bluuebunny/crossref_metadata_2025 huggingface dataset:
Indirect Predictors of Visceral Adipose Tissue in Women with Polycystic Ovary Syndrome: A Comparison of Methods
Authors: Kałużna Małgorzata , Czlapka-Matyasik Magdalena , Bykowska-Derda Aleksandra , Moczko Jerzy , Ruchala Marek , Ziemnicka Katarzyna
Published: July 2021

Visceral adipose tissue (VAT) accumulation, is a part of a polycystic ovary syndrome (PCOS) phenotype. Dual-energy x-ray absorptiometry (DXA) provides a gold standard measurement of VAT. This study aimed to compare ten different indirect methods of VAT estimation in PCOS women. The study included 154 PCOS and 68 age- and BMI-matched control women. Subjects were divided into age groups: 18–30 y.o. and 30–40 y.o. Analysis included: body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), waist/height 0.5 (WHT.5R), visceral adipose index (VAI), lipid accumulation product (LAP), and fat mass index (FMI). VAT accumulation, android-to-gynoid ratio (A/G), and total body fat (TBF) was measured by DXA. ROC analysis revealed that WHtR, WHT.5R, WC, BMI, and LAP demonstrated the highest predictive value in identifying VAT in the PCOS group. Lower cut-off values of BMI (23.43 kg/m2) and WHtR (0.45) were determined in the younger PCOS group and higher thresholds of WHtR (0.52) in the older PCOS group than commonly used. Measuring either: WHtR, WHT.5R, WC, BMI, or LAP, could help identify a subgroup of PCOS patients at high cardiometabolic risk. The current observations reinforce the importance of using special cut-offs to identify VAT, dependent on age and PCOS presence.
The Effect of Amino Acids on Wound Healing: A Systematic Review and Meta-Analysis on Arginine and Glutamine
Authors: Arribas-López Elena , Zand Nazanin , Ojo Omorogieva , Snowden Martin John , Kochhar Tony
Published: July 2021

Under stress conditions, the metabolic demand for nutrients increases, which, if not met, may slow down or indeed stop the wound from healing, thus, becoming chronic wounds. This study aims to perform a systematic review and meta-analysis of the effect of arginine and glutamine supplementation on wound healing. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for the systematic review and ten electronic databases were used. Five and 39 human studies met the inclusion criteria for arginine and glutamine, respectively. The overall meta-analysis demonstrated a significant effect of arginine supplementation on hydroxyproline content (MD: 4.49, 95% CI: 3.54, 4.45, p < 0.00001). Regarding glutamine supplementation, there was significant effect on nitrogen balance levels (MD: 0.39, 95% CI: 0.21, 0.58, p < 0.0001), IL-6 levels (MD: −5.78, 95% CI: −8.71, −2.86, p = 0.0001), TNFα levels (MD: −8.15, 95% CI: −9.34, −6.96, p < 0.00001), lactulose/mannitol (L/M) ratio (MD: −0.01, 95% CI: −0.02, −0.01, p < 0.00001), patient mortality (OR: 0.48, 95% CI: 0.32, 0.72, p = 0.0004), C-reactive protein (CRP) levels (MD: −1.10, 95% CI: −1.26, −0.93, p < 0.00001) and length of hospital stay (LOS) (MD: −2.65, 95% CI: −3.10, −2.21, p < 0.00001). Regarding T-cell lymphocytes, a slight decrease was observed, although it failed to reach significance (MD: −0.16, 95% CI: −0.33, 0.01, p = 0.07). Conclusion: The wound healing might be enhanced in one or at various stages by nutritional supplementation in the right dose.
Designing Nutritionally Adequate and Climate-Friendly Diets for Omnivorous, Pescatarian, Vegetarian and Vegan Adolescents in Sweden Using Linear Optimization
Authors: Eustachio Colombo Patricia , Elinder Liselotte Schäfer , Lindroos Anna Karin , Parlesak Alexandr
Published: July 2021

Low-carbon diets can counteract climate change and promote health if they are nutritionally adequate, affordable and culturally acceptable. This study aimed at developing sustainable diets and to compare these with the EAT-Lancet diet. The Swedish national dietary survey Riksmaten Adolescents 2016–2017 was used as the baseline. Diets were optimized using linear programming for four dietary patterns: omnivores, pescatarians, vegetarians and vegans. The deviation from the baseline Riksmaten diet was minimized for all optimized diets while fulfilling nutrient and climate footprint constraints. Constraining the diet-related carbon dioxide equivalents of omnivores to 1.57 kg/day resulted in a diet associated with a reduction of meat, dairy products, and processed foods and an increase in potatoes, pulses, eggs and seafood. Climate-friendly, nutritionally adequate diets for pescatarians, vegetarians and vegans contained fewer foods and included considerable amounts of fortified dairy and meat substitutes. The optimized diets did not align very well with the food-group pattern of the EAT-Lancet diet. These findings suggest how to design future diets that are climate-friendly, nutritionally adequate, affordable, and culturally acceptable for Swedish adolescents with different dietary patterns. The discrepancies with the EAT diet indicate that the cultural dietary context is likely to play an important role in characterizing sustainable diets for specific populations.
Association between Predictors of Vitamin D Serum Levels and Risk of Retinoblastoma in Children: A Case-Control Study
Authors: Mejía-Rodríguez Fabiola , Flores-Aldana Mario E. , Quezada-Sánchez Amado D. , Shamah-Levy Teresa , Villalpando Salvador , Contreras-Manzano Alejandra , Bhatt-Carreño Silvia , Orjuela-Grimm Manuela
Published: July 2021

Background: vitamin D (VD) may be a protective factor for retinoblastoma, though no temporal association has been reported during pregnancy or the child’s first year of life. Serum VD concentrations are determined by both distal (DF) and proximal factors (PF). Objective: To identify if DF and PF can predict VD insufficiency (VDI) and VD deficiency (VDD) in women of childbearing age; and to test whether maternal exposure to DF and PF during pregnancy and a child’s exposure during the first 11.9 months postpartum are associated with sporadic retinoblastoma (SRb) in children. Methods: This is a secondary analysis of data from the Epidemiology of SRb in Mexico (EpiRbMx) study and the National Health and Nutrition Survey 2018–2019 (ENSANUT 2018–2019, for its acronym in Spanish). The association of DF and PF with VDD or VDI was estimated using ENSANUT 2018–2019, and the association of DF and PF with SRb using EpiRbMx. All were estimated using logistic regression, with comparable samples selected from ENSANUT 2018–2019 and EpiRbMx. Results: Altitude, latitude and obesity predicted VDI and VDD in ENSANUT women. In EpiRbMx, residence in a rural location during pregnancy increased the risk of SRb. For children, rural residence and latitude increased the risk of SRb, while the number of days exposed to the spring–summer season during months 6 to 11.9 of life was protective. Conclusions: risk of VDI and VDD in women (ENSANUT 2018–2019) increased with altitude, urban dwelling, overweight and obesity. The child and mother’s place of residence, including altitude, latitude and rural classification were important predictors of SRb in EpiRbMx.
A Comparison of the Effects of Young-Child Formulas and Cow’s Milk on Nutrient Intakes in Polish Children Aged 13–24 Months
Authors: Kostecka Malgorzata , Jackowska Izabella , Kostecka Julianna
Published: July 2021

Adequately balanced daily food rations that provide the body with sufficient amounts of energy and nutrients, including minerals, are particularly important in early childhood when rapid physical, intellectual and motor development takes place. Cow’s milk (CM) and young-child formulas (YCFs) are introduced to a child’s diet past the first year of age. The main aim of the present study was to perform a qualitative and a quantitative analysis of daily food rations of young children based on the recommendations of the daily food ration model. An attempt was also made to determine whether the type of consumed milk (YCF or CM) adequately meets young children’s energy demands and contributes to the incorporation of different food groups into a balanced and healthy diet for children aged 13–24 months. A total of 714 parents between October 2019 and March 2020 filled out a food frequency questionnaire. In the second stage of the study, the parents participated in a dietary recall and were asked to keep diaries of all meals and foods consumed by children over a period of three days. The mean daily intake of CM/YCF and fermented milks was determined at 360 mL ± 128 mL, and it accounted for 55.4% of the guideline values. Flavored dairy products were consumed more frequently than fermented milks without added sugar or flavoring (94 ± 17 g vs. 56 ± 26 g, p < 0.05). Diets incorporating CM were significantly more abundant in protein than YCF diets (29.3 g vs. 21.9 g; p < 0.01). Liquid intake was somewhat higher in children fed YCFs (1280.8 mL vs. 1120.1; p < 0.05), mainly due to the higher consumption of fruit juice, nectars and sweetened hot beverages (246 ± 35 mL in the YCF group vs. 201 ± 56 mL in the CM group; p < 0.05). Children fed YCF consumed significantly larger amounts of sweetened beverages such as tea sweetened with sugar or honey, sweetened hot chocolate or instant teas (OR = 2.54; Cl: 1.32–3.26; p < 0.001), than children receiving CM. This group was also characterized by higher consumption of sweetened dairy products, mainly cream cheese desserts, fruit yogurt and yogurt with cereal (OR = 1.87; Cl: 1.36–2.54; p < 0.01), as well as a lower daily intake of plain fermented milks (OR = 0.56; Cl: 0.21–0.79; p < 0.001). The daily food intake and the quality of the diets administered to children aged 13–24 months were evaluated and compared with the model food ration. It was found that milk type influenced children’s eating habits and preference for sweet-tasting foods. The study also demonstrated that Polish parents and caregivers only have limited knowledge of nutritional guidelines for toddlers.
Effects of 60-Day Saccharomyces boulardii and Superoxide Dismutase Supplementation on Body Composition, Hunger Sensation, Pro/Antioxidant Ratio, Inflammation and Hormonal Lipo-Metabolic Biomarkers in Obese Adults: A Double-Blind, Placebo-Controlled Trial
Authors: Rondanelli Mariangela , Miraglia Niccolò , Putignano Pietro , Castagliuolo Ignazio , Brun Paola , Dall’Acqua Stefano , Peroni Gabriella , Faliva Milena Anna , Naso Maurizio , Nichetti Mara , Infantino Vittoria , Perna Simone
Published: July 2021

In animals it has been demonstrated that Saccharomyces boulardii and Superoxide Dismutase (SOD) decrease low-grade inflammation and that S. boulardii can also decrease adiposity. The purpose of this study was to evaluate the effect of a 60-day S. boulardii and SOD supplementation on circulating markers of inflammation, body composition, hunger sensation, pro/antioxidant ratio, hormonal, lipid profile, glucose, insulin and HOMA-IR, in obese adults (BMI 30–35 kg/m2). Twenty-five obese adults were randomly assigned to intervention (8/4 women/men, 57 ± 8 years) or Placebo (9/4 women/men, 50 ± 9 years). Intervention group showed a statistically significant (p < 0.05) decrease of body weight, BMI, fat mass, insulin, HOMA Index and uric acid. Patients in intervention and control groups showed a significant decrease (p < 0.05) of GLP-1. Intervention group showed an increase (p < 0.05) of Vitamin D as well. In conclusion, the 60-day S. boulardii-SOD supplementation in obese subjects determined a significant weight loss with consequent decrease on fat mass, with preservation of fat free mass. The decrease of HOMA index and uric acid, produced additional benefits in obesity management. The observed increase in vitamin D levels in treated group requires further investigation.
The Role of Vitamin K in Cholestatic Liver Disease
Authors: Sultana Halima , Komai Michio , Shirakawa Hitoshi
Published: July 2021

Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.
Foot Disorders in Nursing Standing Environments: A Scoping Review Protocol
Authors: Bernardes Rafael A. , Parreira Pedro , Sousa Liliana B. , Stolt Minna , Apóstolo João , Cruz Arménio
Published: July 2021

Musculoskeletal disorders can be significantly disabling, particularly those related to work, when the underlying mechanisms and clinical variables are not well known and understood. Nurses usually remain in standing positions or walk for long periods, thus increasing the risk for the development of musculoskeletal disorders, particularly on the foot, such as plantar fasciitis or edema. This type of disorders is a major cause of sickness, absence from work, and also dropout ratios among nursing students, which contributes to the shortage of nursing professionals. This review will address foot disorders that arise from prolonged standing in nursing professionals and describe the main clinical parameters characterizing them, with exclusions for other health professions or disorders with other identified causes. English, French, Portuguese, and Spanish published studies from 1970 to the current year will be considered. The review will follow the JBI methodology, mainly though the PCC mnemonic, and the reporting guidelines for Scoping Reviews. The search will include main databases and relevant scientific repositories. Two independent reviewers will analyze the titles, abstracts, and full texts. A tool developed by the research team will aid in the data collection.
Temporal Changes in the Genetic Diversity of Plasmodium vivax Merozoite Surface Protein-1 in Myanmar
Authors: Naw Haung , Kang Jung-Mi , Moe Mya , Lee Jinyoung , Lê Hương Giang , Võ Tuấn Cường , Mya Yi Yi , Myint Moe Kyaw , Htun Zaw Than , Kim Tong-Soo , Shin Ho-Joon , Na Byoung-Kuk
Published: July 2021

Despite a significant decline in the incidence of malaria in Myanmar recently, malaria is still an important public health concern in the country. Although Plasmodium falciparum is associated with the highest incidence of malaria in Myanmar, the proportion of P. vivax cases has shown a gradual increase in recent years. The genetic diversity of P. vivax merozoite surface protein-1 block 5-6 (pvmsp-1 ICB 5-6) in the P. vivax population of Myanmar was analyzed to obtain a comprehensive insight into its genetic heterogeneity and evolutionary history. High levels of genetic diversity of pvmsp-1 ICB 5-6 were identified in the P. vivax isolates collected from Myanmar between 2013 and 2015. Thirty-nine distinct haplotypes of pvmsp-1 ICB 5-6 (13 for Sal I type, 20 for recombinant type, and 6 for Belem type) were found at the amino acid level. Comparative analyses of the genetic diversity of pvmsp-1 ICB 5-6 sequences in the recent (2013–2015) and the past (2004) P. vivax populations in Myanmar revealed genetic expansion of the pvmsp-1 ICB 5-6 in recent years, albeit with a declined incidence. The recent increase in the genetic heterogeneity of Myanmar pvmsp-1 ICB 5-6 is attributed to a combination of factors, including accumulated mutations and recombination. These results suggest that the size of the P. vivax population in Myanmar is sufficient to enable the generation and maintenance of genetic diversity, warranting continuous molecular surveillance of genetic variation in Myanmar P. vivax.
Immunogenic Peptides from Pap31 and SCS-α of Bartonella bacilliformis: One Step Closer to a Rapid Diagnostic Tool for Carrion’s Disease
Authors: Gomes Cláudia , Pons Maria J. , del Valle-Mendoza Juana , Matsuoka Mayumi , Ruiz Joaquim
Published: July 2021

Bartonella bacilliformis is the causal agent of Carrion’s disease, an overlooked illness endemic in the Andean Mountains with Peru being the most affected country. The diagnostic of this illness is a challenge due to the limited resources and the common symptomatology with other infectious diseases. The goal of this study was to identify immunogenic peptides from Pap31 and succinyl-CoA synthetase α (SCS-α) of B. bacilliformis that might be suitable for developing a serologic tool. The immunodominant character of Pap31 and SCS-α was determined by Western blotting and in-silico analysis. Subsequently, 35 peptides were selected for epitope mapping and their immunoreactivity was tested by enzyme-linked immunosorbent assay (ELISA). A total of 30 sera were tested including pre-exposed people with high IgM levels for Pap31/SCS-α (23 sera), patients (2 sera) as well as 5 sera with no reactivity to Pap31/SCS-α. The results indicate that Pap31-8 (187QAIGSAILKGTKDTGT202) and SCS-α-12 (59IFASVAEGKEKTGANA74) are the most immunogenic peptides, with Pap31-8 showing potential to discriminate between B. bacilliformis and the remaining Bartonella spp., and SCS-α-12 differentiating Bartonella spp. from other microorganisms.
Subtractive Genomics Approach for Identification of Novel Therapeutic Drug Targets in Mycoplasma genitalium
Authors: Fatoba Abiodun Joseph , Okpeku Moses , Adeleke Matthew Adekunle
Published: July 2021

Mycoplasma genitalium infection is a sexually transmitted infection that causes urethritis, cervicitis, and pelvic inflammatory disease (PID) in men and women. The global rise in antimicrobial resistance against recommended antibiotics for the treatment of M. genitalium infection has triggered the need to explore novel drug targets against this pathogen. The application of a bioinformatics approach through subtractive genomics has proven highly instrumental in predicting novel therapeutic targets against a pathogen. This study aimed to identify essential and non-homologous proteins with unique metabolic pathways in the pathogen that could serve as novel drug targets. Based on this, a manual comparison of the metabolic pathways of M. genitalium and the human host was done, generating nine pathogen-specific metabolic pathways. Additionally, the analysis of the whole proteome of M. genitalium using different bioinformatics databases generated 21 essential, non-homologous, and cytoplasmic proteins involved in nine pathogen-specific metabolic pathways. The further screening of these 21 cytoplasmic proteins in the DrugBank database generated 13 druggable proteins, which showed similarity with FDA-approved and experimental small-molecule drugs. A total of seven proteins that are involved in seven different pathogen-specific metabolic pathways were finally selected as novel putative drug targets after further analysis. Therefore, these proposed drug targets could aid in the design of potent drugs that may inhibit the functionality of these pathogen-specific metabolic pathways and, as such, lead to the eradication of this pathogen.
Treponema pallidum among Female Sex Workers: A Cross-Sectional Study Conducted in Three Major Cities in Northern Brazil
Authors: Machado Luiz Fernando Almeida , Monteiro Jacqueline Cortinhas , Siravenha Leonardo Quintão , Mota Marcelo Pereira , Souza Marlinda de Carvalho , Santos Adalto Sampaio dos , Moreira Márcio Ronaldo Chagas , Laurentino Rogério Valois , Oliveira-Filho Aldemir Branco , Queiroz Maria Alice Freitas , Lima Sandra Souza , Ishak Ricardo , Ishak Marluísa de Oliveira Guimarães
Published: July 2021

Female sex workers (FSWs) are an important group of people vulnerable to sexually transmitted infections. Northern Brazil is a rural and socioeconomically underdeveloped region, with lack of epidemiological information on syphilis in key populations. This study investigated the prevalence and factors associated with exposure to Treponema pallidum among FSWs in three major cities in northern Brazil. This cross-sectional study was conducted with a convenience sample of 415 FSWs from the cities of Belém, Macapá, and Rio Branco. Blood samples and personal data were collected from January 2009 to August 2010. Rapid plasma reagin and immunoenzymatic assays were used to detect antibodies against T. pallidum. Logistic regression models were used to determine factors associated with exposure to T. pallidum. In total, 36.1% were exposed to T. pallidum, and 15.7% had active syphilis. Sexual risk behaviors, use of illicit drugs, low education, and reduced monthly income were associated with exposure to T. pallidum. The high rate of exposure to T. pallidum indicates the urgent need for measures to identify, treat, and prevent syphilis and an education program for the valuation, care, and social inclusion of FSWs in northern Brazil.
Trichuris muris Model: Role in Understanding Intestinal Immune Response, Inflammation and Host Defense
Authors: Yousefi Yeganeh , Haq Sabah , Banskota Suhrid , Kwon Yun Han , Khan Waliul I.
Published: July 2021

Several parasites have evolved to survive in the human intestinal tract and over 1 billion people around the world, specifically in developing countries, are infected with enteric helminths. Trichuris trichiura is one of the world’s most common intestinal parasites that causes human parasitic infections. Trichuris muris, as an immunologically well-defined mouse model of T. trichiura, is extensively used to study different aspects of the innate and adaptive components of the immune system. Studies on T. muris model offer insights into understanding host immunity, since this parasite generates two distinct immune responses in resistant and susceptible strains of mouse. Apart from the immune cells, T. muris infection also influences various components of the intestinal tract, especially the gut microbiota, mucus layer, epithelial cells and smooth muscle cells. Here, we reviewed the different immune responses generated by innate and adaptive immune components during acute and chronic T. muris infections. Furthermore, we discussed the importance of studying T. muris model in understanding host–parasite interaction in the context of alteration in the host’s microbiota, intestinal barrier, inflammation, and host defense, and in parasite infection-mediated modulation of other immune and inflammatory diseases.
2′FL and LNnT Exert Antipathogenic Effects against C. difficile ATCC 9689 In Vitro, Coinciding with Increased Levels of Bifidobacteriaceae and/or Secondary Bile Acids
Authors: Vigsnaes Louise Kristine , Ghyselinck Jonas , Van den Abbeele Pieter , McConnell Bruce , Moens Frédéric , Marzorati Massimo , Bajic Danica
Published: July 2021

Clostridioides difficile (formerly Clostridium difficile) infection (CDI) is one of the most common hospital-acquired infections, which is often triggered by a dysbiosed indigenous gut microbiota (e.g., upon antibiotic therapy). Symptoms can be as severe as life-threatening colitis. The current study assessed the antipathogenic potential of human milk oligosaccharides (HMOs), i.e., 2′-O-fucosyllactose (2′FL), lacto-N-neotetraose (LNnT), and a combination thereof (MIX), against C. difficile ATCC 9689 using in vitro gut models that allowed the evaluation of both direct and, upon microbiota modulation, indirect effects. During a first 48 h fecal batch study, dysbiosis and CDI were induced by dilution of the fecal inoculum. For each of the three donors tested, C. difficile levels strongly decreased (with >4 log CFU/mL) upon treatment with 2′FL, LNnT and MIX versus untreated blanks, coinciding with increased acetate/Bifidobacteriaceae levels. Interindividual differences among donors at an intermediate time point suggested that the antimicrobial effect was microbiota-mediated rather than being a direct effect of the HMOs. During a subsequent 11 week study with the PathogutTM model (specific application of the Simulator of the Human Intestinal Microbial Ecosystem (SHIME®)), dysbiosis and CDI were induced by clindamycin (CLI) treatment. Vancomycin (VNC) treatment cured CDI, but the further dysbiosis of the indigenous microbiota likely contributed to CDI recurrence. Upon co-supplementation with VNC, both 2′FL and MIX boosted microbial activity (acetate and to lesser extent propionate/butyrate). Moreover, 2′FL avoided CDI recurrence, potentially because of increased secondary bile acid production. Overall, while not elucidating the exact antipathogenic mechanisms-of-action, the current study highlights the potential of HMOs to combat CDI recurrence, help the gut microbial community recover after antibiotic treatment, and hence counteract the adverse effects of antibiotic therapies.
Transcranial Focal Electrical Stimulation Modifies Biogenic Amines’ Alterations Induced by 6-Hydroxydopamine in Rat Brain
Authors: Santana-Gómez Cesar Emmanuel , Pérez-Pérez Daniel , Fonseca-Barriendos Daniel , Arias-Carrión Oscar , Besio Walter , Rocha Luisa
Published: July 2021

Transcranial focal stimulation (TFS) is a non-invasive neuromodulation strategy with neuroprotective effects. On the other hand, 6-hidroxidopamine (6-OHDA) induces neurodegeneration of the nigrostriatal system producing modifications in the dopaminergic, serotoninergic, and histaminergic systems. The present study was conducted to test whether repetitive application of TFS avoids the biogenic amines’ changes induced by the intrastriatal injection of 6-OHDA. Experiments were designed to determine the tissue content of dopamine, serotonin, and histamine in the brain of animals injected with 6-OHDA and then receiving daily TFS for 21 days. Tissue content of biogenic amines was evaluated in the cerebral cortex, hippocampus, amygdala, and striatum, ipsi- and contralateral to the side of 6-OHDA injection. Results obtained were compared to animals with 6-OHDA, TFS alone, and a Sham group. The present study revealed that TFS did not avoid the changes in the tissue content of dopamine in striatum. However, TFS was able to avoid several of the changes induced by 6-OHDA in the tissue content of dopamine, serotonin, and histamine in the different brain areas evaluated. Interestingly, TFS alone did not induce significant changes in the different brain areas evaluated. The present study showed that repetitive TFS avoids the biogenic amines’ changes induced by 6-OHDA. TFS can represent a new therapeutic strategy to avoid the neurotoxicity induced by 6-OHDA.
Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention
Authors: Jhunjhunwala Kunal , Dobard Charles W. , Sharma Sunita , Makarova Natalia , Holder Angela , Dinh Chuong , Mitchell James , Wang Lin , Zhang Junmei , Patel Sravan Kumar , Heneine Walid , Rohan Lisa C.
Published: July 2021

Receptive anal intercourse (RAI) contributes significantly to HIV acquisition underscoring the need to develop HIV prevention options for populations engaging in RAI practices. We explored the feasibility of formulating rectal suppositories with potent antiviral drugs for on-demand use. A fixed-dose combination of tenofovir (TFV) and elvitegravir (EVG) (40 mg each) was co-formulated in six different suppository bases (three fat- and three water-soluble). Fat-soluble witepsol H15 and water-soluble polyethylene glycol (PEG) based suppositories demonstrated favorable in vitro release and were advanced to assess in vivo pharmacokinetics following rectal administration in macaques. In vivo drug release profiles were similar for both suppository bases. Median concentrations of TFV and EVG detected in rectal fluids at 2 h were 1- and 2-logs higher than the in vitro IC50, respectively; TFV-diphosphate levels in rectal tissues met or exceeded those associated with high efficacy against rectal simian HIV (SHIV) exposure in macaques. Leveraging on these findings, a PEG-based suppository with a lower dose combination of tenofovir alafenamide (TAF) and EVG (8 mg each) was developed and found to achieve similar rectal drug exposures in macaques. This study establishes the utility of rectal suppositories as a promising on-demand strategy for HIV PrEP and supports their clinical development.
Preparation of Magnetic–Luminescent Bifunctional Rapeseed Pod-Like Drug Delivery System for Sequential Release of Dual Drugs
Authors: Xu Junwei , Jia Yunxue , Liu Meili , Gu Xuenan , Li Ping , Fan Yubo
Published: July 2021

Drug delivery systems (DDSs) limited to a single function or single-drug loading are struggling to meet the requirements of clinical medical applications. It is of great significance to fabricate DDSs with multiple functions such as magnetic targeting or fluorescent labeling, as well as with multiple-drug loading for enhancing drug efficacy and accelerating actions. In this study, inspired by the dual-chamber structure of rapeseed pods, biomimetic magnetic–luminescent bifunctional drug delivery carriers (DDCs) of 1.9 ± 0.3 μm diameter and 19.6 ± 4.4 μm length for dual drug release were fabricated via double-needle electrospraying. Morphological images showed that the rapeseed pod-like DDCs had a rod-like morphology and Janus dual-chamber structure. Magnetic nanoparticles and luminescent materials were elaborately designed to be dispersed in two different chambers to endow the DDCs with excellent magnetic and luminescent properties. Synchronously, the Janus structure of DDCs promoted the luminescent intensity by at least threefold compared to single-chamber DDCs. The results of the hemolysis experiment and cytotoxicity assay suggested the great blood and cell compatibilities of DDCs. Further inspired by the core–shell structure of rapeseeds containing oil wrapped in rapeseed pods, DDCs were fabricated to carry benzimidazole molecules and doxorubicin@chitosan nanoparticles in different chambers, realizing the sequential release of benzimidazole within 12 h and of doxorubicin from day 3 to day 18. These rapeseed pod-like DDSs with excellent magnetic and luminescent properties and sequential release of dual drugs have potential for biomedical applications such as targeted drug delivery, bioimaging, and sustained treatment of diseases.
A Repeated Time-to-Positive Symptoms Improvement among Malaysian Patients with Schizophrenia Spectrum Disorders Treated with Clozapine
Authors: Albitar Orwa , Harun Sabariah Noor , Ahmad Siti Nor Aizah , Sheikh Ghadzi Siti Maisharah
Published: July 2021

Clozapine remains the drug of choice for resistant schizophrenia. However, its dose-response relationship is still controversial. The current investigation aimed to develop a repeated time-to-positive symptoms improvement following the onset of clozapine treatment in Malaysian schizophrenia spectrum disorder patients. Data from patients’ medical records in the Psychiatric Clinic, Penang General Hospital, were retrospectively analyzed. Several parametric survival models were evaluated using nonlinear mixed-effect modeling software (NONMEM 7.3.0). Kaplan–Meier-visual predictive check (KM-VPC) and sampling-importance resampling (SIR) methods were used to validate the final model. A total of 116 patients were included in the study, with a mean follow-up of 306 weeks. Weibull hazard function best fitted the data. The hazard of positive symptoms improvement decreased 4% for every one-year increase in age over the median of 41 years (adjusted hazard ratio (aHR), 0.96; 95% confidence intervals (95% CI), (0.93–0.98)). However, patients receiving a second atypical antipsychotic agent had four-folds higher hazard (aHR, 4.01; 95% CI, (1.97–7.17)). The hazard increased 2% (aHR, 1.02; 95% CI, (1.01–1.03)) for every 1 g increase in the clozapine six months cumulative dose over the median of 34 g. The developed model provides essential information on the hazard of positive symptoms improvement after the first clozapine dose administration, including modifiable predictors of high clinical importance.
Nanoradiopharmaceuticals Based on Alpha Emitters: Recent Developments for Medical Applications
Authors: Trujillo-Nolasco Maydelid , Morales-Avila Enrique , Cruz-Nova Pedro , Katti Kattesh , Ocampo-García Blanca
Published: July 2021

The application of nanotechnology in nuclear medicine offers attractive therapeutic opportunities for the treatment of various diseases, including cancer. Indeed, nanoparticles-conjugated targeted alpha-particle therapy (TAT) would be ideal for localized cell killing due to high linear energy transfer and short ranges of alpha emitters. New approaches in radiolabeling are necessary because chemical radiolabeling techniques are rendered sub-optimal due to the presence of recoil energy generated by alpha decay, which causes chemical bonds to break. This review attempts to cover, in a concise fashion, various aspects of physics, radiobiology, and production of alpha emitters, as well as highlight the main problems they present, with possible new approaches to mitigate those problems. Special emphasis is placed on the strategies proposed for managing recoil energy. We will also provide an account of the recent studies in vitro and in vivo preclinical investigations of α-particle therapy delivered by various nanosystems from different materials, including inorganic nanoparticles, liposomes, and polymersomes, and some carbon-based systems are also summarized.
“Plurethosome” as Vesicular System for Cutaneous Administration of Mangiferin: Formulative Study and 3D Skin Tissue Evaluation
Authors: Sguizzato Maddalena , Ferrara Francesca , Mariani Paolo , Pepe Alessia , Cortesi Rita , Huang Nicolas , Simelière Fanny , Boldrini Paola , Baldisserotto Anna , Valacchi Giuseppe , Esposito Elisabetta
Published: July 2021

Human skin is dramatically exposed to toxic pollutants such as ozone. To counteract the skin disorders induced by the air pollution, natural antioxidants such as mangiferin could be employed. A formulative study for the development of vesicular systems for mangiferin based on phosphatidylcholine and the block copolymer pluronic is described. Plurethosomes were designed for mangiferin transdermal administration and compared to ethosome and transethosome. Particularly, the effect of vesicle composition was investigated on size distribution, inner and outer morphology by photon correlation spectroscopy, small angle X-ray diffraction, and transmission electron microscopy. The potential of selected formulations as vehicles for mangiferin was studied, evaluating encapsulation efficiency and in vitro diffusion parameters by Franz cells. The mangiferin antioxidant capacity was verified by the 2,2-diphenyl-1-picrylhydrazyl assay. Vesicle size spanned between 200 and 550 nm, being influenced by phosphatidylcholine concentration and by the presence of polysorbate or pluronic. The vesicle supramolecular structure was multilamellar in the case of ethosome or plurethosome and unilamellar in the case of transethosome. A linear diffusion of mangiferin in the case of ethosome and transethosomes and a biphasic profile in the case of plurethosomes indicated the capability of multilamellar vesicles to retain the drug more efficaciously than the unilamellar ones. The antioxidant and anti-inflammatory potential effect of mangiferin against pollutants was evaluated on 3D human skin models exposed to O3. The protective effect exerted by plurethosomes and transethosomes suggests their possible application to enhance the cutaneous antioxidant defense status.
Evaluation of Ribavirin–Poloxamer Microparticles for Improved Intranasal Absorption
Authors: Vasa Dipy M. , Bakri Zainab , Donovan Maureen D. , O’Donnell Lauren A. , Wildfong Peter L. D.
Published: July 2021

Ribavirin is a water-soluble antiviral compound which, owing to its inability to cross the blood–brain barrier, has limited effectiveness in treating viruses affecting the central nervous system. Direct nose-to-brain delivery was investigated for ribavirin in combination with poloxamer 188, an excipient known to enhance the absorption of drug compounds administered intranasally. Composite solid microparticles suitable for intranasal insufflation were prepared by suspending fine crystals of ribavirin in a matrix of poloxamer 188, which were cryogenically milled and characterized to ensure that ribavirin remained stable throughout preparation. In vitro diffusion of ribavirin across a semi-permeable regenerated cellulose membrane showed comparable cumulative drug release after 180 min from both fine solid particles (<20 µm) and 1:1 ribavirin:poloxamer microparticles (d50 = 20 µm); however, the initial release from polymer microparticles was slower, owing to gel formation on the membrane surface. When solid ribavirin was directly deposited on excised olfactory mucosa, either as fine drug particles or 1:1 ribavirin:poloxamer microparticles, permeation was significantly increased from microparticles containing poloxamer 188, suggesting additional interactions between the polymer and olfactory mucosa. These data indicate that for highly water-soluble drugs such as ribavirin or drugs subject to efflux by the nasal mucosa, a formulation of poloxmer-containing microparticles can enhance permeability across the olfactory epithelium and may improve direct nose-to-brain transport.
Increased Water-Solubility and Maintained Antioxidant Power of Resveratrol by Its Encapsulation in Vitamin E TPGS Micelles: A Potential Nutritional Supplement for Chronic Liver Disease
Authors: Zuccari Guendalina , Alfei Silvana , Zorzoli Alessia , Marimpietri Danilo , Turrini Federica , Baldassari Sara , Marchitto Leonardo , Caviglioli Gabriele
Published: July 2021

Children affected by chronic liver disease exhibit impaired neurocognitive development and growth due to the low absorption and digestion of nutrients. Furthermore, malnutrition is an adverse prognostic factor in liver transplantation as it is associated with an increase in morbidity and mortality. D-α-tocopheryl-polyethylene-glycol-succinate (TPGS) is currently administered per os as a vitamin E source to improve children’s survival and well-being; however, TPGS alone does not reverse spinocerebellar degeneration and lipid peroxidation. To potentiate the effects of TPGS, we loaded micelles with resveratrol (RES), a natural polyphenol, with antioxidant and antiinflammatory activities, which has demonstrated protective action in the liver. Firstly, we investigated the suitability of TPGS to encapsulate RES in micelles by means of a phase-solubility study, then RES-TPGS formulations were prepared via solvent casting and solvent diffusion evaporation methods. RES-TPGS colloidal dispersions showed small mean diameters (12 nm), low polydispersity, and quite neutral Zeta potentials. The formulations showed a sustained drug release and a good drug loading capacity, further confirmed by infrared spectroscopy and differential scanning calorimetry. RES-TPGSs exhibited unaltered antioxidant activity compared to pristine RES via the DPPH assay and a significant reduction in toxicity compared to empty TPGS on HaCaT cells. Thus, RES-TPGS micelles may overcome the challenges of current liver disease therapy by providing more protective effects thanks to the antioxidant activity of RES and by reducing the surfactant toxicity on normal cells.
Pheophorbide A and Paclitaxel Bioresponsive Nanoparticles as Double-Punch Platform for Cancer Therapy
Authors: Moret Francesca , Menilli Luca , Battan Manuele , Tedesco Daniele , Columbaro Marta , Guerrini Andrea , Avancini Greta , Ferroni Claudia , Varchi Greta
Published: July 2021

Cancer therapy is still a challenging issue. To address this, the combination of anticancer drugs with other therapeutic modalities, such as light-triggered therapies, has emerged as a promising approach, primarily when both active ingredients are provided within a single nanosystem. Herein, we describe the unprecedented preparation of tumor microenvironment (TME) responsive nanoparticles exclusively composed of a paclitaxel (PTX) prodrug and the photosensitizer pheophorbide A (PheoA), e.g., PheoA≅PTX2S. This system aimed to achieve both the TME-triggered and controlled release of PTX and the synergistic/additive effect by PheoA-mediated photodynamic therapy. PheoA≅PTX2S were produced in a simple one-pot process, exhibiting excellent reproducibility, stability, and the ability to load up to 100% PTX and 40% of PheoA. Exposure of PheoA≅PTX2S nanoparticles to TME-mimicked environment provided fast disassembly compared to normal conditions, leading to PTX and PheoA release and consequently elevated cytotoxicity. Our data indicate that PheoA incorporation into nanoparticles prevents its aggregation, thus providing a greater extent of ROS and singlet oxygen production. Importantly, in SK-OV-3 cells, PheoA≅PTX2S allowed a 30-fold PTX dose reduction and a 3-fold dose reduction of PheoA. Our data confirm that prodrug-based nanocarriers represent valuable and sustainable drug delivery systems, possibly reducing toxicity and expediting preclinical and clinical translation.
Single-Port Homodyne Detection in a Squeezed-State Interferometry with Optimal Data Processing
Authors: Zhou Likun , Liu Pan , Jin Guang-Ri
Published: July 2021

Performing homodyne detection at a single output port of a squeezed-state light interferometer and then separating the measurement quadrature into several bins can realize superresolving and supersensitive phase measurements. However, the phase resolution and the achievable phase sensitivity depend on the bin size that is adopted in the data processing. By maximizing classical Fisher information, we analytically derive an optimal value of the bin size and the associated best sensitivity for the case of three bins, which can be regarded as a three-outcome measurement. Our results indicate that both the resolution and the achievable sensitivity are better than that of the previous binary–outcome case. Finally, we present an approximate maximum Likelihood estimator to asymptotically saturate the ultimate lower bound of the phase sensitivity.
Status of Leaky Mode Holography
Authors: Smalley Daniel E. , Jolly Sundeep , Favalora Gregg E. , Moebius Michael G.
Published: July 2021

It will soon be a decade since leaky mode waveguide devices were presented as a solution for holographic video displays. This paper seeks to provide a brief, topical review of advances made during that time. Specifically, we review the new methods and architectures that have been developed over this period. This work draws primarily from papers seeking to present dynamic holographic patterns using mode coupling from indiffused waveguides on lithium niobate. The primary participants during this time period have been groups from the Massachusetts Institute of Technology, Brigham Young University, and Draper. We also describe the challenges that remain. The body of work reviewed speaks to the need for further development, but it also reaffirms that leaky mode waveguides continue to hold a unique place within spatial light modulation for holographic video displays.
Editorial for Special Issue “Leaf Senescence” in Plants
Authors: Zentgraf Ulrike , Andrade Ana G. , Doll Jasmin
Published: July 2021

Senescence in plants is often described as the last step in the life history of a plant [...]
Detecting Introgressed Populations in the Iberian Endemic Centaurea podospermifolia through Genome Size
Authors: Pellicer Jaume , López-Pujol Jordi , Aixarch Marc , Garnatje Teresa , Vallès Joan , Hidalgo Oriane
Published: July 2021

Based on results from previous studies, populations of the Iberian endemic Centaurea podospermifolia north of the Ebro River are considered genetically pure, while those southward are introgressed, with genetic input from C. cephalariifolia. This phenomenon is particularly relevant, especially given both the endangered and protected status for the species, which can have consequences in how to best apply conservation strategies to maintain genetic resources in the species. The main goal of this study was to evaluate whether genome size assessments using flow cytometry can help distinguishing between pure, hybrid and introgressed populations, and hence become a powerful and cost-effective tool to complement comprehensive population genetic surveys. The results indicate that there are significant genome size differences between populations of C. podospermifolia, which are coincident with previous considerations of pure and introgressed populations. Given the simplicity and reproducibility of this technique, flow cytometry could become an effective tool for monitoring pure populations of this species and, indeed, become an integral part of the management plans that are mandatory for listed taxa.
Plant Disease Control Efficacy of Platycladus orientalis and Its Antifungal Compounds
Authors: Bae Sohyun , Han Jae Woo , Dang Quang Le , Kim Hun , Choi Gyung Ja
Published: July 2021

Plants contain a number of bioactive compounds that exhibit antimicrobial activity, which can be recognized as an important source of agrochemicals for plant disease control. In searching for natural alternatives to synthetic fungicides, we found that a methanol extract of the plant species Platycladus orientalis suppressed the disease development of rice blast caused by Magnaporthe oryzae. Through a series of chromatography procedures in combination with activity-guided fractionation, we isolated and identified a total of eleven compounds including four labdane-type diterpenes (1–4), six isopimarane-type diterpenes (5–10), and one sesquiterpene (11). Of the identified compounds, the MIC values of compounds 1, 2, 5 & 6 mixture, 9, and 11 ranged from 100 to 200 μg/mL against M. oryzae, whereas the other compounds were over 200 μg/mL. When rice plants were treated with the antifungal compounds, compounds 1, 2, and 9 effectively suppressed the development of rice blast at all concentrations tested by over 75% compared to the non-treatment control. In addition, a mixture of compounds 5 & 6 that constituted 66% of the P. orientalis ethyl acetate fraction also exhibited a moderate disease control efficacy. Together, our data suggest that the methanol extract of P. orientalis including terpenoid compounds has potential as a crop protection agent.