism in the development of aseptic loosening. Our data suggest that further research on a female design for PJI-dependent revision prostheses is warranted.
Heavy-Ion Collisions at FAIR-NICA Energies
Authors: Senger Peter
Published: May 2021

The “Facility for Antiproton and Ion Research” (FAIR) in Darmstadt, Germany, and the “Nuclotron-based Ion Collider Facility” (NICA) in Dubna, Russia, are two accelerator centers under construction. FAIR will provide beams and experimental setups to perform forefront research in hadron, nuclear, atomic, and plasma physics, as well as in radiation biology and material science. At NICA, a unique research program on nuclear matter and spin physics will be conducted. Both facilities will execute experiments to explore the properties of QCD matter at neutron star core densities, in order to study the high-density equation of state, and to shed light on the quark degrees-of-freedom emerging in QCD matter at high densities. The research programs will be performed at FAIR with the CBM experiment, and at NICA with the MPD setup at the collider, and with the BM@N experiment at the Nuclotron. These three experiments are complementary, with respect to the beam energy. The physics programs and the relevant experimental observables will be discussed.
Altered Nasal Microbiota Composition Associated with Development of Polyserositis by Mycoplasma hyorhinis
Authors: Blanco-Fuertes Miguel , Correa-Fiz Florencia , Fraile Lorenzo , Sibila Marina , Aragon Virginia
Published: May 2021

Fibrinous polyserositis in swine farming is a common pathological finding in nursery animals. The differential diagnosis of this finding should include Glaesserella parasuis (aetiological agent of Glässer’s disease) and Mycoplasma hyorhinis, among others. These microorganisms are early colonizers of the upper respiratory tract of piglets. The composition of the nasal microbiota at weaning was shown to constitute a predisposing factor for the development of Glässer’s disease. Here, we unravel the role of the nasal microbiota in the subsequent systemic infection by M. hyorhinis, and the similarities and differences with Glässer’s disease. Nasal samples from farms with recurrent problems with polyserositis associated with M. hyorhinis (MH) or Glässer’s disease (GD) were included in this study, together with healthy control farms (HC). Nasal swabs were taken from piglets in MH farms at weaning, before the onset of the clinical outbreaks, and were submitted to 16S rRNA gene amplicon sequencing (V3–V4 region). These sequences were analyzed together with sequences from similar samples previously obtained in GD and HC farms. Animals from farms with disease (MH and GD) had a nasal microbiota with lower diversity than those from the HC farms. However, the composition of the nasal microbiota of the piglets from these disease farms was different, suggesting that divergent microbiota imbalances may predispose the animals to the two systemic infections. We also found variants of the pathogens that were associated with the farms with the corresponding disease, highlighting the importance of studying the microbiome at strain-level resolution.
Neonatal SARS-CoV-2 Infection: Practical Tips
Authors: Auriti Cinzia , De Rose Domenico , Mondì Vito , Stolfi Ilaria , Tzialla Chryssoula ,   on behalf of the Study Group of Neonatal Infectious Diseases
Published: May 2021

The recent viral pandemic in Wuhan, Hubei, China has led to the identification of a new species of beta-coronavirus, able to infect humans, the 2019-nCoV, later named SARS-CoV-2. SARS-CoV-2 causes a clinical syndrome named COVID-19, which presents with a spectrum of symptoms ranging from mild upper respiratory tract infection to severe pneumonia, with acute respiratory distress syndrome and frequent death. All age groups are susceptible to the infection, but children, especially infants, seem to be partially spared, having a more favorable clinical course than other age groups. There is currently no clear evidence showing vertical transmission and intrauterine SARS-CoV-2 infection in fetuses of women developing COVID-19 pneumonia in late pregnancy, and even if transmission is possible, the SARS-CoV2 positivity of the mother does not require delivery by caesarean section, does not contraindicate the management of the infant in rooming-in and allows breastfeeding. This review provides an overview on the biology of the virus, on the pathogenesis of the infection, with particular attention to pregnancy and neonatal age, on the clinical presentation of infection in newborns and young infants and summarizes the international recommendations currently available on the clinical care of neonates with SARS-CoV2 infection or at risk of catching the virus. The main objective of the review is to provide an update especially focused to the clinical management of COVID-19 infection in the perinatal and neonatal age.
Analysis of Cannabinoids Concentration in Cannabis Oil Galenic Preparations: Harmonization between Three Laboratories in Northern Italy
Authors: Palermiti Alice , Cafaro Alessia , Barco Sebastiano , Bucchioni Paolo , Franceschini Paolo , Cusato Jessica , De Nicolò Amedeo , Manca Alessandra , De Vivo Elisa Delia , Russo Eleonora , Cecchi Francesco , Pigliasco Federica , Lillo Flavia , Tripodi Gino , D’Avolio Antonio , Cangemi Giuliana
Published: May 2021

Medical cannabis is increasingly being used in the treatment and support of several diseases and syndromes. The quantitative determination of active ingredients (delta-9 tetrahydrocannabinol, THC, and cannabidiol, CBD) in galenic oily preparations is prescribed by law for each produced batch. The aim of this work is to describe the organization of the titration activity centralized at three regional reference laboratories in Northern Italy. Pre-analytical, analytical, and post-analytical phases have been defined in order to guarantee high quality standards. A cross-validation between laboratories allowed for the definition of the procedures that guarantee the interchangeability between reference laboratories. The risk management protocol adopted can be useful for others who need to undertake this activity.
Potential Role of Methotrexate Polyglutamates in Therapeutic Drug Monitoring for Pediatric Inflammatory Bowel Disease
Authors: Morrow Ryan , Funk Ryan , Becker Mara , Sherman Ashley , Van Haandel Leon , Hudson Taina , Casini Rebecca , Shakhnovich Valentina
Published: May 2021

Inside cells, the immunomodulator methotrexate (MTX) undergoes the addition of glutamates to form methotrexate polyglutamates (MTX-Glu)—promising biomarkers of systemic exposure and treatment response to MTX in rheumatology. MTX-Glu are underexplored in Inflammatory Bowel Disease (IBD), with no data in pediatrics. In this cross-sectional secondary analysis, we assessed the relationships between MTX-Glu and MTX dose and treatment response in pediatric IBD. Twenty-one children with IBD, receiving maintenance therapy with infliximab (IFX) and MTX, had MTX-Glu1–6 concentrations and IFX troughs/antibodies measured and disease activity assessed for comparison in remission vs. active IBD using non-parametric tests, with associations explored using Spearman’s correlation (ρ) and regression analyses; SASv9.4 (α = 0.05). Total and long-chain MTX-Glu correlated with MTX dose (ρ = 0.51 and 0.56, respectively; p ≤ 0.02). In children with Crohn’s disease (n = 19), short-chain MTX-Glu1–2 were 2.5-fold higher in remission vs. active disease, approaching statistical significance (p = 0.066), with no statistical differences in IFX trough (p = 0.549) between groups. Our study highlights a potential role for long-chain MTX-Glu in the therapeutic drug monitoring of MTX in IBD. It is the first study in pediatric IBD and, although statistical significance was not reached, our findings also suggest that higher short-chain MTX-Glu levels may be associated with IBD treatment response to MTX in children.
Adequacy of Anesthesia Guidance for Colonoscopy Procedures
Authors: Stasiowski Michał Jan , Starzewska Małgorzata , Niewiadomska Ewa , Król Seweryn , Marczak Kaja , Żak Jakub , Pluta Aleksandra , Eszyk Jerzy , Grabarek Beniamin Oskar , Szumera Izabela , Nycz Michał , Missir Anna , Krawczyk Lech , Jałowiecki Przemysław
Published: May 2021

In patients undergoing colonoscopy procedures (CPs), inadequate dosing of hypnotic drugs (HD) and opioid analgesics (OA) during intravenous sedoanalgesia (ISA) may lead to intraprocedural awareness with recall (IAwR), intraprocedural (IPP) and postprocedural pain (PPP), as well as postoperative nausea and vomiting (PONV). The aim of this study was to evaluate whether the titration of HD and OA based on the observance of changing values of state entropy (SE) and surgical pleth index (SPI) (adequacy of anesthesia—AoA), state entropy alone, or standard practice may reduce the number of adverse events. One hundred and fifty-eight patients were included in the final analysis. The rate of IAwR and IPP was statistically more frequent in patients from the C group in comparison with the AoA and SE groups (p < 0.01 and p < 0.05, respectively). In turn, the rate of PPP, PONV, and patients’ and operators’ satisfaction with ISA between groups was not statistically significant (p > 0.05). Changes in hemodynamic parameters, demand for HD, and OA were statistically significant, but of no clinical value. In patients undergoing CPs under ISA using propofol and FNT, as compared to standard practice, intraprocedural SE monitoring reduced the rate of IAwR and IPP, with no influence on the rate of PPP, PONV, or patients’ and endoscopists’ satisfaction. AoA guidance on propofol and FNT titration, as compared to SE monitoring only, did not reduce the occurrence of the aforementioned studied parameters, imposing an unnecessary extra cost.
The Embryonic Chick Femur Organotypic Model as a Tool to Analyze the Angiotensin II Axis on Bone Tissue
Authors: Garbieri Thais Francini , Martin Victor , Santos Carlos Ferreira , Gomes Pedro de Sousa , Fernandes Maria Helena
Published: May 2021

Activation of renin–angiotensin system (RAS) plays a role in bone deterioration associated with bone metabolic disorders, via increased Angiotensin II (AngII) targeting Angiotensin II type 1 receptor/Angiotensin II type 2 receptor (AT1R/AT2R). Despite the wide data availability, the RAS role remains controversial. This study analyzes the feasibility of using the embryonic chick femur organotypic model to address AngII/AT1R/AT2R axis in bone, which is an application not yet considered. Embryonic day-11 femurs were cultured ex vivo for 11 days in three settings: basal conditions, exposure to AngII, and modulation of AngII effects by prior receptor blockade, i.e., AT1R, AT2R, and AT1R + AT2R. Tissue response was evaluated by combining µCT and histological analysis. Basal-cultured femurs expressed components of RAS, namely ACE, AT1R, AT2R, and MasR (qPCR analysis). Bone formation occurred in the diaphyseal region in all conditions. In basal-cultured femurs, AT1R blocking increased Bone Surface/Bone Volume (BS/BV), whereas Bone Volume/Tissue Volume (BV/TV) decreased with AT2R or AT1R + AT2R blockade. Exposure to AngII greatly decreased BV/TV compared to basal conditions. Receptor blockade prior to AngII addition prevented this effect, i.e., AT1R blockade induced BV/TV, whereas blocking AT2R caused lower BV/TV increase but greater BS/BV; AT1R + AT2R blockade also improved BV/TV. Concluding, the embryonic chick femur model was sensitive to three relevant RAS research setups, proving its usefulness to address AngII/AT1R/AT2R axis in bone both in basal and activated conditions.
Treatment with an Anti-CX3CL1 Antibody Suppresses M1 Macrophage Infiltration in Interstitial Lung Disease in SKG Mice
Authors: Mizutani Satoshi , Nishio Junko , Kondo Kanoh , Motomura Kaori , Yamada Zento , Masuoka Shotaro , Yamada Soichi , Muraoka Sei , Ishii Naoto , Kuboi Yoshikazu , Sendo Sho , Mikami Tetuo , Imai Toshio , Nanki Toshihiro
Published: May 2021

CX3C Motif Chemokine Ligand 1 (CX3CL1; fractalkine) has been implicated in the pathogenesis of rheumatoid arthritis (RA) and its inhibition was found to attenuate arthritis in mice as well as in a clinical trial. Therefore, we investigated the effects of an anti-CX3CL1 monoclonal antibody (mAb) on immune-mediated interstitial lung disease (ILD) in SKG mice, which exhibit similar pathological and clinical features to human RA-ILD. CX3CL1 and CX3C chemokine receptor 1 (CX3CR1), the receptor for CX3CL1, were both expressed in the fibroblastic foci of lung tissue and the number of bronchoalveolar fluid (BALF) cells was elevated in ILD in SKG mice. No significant changes were observed in lung fibrosis or the number of BALF cells by the treatment with anti-CX3CL1 mAb. However, significantly greater reductions were observed in the number of M1 macrophages than in M2 macrophages in the BALF of treated mice. Furthermore, CX3CR1 expression levels were significantly higher in M1 macrophages than in M2 macrophages. These results suggest the stronger inhibitory effects of the anti-CX3CL1 mAb treatment against the alveolar infiltration of M1 macrophages than M2 macrophages in ILD in SKG mice. Thus, the CX3CL1-CX3CR1 axis may be involved in the infiltration of inflammatory M1 macrophages in RA-ILD.
Activity and Safety of Immune Checkpoint Inhibitors in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis
Authors: Bongiovanni Alberto , Maiorano Brigida Anna , Azzali Irene , Liverani Chiara , Bocchini Martine , Fausti Valentina , Di Menna Giandomenico , Grassi Ilaria , Sansovini Maddalena , Riva Nada , Ibrahim Toni
Published: May 2021

Immune-checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different cancer types. Phase I/II trials have been designed to evaluate the role of ICIs both as single agents and in combination in neuroendocrine neoplasms (NENs), but as yet no randomized controlled phase III trials have been carried out. A systematic review and meta-analysis of studies published could help to reduce the biases of single-phase II trials. Efficacy data were obtained on 636 patients. Pooled percentages of the overall response rate (ORR) and disease control rate (DCR) were 10% (95% CI: 6–15%, I2 = 67%, p < 0.1) and 42% (95% CI: 28–56%, I2 = 93%, p < 0.1), respectively. Median progression-free survival (mPFS) was 4.1 months (95% CI 2.6–5.4; I2 = 96%, p < 0.1) and median overall survival (mOS) was 11 months (95% CI 4.8–21.1; I2 = 98%, p < 0.1). Among the ICIs used as single agents, the anti-PD1 toripalimab achieved the highest ORR. Combination regimens were superior to monotherapy, e.g., the ICI combination nivolumab + ipilimumab, and the ICI + anti-angiogenetic combination atezolizumab + bevacizumab, both of which warrant further investigation. Promising efficacy and a good safety profile of ICIs represent a valid opportunity for expanding the therapeutic landscape of NENs. Predictive biomarkers are needed to identify the most suitable candidates for these regimens.
Metronomic 5-Fluorouracil Delivery Primes Skeletal Muscle for Myopathy but Does Not Cause Cachexia
Authors: Campelj Dean G. , Timpani Cara A. , Cree Tabitha , Petersen Aaron C. , Hayes Alan , Goodman Craig A. , Rybalka Emma
Published: May 2021

Skeletal myopathy encompasses both atrophy and dysfunction and is a prominent event in cancer and chemotherapy-induced cachexia. Here, we investigate the effects of a chemotherapeutic agent, 5-fluorouracil (5FU), on skeletal muscle mass and function, and whether small-molecule therapeutic candidate, BGP-15, could be protective against the chemotoxic challenge exerted by 5FU. Additionally, we explore the molecular signature of 5FU treatment. Male Balb/c mice received metronomic tri-weekly intraperitoneal delivery of 5FU (23 mg/kg), with and without BGP-15 (15 mg/kg), 6 times in total over a 15 day treatment period. We demonstrated that neither 5FU, nor 5FU combined with BGP-15, affected body composition indices, skeletal muscle mass or function. Adjuvant BGP-15 treatment did, however, prevent the 5FU-induced phosphorylation of p38 MAPK and p65 NF-B subunit, signalling pathways involved in cell stress and inflammatory signalling, respectively. This as associated with mitoprotection. 5FU reduced the expression of the key cytoskeletal proteins, desmin and dystrophin, which was not prevented by BGP-15. Combined, these data show that metronomic delivery of 5FU does not elicit physiological consequences to skeletal muscle mass and function but is implicit in priming skeletal muscle with a molecular signature for myopathy. BGP-15 has modest protective efficacy against the molecular changes induced by 5FU.
Recent Advances in pH- or/and Photo-Responsive Nanovehicles
Authors: Shin Yuseon , Husni Patihul , Kang Kioh , Lee Dayoon , Lee Sehwa , Lee Eunseong , Youn Yuseok , Oh Kyungtaek
Published: May 2021

The combination of nanotechnology and chemotherapy has resulted in more effective drug design via the development of nanomaterial-based drug delivery systems (DDSs) for tumor targeting. Stimulus-responsive DDSs in response to internal or external signals can offer precisely controlled delivery of preloaded therapeutics. Among the various DDSs, the photo-triggered system improves the efficacy and safety of treatment through spatiotemporal manipulation of light. Additionally, pH-induced delivery is one of the most widely studied strategies for targeting the acidic micro-environment of solid tumors. Accordingly, in this review, we discuss representative strategies for designing DDSs using light as an exogenous signal or pH as an endogenous trigger.
Gemini Cationic Lipid-Type Nanovectors Suitable for the Transfection of Therapeutic Plasmid DNA Encoding for Pro-Inflammatory Cytokine Interleukin-12
Authors: Sánchez-Arribas Natalia , Martínez-Negro María , Aicart-Ramos Clara , Tros de Ilarduya Conchita , Aicart Emilio , Guerrero-Martínez Andrés , Junquera Elena
Published: May 2021

Ample evidence exists on the role of interleukin-12 (IL-12) in the response against many pathogens, as well as on its remarkable antitumor properties. However, the unexpected toxicity and disappointing results in some clinical trials are prompting the design of new strategies and/or vectors for IL-12 delivery. This study was conceived to further endorse the use of gemini cationic lipids (GCLs) in combination with zwitterionic helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphatidyl ethanol amine) as nanovectors for the insertion of plasmid DNA encoding for IL-12 (pCMV-IL12) into cells. Optimal GCL formulations previously reported by us were selected for IL-12-based biophysical experiments. In vitro studies demonstrated efficient pCMV-IL12 transfection by GCLs with comparable or superior cytokine levels than those obtained with commercial control Lipofectamine2000*. Furthermore, the nanovectors did not present significant toxicity, showing high cell viability values. The proteins adsorbed on the nanovector surface were found to be mostly lipoproteins and serum albumin, which are both beneficial to increase the blood circulation time. These outstanding results are accompanied by an initial physicochemical characterization to confirm DNA compaction and protection by the lipid mixture. Although further studies would be necessary, the present GCLs exhibit promising characteristics as candidates for pCMV-IL12 transfection in future in vivo applications.
Chondroitin Sulfate in USA Dietary Supplements in Comparison to Pharma Grade Products: Analytical Fingerprint and Potential Anti-Inflammatory Effect on Human Osteoartritic Chondrocytes and Synoviocytes
Authors: Stellavato Antonietta , Restaino Odile Francesca , Vassallo Valentina , Cassese Elisabetta , Finamore Rosario , Ruosi Carlo , Schiraldi Chiara
Published: May 2021

The biological activity of chondroitin sulfate (CS) and glucosamine (GlcN) food supplements (FS), sold in USA against osteoarthritis, might depend on the effective CS and GlcN contents and on the CS structural characteristics. In this paper three USA FS were compared to two pharmaceutical products (Ph). Analyses performed by HPAE-PAD, by HPCE and by SEC-TDA revealed that the CS and GlcN titers were up to −68.8% lower than the contents declared on the labels and that CS of mixed animal origin and variable molecular weights was present together with undesired keratan sulfate. Simulated gastric and intestinal digestions were performed in vitro to evaluate the real CS amount that may reach the gut as biopolymer. Chondrocytes and synoviocytes primary cells derived from human pathological joints were used to assess: cell viability, modulation of the NF-κB, quantification of cartilage oligomeric matrix protein (COMP-2), hyaluronate synthase enzyme (HAS-1), pentraxin (PTX-3) and the secreted IL-6 and IL-8 to assess inflammation. Of the three FS tested only one (US FS1) enhanced chondrocytes viability, while all of them supported synoviocytes growth. Although US FS1 proved to be less effective than Ph as it reduced NF-kB, it could not down-regulate COMP-2; HAS-1 was up-regulated but with a lower efficacy. Inflammatory cytokines were markedly reduced by Ph while a slight decrease was only found for US-FS1.
Gold Nanoparticles Affect Pericyte Biology and Capillary Tube Formation
Authors: Looprasertkul Sasikarn , Sereemaspun Amornpun , Kitkumthorn Nakarin , Sooklert Kanidta , Sarachana Tewarit , Jindatip Depicha
Published: May 2021

Gold nanoparticles (AuNPs) are used for diagnostic and therapeutic purposes, especially antiangiogenesis, which are accomplished via inhibition of endothelial cell proliferation, migration, and tube formation. However, no research has been performed on the effects of AuNPs in pericytes, which play vital roles in endothelial cell functions and capillary tube formation during physiological and pathological processes. Therefore, the effects of AuNPs on the morphology and functions of pericytes need to be elucidated. This study treated human placental pericytes in monoculture with 20 nm AuNPs at a concentration of 30 ppm. Ki-67 and platelet-derived growth factor receptor-β (PDGFR-β) mRNA expression was measured using real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell migration was assessed by Transwell migration assay. The fine structures of pericytes were observed by transmission electron microscopy. In addition, 30 ppm AuNP-treated pericytes and intact human umbilical vein endothelial cells were cocultured on Matrigel to form three-dimensional (3D) capillary tubes. The results demonstrated that AuNPs significantly inhibited proliferation, reduced PDGFR-β mRNA expression, and decreased migration in pericytes. Ultrastructural analysis of pericytes revealed AuNPs in late endosomes, autolysosomes, and mitochondria. Remarkably, many mitochondria were swollen or damaged. Additionally, capillary tube formation was reduced. We found that numerous pericytes on 3D capillary tubes were round and did not extend their processes along the tubes, which resulted in more incomplete tube formation in the treatment group compared with the control group. In summary, AuNPs can affect pericyte proliferation, PDGFR-β mRNA expression, migration, morphology, and capillary tube formation. The findings highlight the possible application of AuNPs in pericyte-targeted therapy for antiangiogenesis.