bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa
Authors: Ndayisaba Gilles , Yeka Adoke , Asante Kwaku Poku , Grobusch Martin P. , Karita Etienne , Mugerwa Henry , Asiimwe Stephen , Oduro Abraham , Fofana Bakary , Doumbia Seydou , Jain Jay Prakash , Barsainya Sarita , Kullak-Ublick Gerd A. , Su Guoqin , Schmitt Esther K. , Csermak Katalin , Gandhi Preetam , Hughes David
Published: December 2021

Background

The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether–lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa.

Methods

This was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether–lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial.

Results

Overall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether–lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether–lumefantrine. Cipargamin was well tolerated with no safety concerns.

Conclusions

This active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin.

Trial registration ClinicalTrials.gov number: NCT03334747 (7 Nov 2017), other study ID CKAE609A2202
Maplaria: a user friendly web-application for spatio-temporal malaria prevalence mapping
Authors: Giorgi Emanuele , Macharia Peter M. , Woodmansey Jack , Snow Robert W. , Rowlingson Barry
Published: December 2021

Background

Model-based geostatistical (MBG) methods have been extensively used to map malaria risk using community survey data in low-resource settings where disease registries are incomplete or non-existent. However, the wider adoption of MBG methods by national control programmes to inform health policy decisions is hindered by the lack of advanced statistical expertise and suitable computational equipment. Here, Maplaria, an interactive, user-friendly web-application that allows users to upload their own malaria prevalence data and carry out geostatistical prediction of annual malaria prevalence at any desired spatial scale, is introduced.

Methods

In the design of the Maplaria web application, two main criteria were considered: the application should be able to classify subnational divisions into the most likely endemicity levels; the web application should allow only minimal input from the user in the set-up of the geostatistical inference process. To achieve this, the process of fitting and validating the geostatistical models is carried out by statistical experts using publicly available malaria survey data from the Harvard database. The stage of geostatistical prediction is entirely user-driven and allows the user to upload malaria data, as well as vector data that define the administrative boundaries for the generation of spatially aggregated inferences.

Results

The process of data uploading and processing is split into a series of steps spread across screens through the progressive disclosure technique that prevents the user being immediately overwhelmed by the length of the form. Each of these is illustrated using a data set from the Malaria Indicator carried out in Tanzania in 2017 as an example.

Conclusions

Maplaria application provides a user-friendly solution to the problem making geostatistical methods more accessible to users that have not undertaken formal training in statistics. The application is a useful tool that can be used to foster ownership, among policy makers, of disease risk maps and promote better use of data for decision-making in low resource settings.
RETRACTED ARTICLE: Ginsenoside Rg3 alleviates septic liver injury by regulating the lncRNA TUG1/miR-200c-3p/SIRT1 axis
Authors: Wu Pan , Yu Xiao , Peng Yue , Wang Qian-Lu , Deng Long-Tian , Xing Wei
Published: December 2021

Background

Studies have shown that ginsenoside R3 (Rg3) plays a protective role in sepsis-induced organ injuries and mitochondrial dysfunction. Long noncoding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) is regarded as a regulator in sepsis. However, the association between TUG1 and Rg3 remains elusive.

Methods

A sepsis mouse model was established by caecal ligation and puncture (CLP), and liver injury was induced by haematoxylin-eosin (H&E) staining. Lipopolysaccharide (LPS) was used to induce hepatocyte damage. The expression levels of TUG1, microRNA (miR)-200a-3p, and silencing information regulator 1 (SIRT1) were examined by quantitative real-time polymerase chain reaction (qRT–PCR) assays. Cell viability was monitored using the Cell Counting Kit-8 (CCK-8) assay. MitoSOX Red staining and CBIC2 (JC-1) dye were employed to detect mitochondrial reactive oxygen species (ROS) and mitochondrial transmembrane potential (MTP) levels, respectively. The interaction between miR-200a-3p and TUG1 or SIRT1 was confirmed via dual-luciferase reporter or RNA immunoprecipitation (RIP) assay.

Results

Rg3 upregulated TUG1 expression in liver tissues of CLP mice and LPS-induced hepatocytes. Rg3 could activate autophagy to improve mitochondrial dysfunction in LPS-treated hepatocytes, which was partially reversed by TUG1 depletion or miR-200a-3p overexpression. Importantly, TUG1 targeted miR-200a-3p to activate the SIRT1/AMP-activated protein kinase (AMPK) pathway in LPS-treated hepatocytes. Moreover, gain of TUG1 ameliorated mitochondrial dysfunction in LPS-treated hepatocytes by sequestering miR-200a-3p.

Conclusion

Our study revealed that Rg3 increased TUG1 expression and reduced miR-200a-3p expression to stimulate the SIRT1/AMPK pathway, thereby enhancing autophagy to improve sepsis-induced liver injury and mitochondrial dysfunction.
Remodeling immune microenvironment in periodontitis using resveratrol liposomes as an antibiotic-free therapeutic strategy
Authors: Shi Junyu , Zhang Yi , Zhang Xiaomeng , Chen Ruiying , Wei Jianxu , Hou Jiazhen , Wang Bing , Lai Hongchang , Huang Yongzhuo
Published: December 2021

Background

Periodontitis is a complicated inflammatory disease that damages the tooth-supporting tissues, with limited pharmacotherapy available. Macrophage-targeting therapy is promising for inflammatory diseases. Resveratrol (RSV), a nonflavonoid polyphenol, is known for its anti-inflammatory and immunomodulatory effects. However, its medical application is limited by its poor stability and water-solubility, as well as its low bioavailability.

Result

A therapeutic resveratrol-loaded liposomal system (Lipo-RSV) was developed to treat periodontitis. The physical properties of Lipo-RSV and its ability to regulate macrophages were investigated. The results showed that Lipo-RSV had good biocompatibility and could re-educate the inflammatory macrophages from M1- to M2-like phenotype through activating p-STAT3 and downregulating p-STAT1. Besides, the Lipo-RSV could scavenge ROS and inhibit the NF-κB signal and inflammasomes, thereby reducing the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α.

Conclusion

These results revealed that Lipo-RSV could be a potential therapeutic system for the antibiotic-free treatment for periodontal diseases.

Graphical Abstract
Phytonanotechnology applications in modern agriculture
Authors: Jiang Meng , Song Yue , Kanwar Mukesh Kumar , Ahammed Golam Jalal , Shao Shujun , Zhou Jie
Published: December 2021

With the rapidly changing global climate, the agricultural systems are confronted with more unpredictable and harsh environmental conditions than before which lead to compromised food production. Thus, to ensure safer and sustainable crop production, the use of advanced nanotechnological approaches in plants (phytonanotechnology) is of great significance. In this review, we summarize recent advances in phytonanotechnology in agricultural systems that can assist to meet ever-growing demands of food sustainability. The application of phytonanotechnology can change traditional agricultural systems, allowing the target-specific delivery of biomolecules (such as nucleotides and proteins) and cater the organized release of agrochemicals (such as pesticides and fertilizers). An amended comprehension of the communications between crops and nanoparticles (NPs) can improve the production of crops by enhancing tolerance towards environmental stresses and optimizing the utilization of nutrients. Besides, approaches like nanoliposomes, nanoemulsions, edible coatings, and other kinds of NPs offer numerous selections in the postharvest preservation of crops for minimizing food spoilage and thus establishing phtonanotechnology as a sustainable tool to architect modern agricultural practices.

Graphical Abstract
A novel targeted multifunctional nanoplatform for visual chemo-hyperthermia synergy therapy on metastatic lymph nodes via lymphatic delivery
Authors: Liu Weiwei , Ye Xiaoping , He Lingyun , Cheng Juan , Luo Wenpei , Zheng Min , Hu Yaqin , Zhang Wei , Cao Yang , Ran Haitao , Yang Lu
Published: December 2021

Background

Distant metastasis to vital organs is the major contributor to breast cancer mortality, and regional lymph node metastasis is an important facilitator of distant metastasis and recurrence in this cancer. The early diagnosis and precise treatment of lymph node metastasis are crucial for staging and prognosis in breast cancer. Herein, we report a visualized precision medicine nanoplatform of metastatic lymph nodes for ultrasonic/photoacoustic (US/PA) dual modal imaging-guided in situ targeted hyperthermia-combined chemotherapy.

Results

Carbon nanoparticles (CNs), approved by the China Food and Drug Administration, were loaded with docetaxel and rationally combined with anti-hypoxia-inducible factor 1α antibody-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles to achieve the combination of passive targeting at the lymph nodes and intracellular targeting at HIF 1α factor. The accumulation and retention of nanoparticles in metastatic lymph nodes via lymphatic delivery were enhanced. Docetaxel could be effectively offloaded by CNs that have active carbon nanoparticles, and the PLGA membrane prevented drug leakage. The nanoparticles exhibited excellent photothermal performance with a photothermal conversion efficiency of 28.9%, killing tumor cells in metastatic lymph nodes through hyperthermia. In vitro and in vivo systematic evaluations revealed that hyperpyrexia triggered the rupture of nanoparticles caused by the phase transition of perfluorohexane, resulting in docetaxel release for achieving in situ hyperthermia-combined chemotherapy.

Conclusions

The laser-triggered highly efficient in situ chemotherapy nanosystem achieves targeted synergistic chemo-hyperthermia treatment of metastatic lymph nodes, and lymphatic delivery represents a strategy to avoid additional injury caused by drugs entering the blood circulation.

Graphical Abstract
Aloe derived nanovesicle as a functional carrier for indocyanine green encapsulation and phototherapy
Authors: Zeng Lupeng , Wang Huaying , Shi Wanhua , Chen Lingfan , Chen Tingting , Chen Guanyu , Wang Wenshen , Lan Jianming , Huang Zhihong , Zhang Jing , Chen Jinghua
Published: December 2021

Background

Cancer is one of the devastating diseases in the world. The development of nanocarrier provides a promising perspective for improving cancer therapeutic efficacy. However, the issues with potential toxicity, quantity production, and excessive costs limit their further applications in clinical practice.

Results

Herein, we proposed a nanocarrier obtained from aloe with stability and leak-proofness. We isolated nanovesicles from the gel and rind of aloe (gADNVs and rADNVs) with higher quality and yield by controlling the final centrifugation time within 20 min, and modulating the viscosity at 2.98 mPa S and 1.57 mPa S respectively. The gADNVs showed great structure and storage stability, antioxidant and antidetergent capacity. They could be efficiently taken up by melanoma cells, and with no toxicity in vitro or in vivo. Indocyanine green (ICG) loaded in gADNVs (ICG/gADNVs) showed great stability in both heating system and in serum, and its retention rate exceeded 90% after 30 days stored in gADNVs. ICG/gADNVs stored 30 days could still effectively damage melanoma cells and inhibit melanoma growth, outperforming free ICG and ICG liposomes. Interestingly, gADNVs showed prominent penetrability to mice skin which might be beneficial to noninvasive transdermal administration.

Conclusions

Our research was designed to simplify the preparation of drug carrier, and reduce production cost, which provided an alternative for the development of economic and safe drug delivery system.

Graphical Abstract
Mitochondria-targeted nanoplatforms for enhanced photodynamic therapy against hypoxia tumor
Authors: Wen Jiexin , Luo Yong , Gao Hui , Zhang Liang , Wang Xiang , Huang Ju , Shang Tingting , Zhou Di , Wang Dong , Wang Zhigang , Li Pan , Wang Zhaoxia
Published: December 2021

Background

Photodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. However, hypoxia and the unsatisfactory accumulation of photosensitizers in tumors severely diminish the therapeutic effect of PDT. In this study, a multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers.

Results

The as-synthesized nanoplatforms penetrated deeply into the interior region of tumors and preferentially remained in mitochondria due to the intrinsic characteristics of IR780. Meanwhile, 3BP could efficiently suppress oxygen consumption of tumor cells by inhibiting mitochondrial respiratory chain to further improve the generation of ROS. Furthermore, 3BP could abolish the excessive glycolytic capacity of tumor cells and lead to the collapse of ATP production, rendering tumor cells more susceptible to PDT. Successful tumor inhibition in animal models confirmed the therapeutic precision and efficiency. In addition, these nanoplatforms could act as fluorescence (FL) and photoacoustic (PA) imaging contrast agents, effectuating imaging-guided cancer treatment.

Conclusions

This study provides an ideal strategy for cancer therapy by concurrent oxygen consumption reduction, oxygen-augmented PDT, energy supply reduction, mitochondria-targeted/deep-penetrated nanoplatforms and PA/FL dual-modal imaging guidance/monitoring. It is expected that such strategy will provide a promising alternative to maximize the performance of PDT in preclinical/clinical cancer treatment.

Graphical Abstract
Second near-infrared photothermal-amplified immunotherapy using photoactivatable composite nanostimulators
Authors: Sun Haitao , Yu Tianzhu , Li Xin , Lei Yangyang , Li Jianke , Wang Xiuhui , Peng Peike , Ni Dalong , Wang Xiaolin , Luo Yu
Published: December 2021

Background

The construction of a nanoimmune controlled-release system that spatiotemporally recognizes tumor lesions and stimulates the immune system response step by step is one of the most potent cancer treatment strategies for improving the sensitivity of immunotherapy response.

Results

Here, a composite nanostimulator (CNS) was constructed for the release of second near-infrared (NIR-II) photothermal-mediated immune agents, thereby achieving spatiotemporally controllable photothermal-synergized immunotherapy. CNS nanoparticles comprise thermosensitive liposomes as an outer shell and are internally loaded with a NIR-II photothermal agent, copper sulfide (CuS), toll-like receptor-9 (TLR-9) agonist, cytosine-phospho-guanine oligodeoxynucleotides, and programmed death-ligand 1 (PD-L1) inhibitors (JQ1). Following NIR-II photoirradiation, CuS enabled the rapid elevation of localized temperature, achieving tumor ablation and induction of immunogenic cell death (ICD) as well as disruption of the lipid shell, enabling the precise release of two immune-therapeutical drugs in the tumor region. Combining ICD, TLR-9 stimulation, and inhibited expression of PD-L1 allows the subsequent enhancement of dendritic cell maturation and increases infiltration of cytotoxic T lymphocytes, facilitating regional antitumor immune responses.

Conclusion

CNS nanoparticle-mediated photothermal-synergized immunotherapy efficiently suppressed the growth of primary and distant tumors in two mouse models and prevented pulmonary metastasis. This study thus provides a novel sight into photo-controllably safe and efficient immunotherapy.

Graphical Abstract
Polydopamine nanoparticles attenuate retina ganglion cell degeneration and restore visual function after optic nerve injury
Authors: Lou Xiaotong , Hu Yuanyuan , Zhang Hong , Liu Jia , Zhao Yin
Published: December 2021

Background

Oxidative stress contributes to retina ganglion cells (RGCs) loss in variety of ocular diseases, including ocular trauma, ocular vein occlusion, and glaucoma. Scavenging the excessed reactive oxygen species (ROS) in retinal neurovascular unit could be beneficial to RGCs survival. In this study, a polydopamine (PDA)-based nanoplatform is developed to protect RGCs.

Results

The PDA nanoparticles efficiently eliminate multi-types of ROS, protect endothelia and neuronal cells from oxidative damage, and inhibit microglia activation in retinas. In an optic nerve crush (ONC) model, single intravitreal injection of PDA nanoparticles could significantly attenuate RGCs loss via eliminating ROS in retinas, reducing the inflammatory response and maintaining barrier function of retinal vascular endothelia. Comparative transcriptome analysis of the retina implied that PDA nanoparticles improve RGCs survival probably by altering the expression of genes involved in inflammation and ROS production. Importantly, as a versatile drug carrier, PDA nanoparticles could deliver brimonidine (a neuroprotection drug) to synergistically attenuate RGCs loss and promote axon regeneration, thus restore visual function.

Conclusions

The PDA nanoparticle-based therapeutic nanoplatform displayed excellent performance in ROS elimination, providing a promising probability for treating retinal degeneration diseases.

Graphical Abstract
The effects of statins on hyperandrogenism in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials
Authors: Chen Jianguo , Huang Chaoran , Zhang Tongtong , Gong Wuqing , Deng Xiaofeng , Liu Hua , Liu Jinbo , Guo Yuanbiao
Published: December 2021

Several clinical studies showed that statins were potential to treat polycystic ovary syndrome (PCOS). Through comprehensive search PubMed, EMBASE, the Web of Science, BIOSIS, the ClinialTrails.gov, and the Cochrane Library database up to 14 Feb 2020, we identified the randomized controlled trials about the treatment of statins on hyperandrogenism in PCOS women, and performed a systematic review and meta-analysis. The quality of the included studies was assessed by the Cochrane risk of bias tool and the Jadda score. Subgroup analysis and sensitivity analysis were conducted to analyze the pooled results. Nine trials included 682 PCOS patients were identified. Statins showed a significant potential to reduce testosterone (SMD = -0.47; 95% CI, − 0.76−− 0.18; P = 0.002) and dehydroepiandrosterone (SMD = -0.51; 95% CI, − 0.97−− 0.05; P = 0.03) levels, compared to the control treatments. The cutaneous symptoms hirsutism (SMD = -0.61; 95% CI, − 1.13−− 0.10; P = 0.02) and acne (SMD = -0.92; 95% CI, − 1.49−− 0.34; P = 0.002) were significantly improved by statins in PCOS women. Subgroup analysis showed that the two types of statins, and the different control treatments as well, presented no significantly different effect on testosterone and dehydroepiandrosterone. Sensitivity analysis confirmed the stability of the findings from the meta-analysis. In conclusion, statin treatment could significantly reduce androgen levels and improve cutaneous manifestations of hyperandrogenism of PCOS.
A catastrophic seronegative anti-phospholipid syndrome: case and literature review
Authors: Pinto Vanda , Ministro Augusto , Carreira Nuno Reis , Cardoso Ana , Gonçalves Catarina Sousa , Henriques Mickael , Rato João , Silva Emanuel , Pedro Luís Mendes
Published: December 2021

Background

Antiphospholipid Syndrome (APS) is a multisystemic autoimmune disease characterized by arterial and venous thrombosis and / or obstetric morbidity in the presence of at least one circulating anti-phospholipid antibody. The spectrum of vascular events varies from deep venous thrombosis to catastrophic APS, a rare form characterized by acute multiorgan thrombosis and high mortality.

Case report

We present the case of a 32-week pregnant woman arriving in the hospital emergency room with bilateral acute lower limb ischemia. In the obstetric evaluation, fetal death was declared. Computerized Tomography angiography showed pulmonary embolism of both pulmonary arteries, areas of splenic and right renal infarction and multiple arterial and venous thrombosis. The patient underwent urgent caesarean section and axillary-bifemoral bypass. No events registered. In the postoperative period, in an intensive care unit, treatment with rituximab and plasmapheresis were added to anticoagulant therapy. The laboratorial investigation was negative for thrombophilia and autoimmune diseases.

Conclusion

Catastrophic APS develops quickly, with multiorgan involvement and high mortality rate. The presented case poses a multidisciplinary challenge, with the surgical approach of extra-anatomical revascularization being less invasive and guaranteeing immediate perfusion of the lower limbs. Although the serological tests were negative for anti-phospholipid antibodies, this case hardly fits into another diagnosis. Therefore, it was treated as a catastrophic APS, having shown a favorable evolution.
Cancer-associated fibroblasts promote oral squamous cell carcinoma progression through LOX-mediated matrix stiffness
Authors: Zhang Jia-Yi , Zhu Wei-Wen , Wang Meng-Yao , Zhai Run-Dong , Wang Qiong , Shen Wei-Li , Liu Lai-Kui
Published: December 2021

Background

Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment, have prominent roles in the development of solid tumors as stromal targets. However, the underlying mechanism of CAFs’ function in oral squamous cell carcinoma (OSCC) development remains unclear. Here, we investigated the role of lysyl oxidase (LOX) expression in CAFs in tumor stromal remodeling and the mechanism of its effect on OSCC progression.

Methods

Multiple immunohistochemistry (IHC) staining was performed to detect the correlation of CAFs and LOX in the stroma of OSCC specimens, as well as the correlation with clinicopathological parameters and prognosis. The expression of LOX in CAFs were detected by RT-qPCR and western blot. The effects of LOX in CAFs on the biological characteristics of OSCC cell line were investigated using CCK-8, wound-healing and transwell assay. CAFs were co-cultured with type I collagen in vitro, and collagen contraction test, microstructure observation and rheometer were used to detect the effect of CAFs on remodeling collagen matrix. Then, collagen with different stiffness were established to investigate the effect of matrix stiffness on the progression of OSCC. Moreover, we used focal adhesion kinase (FAK) phosphorylation inhibitors to explored whether the increase in matrix stiffness promote the progression of OSCC through activating FAK phosphorylation pathway.

Results

LOX was colocalized with CAFs in the stroma of OSCC tissues, and its expression was significantly related to the degree of malignant differentiation and poor prognosis in OSCC. LOX was highly expressed in CAFs, and its knockdown impaired the proliferation, migration, invasion and EMT process of OSCC cells. The expression of LOX in CAFs can catalyze collagen crosslinking and increase matrix stiffness. Furthermore, CAFs-derived LOX-mediated increase in collagen stiffness induced morphological changes and promoted invasion and EMT process in OSCC cells by activating FAK phosphorylation pathway.

Conclusions

Our findings suggest that CAFs highly express LOX in the stroma of OSCC and can remodel the matrix collagen microenvironment, and the increase in matrix stiffness mediated by CAFs-derived LOX promotes OSCC development through FAK phosphorylation pathway. Thus, LOX may be a potential target for the early diagnosis and therapeutic treatment of OSCC.
Development of an ultra-sensitive human IL-33 biomarker assay for age-related macular degeneration and asthma drug development
Authors: Mai Elaine , Chan Joyce , Goon Levina , Ego Braeden K. , Bevers Jack , Wong Tiffany , Wong Manda , Corpuz Racquel , Xi Hongkang , Wu Jia , Schneider Kellen , Seshasayee Dhaya , Grimbaldeston Michele , Nakamura Gerald , Indjeian Vahan B. , van Lookeren Campagne Menno , Loyet Kelly M. , Comps-Agrar Laetitia
Published: December 2021

Background

Over the past decade, human Interleukin 33 (hIL-33) has emerged as a key contributor to the pathogenesis of numerous inflammatory diseases. Despite the existence of several commercial hIL-33 assays spanning multiple platform technologies, their ability to provide accurate hIL-33 concentration measurements and to differentiate between active (reduced) and inactive (oxidized) hIL-33 in various matrices remains uncertain. This is especially true for lower sample volumes, matrices with low hIL-33 concentrations, and matrices with elevated levels of soluble Interleukin 1 Receptor-Like 1 (sST2), an inactive form of ST2 that competes with membrane bound ST2 for hIL-33 binding.

Results

We tested the performance of several commercially available hIL-33 detection assays in various human matrices and found that most of these assays lacked the sensitivity to accurately detect reduced hIL-33 at biologically relevant levels (sub-to-low pg/mL), especially in the presence of human sST2 (hsST2), and/or lacked sufficient target specificity. To address this, we developed and validated a sensitive and specific enzyme-linked immunosorbent assay (ELISA) capable of detecting reduced and total hIL-33 levels even in the presence of high concentrations of sST2. By incorporating the immuno-polymerase chain reaction (iPCR) platform, we further increased the sensitivity of this assay for the reduced form of hIL-33 by ~ 52-fold. Using this hIL-33 iPCR assay, we detected hIL-33 in postmortem human vitreous humor (VH) samples from donors with age-related macular degeneration (AMD) and found significantly increased hIL-33 levels when compared to control individuals. No statistically significant difference was observed in aqueous humor (AH) from AMD donors nor in plasma and nasosorption fluid (NF) from asthma patients compared to control individuals.

Conclusions

Unlike existing commercial hIL-33 assays, our hIL-33 bioassays are highly sensitive and specific and can accurately quantify hIL-33 in various human clinical matrices, including those with high levels of hsST2. Our results provide a proof of concept of the utility of these assays in clinical trials targeting the hIL-33/hST2 pathway.
TRPC3, but not TRPC1, as a good therapeutic target for standalone or complementary treatment of DMD
Authors: Creisméas Anna , Gazaille Claire , Bourdon Audrey , Lallemand Marc-Antoine , François Virginie , Allais Marine , Ledevin Mireille , Larcher Thibaut , Toumaniantz Gilles , Lafoux Aude , Huchet Corinne , Anegon Ignacio , Adjali Oumeya , Le Guiner Caroline , Fraysse Bodvaël
Published: December 2021

Background

Duchenne muscular dystrophy (DMD) is an X-linked inherited disease caused by mutations in the gene encoding dystrophin that leads to a severe and ultimately life limiting muscle-wasting condition. Recombinant adeno-associated vector (rAAV)-based gene therapy is promising, but the size of the full-length dystrophin cDNA exceeds the packaging capacity of a rAAV. Alternative or complementary strategies that could treat DMD patients are thus needed. Intracellular calcium overload due to a sarcolemma permeability to calcium (SPCa) increase is an early and critical step of the DMD pathogenesis. We assessed herein whether TRPC1 and TRPC3 calcium channels may be involved in skeletal muscle SPCa alterations and could represent therapeutic targets to treat DMD.

Methods

All experiments were conducted in the DMDmdx rat, an animal model that closely reproduces the human DMD disease. We measured the cytosolic calcium concentration ([Ca2+]c) and SPCa in EDL (Extensor Digitorum Longus) muscle fibers from age-matched WT and DMDmdx rats of 1.5 to 7 months old. TRPC1 and TRPC3 expressions were measured in the EDL muscles at both the mRNA and protein levels, by RT-qPCR, western blot and immunocytofluorescence analysis.

Results

As expected from the malignant hyperthermia like episodes observed in several DMDmdx rats, calcium homeostasis alterations were confirmed by measurements of early increases in [Ca2+]c and SPCa in muscle fibers. TRPC3 and TRPC1 protein levels were increased in DMDmdx rats. This was observed as soon as 1.5 months of age for TRPC3 but only at 7 months of age for TRPC1. A slight but reliable shift of the TRPC3 apparent molecular weight was observed in DMDmdx rat muscles. Intracellular localization of both channels was not altered. We thus focused our attention on TRPC3. Application of Pyr10, a specific inhibitor of TRPC3, abolished the differences between SPCa values measured in WT and DMDmdx. Finally, we showed that a rAAV-microdystrophin based treatment induced a high microdystrophin expression but only partial prevention of calcium homeostasis alterations, skeletal muscle force and TRPC3 protein increase.

Conclusions

All together our results show that correcting TRPC3 channel expression and/or activity appear to be a promising approach as a single or as a rAAV-based complementary therapy to treat DMD.
Prevalence and associated factors of infertility among 20–49 year old women in Henan Province, China
Authors: Liang Shoujing , Chen Yuanhui , Wang Qian , Chen Huanhuan , Cui Chenchen , Xu Xiaohang , Zhang Qingwen , Zhang Cuilian
Published: December 2021

Background

Infertility is a reproductive health problem which affects not only individuals, families and social populations. Recently, the infertility rate in China has a trend of increase year by year, and few studies have reported the infertility rate in Henan Province, China. The aim of this study was to investigate the current prevalence and associated factors of infertility among women of childbearing age in Henan Province, China.

Methods

This cross-sectional study was conducted from March 2019 to October 2019. We sampled 765 women who were 20–49 years old in eight hospitals of four cities in Henan Province, China. This survey included a questionnaire, physical examination, vaginal ultrasound examinations, and serum anti-Mullerian hormone (AMH) assessment, all of which were conducted under uniform standards by trained personnel. According to the data collected from questionnaire, participants were divided into infertile and fertile groups and analyzed associated factors.

Results

Among all the 765 participants in this study, the prevalence of infertility was 24.58%. The prevalence of primary infertility was 6.54%, and the prevalence of secondary infertility was 18.04%. In logistic multivariate regression analyses, infertility was associated with age (p < 0.001), history of gynecological surgery (p < 0.001), sweet food (p = 0.003) and decreased ovarian reserve (DOR) (p < 0.001). After further analyses, factors associated with primary infertility were age of marriage (p = 0.006), age of first sexual intercourse (p = 0.003), long-term air-conditioning environment (p < 0.001), decreased ovarian reserve (p = 0.005) and age (p = 0.002). And factors associated with secondary infertility were history of gynecological surgery (p < 0.001), decreased ovarian reserve (p = 0.002), waist-to-hip ratio (WHR) above 0.85 (p = 0.043), delivery times (p = 0.001) and ages (p < 0.001).

Conclusion

The prevalence of infertility among women aged 20–49 was 24.58% and only 61.17% infertile women sought medical help in Henan Province, China. Age, history of gynecological surgeries and DOR may increase the risk of infertility. Local public health departments and medical professionals need to discharge their duty of reducing the high incidence of infertility and protecting women’s reproductive health.
The mediational role of social support in the relationship between stress and antenatal anxiety and depressive symptoms among Australian women: a mediational analysis
Authors: Bedaso Asres , Adams Jon , Peng Wenbo , Sibbritt David
Published: December 2021

Background

Pregnancy can be a stressful period for most women and their family members, and the mental wellbeing of pregnant women can face serious challenges. Social support can play a role in improving the psychological well-being of pregnant women by enhancing the stress coping ability and alleviating stressful conditions. The current study aimed to assess the mediating effects of social support in the relationship between perceived stress and depressive symptoms as well as anxiety symptoms during pregnancy among Australian women.

Methods

Of the 8,010 women who completed Survey 6 of the 1973–78 Australian Longitudinal Study on Women’s Health (ALSWH) cohort in 2012, those who reported being pregnant (n = 493) were included in the current analyses. Antenatal depressive and anxiety symptoms were assessed using the 10 item Center for Epidemiological Studies Depression (CES-D-10) scale, and the 9-item Goldberg Anxiety and Depression scale (GADS) respectively. The 19 item-Medical Outcomes Study Social Support index (MOSS) was used to examine social support. A parallel mediation model was used to explore the mediational role of each domain of social support between perceived stress and antenatal depressive and anxiety symptoms.

Result

The study found that emotional/informational support has a partial mediating effect on the relationship between perceived stress and antenatal depressive symptoms (β = 0.371, 95% CI: 0.067, 0.799) and on the relationship between perceived stress and antenatal anxiety symptoms (β = 0.217, 95% CI: 0.029, 0.462). Affectionate support/positive social interaction and tangible support was found to play no significant mediation role between stress and antenatal depressive and anxiety symptoms.

Conclusions

Emotional/informational support appears to play a mediating role in the relationship between stress and antenatal depressive as well as between stress and antenatal anxiety symptoms. In order to further protect pregnant women from the effects of stress, policy makers and maternal health professionals are advised to develop community-based social support programs to enhance prenatal psychosocial support and ensure pregnant women have adequate emotional/information support.
Contraception for married adolescents (15–19 years) in India: insights from the National Family Health Survey-4 (NFHS-4)
Authors: Singh Ijyaa , Shukla Ankita , Thulaseedharan Jissa Vinoda , Singh Gurpreet
Published: December 2021

Purpose

Despite the fact that marriage below the age of 18 years is illegal in India, a considerable number of females get married and start childbearing during their adolescent years. There is low prevalence of contraceptive methods and high unmet need for family planning (FP). Realizing this, new government programs have been launched to increase the uptake of sexual and reproductive health services among adolescents. However, evidence specific to this age group remains scarce.

Aim and objectives

The present study was conducted to assess the prevalence of modern contraceptives among married adolescents, and to determine its association with sociodemographic variables, health worker outreach, and media exposure to FP messages in India.

Methods

Data for this analysis was drawn from the fourth round of the National Family Health Survey (NFHS-4) conducted in India during 2015–16. The sample size is restricted to 13,232 currently married adolescent girls aged 15–19 years, who were not pregnant at the time of the survey. Bivariate and multivariate analysis were conducted to assess the levels of contraceptive use and its predictors among married adolescents.

Results

The use of modern contraceptives among married adolescents increased from 4 to 10% between 1992–93 and 2015–16. The uptake of modern contraceptives was found to be low among the uneducated, those residing in rural areas, among backward classes, those practising Hindu religion, women in the poorest wealth quintile, women without children, and those with no exposure to FP messages via media or health care workers. Among those who met health care workers and discussed FP issues with them, 34.11% were using modern contraceptives as compared to 11.53% of those who did not have discussions with health care workers.

Conclusions

The evidence suggests that contact with health care workers significantly influences the use of modern contraceptives. Further focus on increasing contact between married adolescents’ and health care workers, and improving the quality of counselling will protect adolescents from early marriage and pregnancy.
Proximal and distal movement patterns during a graphomotor task in typically developing children and children with handwriting problems
Authors: Steinhart Shoshana , Weiss Patrice L. , Friedman Jason
Published: December 2021

Background

Therapists specializing in handwriting difficulties in children often address motor problems including both proximal and distal movements in the upper extremity. Kinematic measures can be used to investigate various aspects of handwriting. This study examined differences in movement patterns in proximal and distal joints of the upper extremity during graphomotor tasks between typically developing children with and without handwriting problems. Additionally, it explored relationships between movement patterns, speed, and legibility of writing.

Methods

Forty-one children, aged 7–11 years, were assessed with the Aleph Aleph Ktav Yad Hebrew Handwriting assessment and the Beery Test of Visual Motor Integration and, based on their scores, were divided into a research group (with handwriting difficulties) and a control group (without handwriting difficulties). Upper extremity joint movement patterns were analyzed with a motion capture system. Differences in the quality of shapes traced and copied on a graphics tablet positioned horizontally and vertically were compared. Between-group differences and relationships with speed and legibility were analyzed.

Results

In both groups, there was greater movement in the distal compared to the proximal joints, greater movement when performing the task in a horizontal compared to a vertical plane, and greater movement when tracing than copying. Joint movements in the arm executed scaled-down versions of the shapes being drawn. While the amount of joint displacement was similar between groups, children in the research group showed greater dissimilarity between the drawn shape and the shape produced by the proximal joints. Finally, the drawing measure on the tablet was a significant predictor of legibility, speed of writing, visual motor integration and motor coordination, whereas the dissimilarity measure of joint movement was a significant predictor of speed of writing and motor coordination.

Conclusions

This study provides support for the role of the distal upper extremity joints in the writing process and some guidance to assist clinicians in devising treatment strategies for movement-related handwriting problems. While we observed differences in proximal joint movements between the children with and without handwriting difficulties, the extent to which they are responsible for the differences in drawing quality remains to be determined. Further studies should use a similar methodology to examine additional tasks such as drawing shapes of varying sizes.
3C protease of enterovirus 71 cleaves promyelocytic leukemia protein and impairs PML-NBs production
Authors: Li Zhuoran , Wu Ya’ni , Li Hui , Li Wenqian , Tan Juan , Qiao Wentao
Published: December 2021

Background

Enterovirus 71 (EV71) usually infects infants causing hand-foot-mouth disease (HFMD), even fatal neurological disease like aseptic meningitis. Effective drug for preventing and treating EV71 infection is unavailable currently. EV71 3C mediated the cleavage of many proteins and played an important role in viral inhibiting host innate immunity. Promyelocytic leukemia (PML) protein, the primary organizer of PML nuclear bodies (PML-NBs), can be induced by interferon and is involved in antiviral activity. PML inhibits EV71 replication, and EV71 infection reduces PML expression, but the molecular mechanism is unclear.

Methods

The cleavage of PMLIII and IV was confirmed by co-transfection of EV71 3C protease and PML. The detailed cleavage sites were evaluated further by constructing the Q to A mutant of PML. PML knockout cells were infected with EV71 to identify the effect of cleavage on EV71 replication. Immunofluorescence analysis to examine the interference of EV71 3C on the formation of PML-NBs.

Results

EV71 3C directly cleaved PMLIII and IV. Furthermore, 3C cleaved PMLIV at the sites of Q430–A431 and Q444–S445 through its protease activity. Overexpression of PMLIV Q430A/Q444A variant exhibited stronger antiviral potential than the wild type. PMLIV Q430A/Q444A formed normal nuclear bodies that were not affected by 3C, suggesting that 3C may impair PML-NBs production via PMLIV cleavage and counter its antiviral activities. PML, especially PMLIV, which sequesters viral proteins in PML-NBs and inhibits viral production, is a novel target of EV71 3C cleavage.

Conclusions

EV71 3C cleaves PMLIV at Q430–A431 and Q444–S445. Cleavage reduces the antiviral function of PML and decomposes the formation of PML-NBs, which is conducive to virus replication.
A case of Pseudomyxoma Peritonei of an unexpected origin
Authors: Csanyi-Bastien Marie , Blanchard France , Lamy Aude , Sabourin Jean-Christophe
Published: December 2021

Background

Pseudomyxoma peritonei (PMP) is a complex and partially understood disease defined by mucin deposits in the peritoneal cavity, mostly of appendiceal origin caused by the rupture of a mucocele often containing Low or High grade Appendiceal Mucinous Neoplasm (LAMN/HAMN). Other origins include primitive ovarian mucinous cystadenoma or cystadenocarcinoma almost always with an associated teratoma, but to our knowledge no case of ovarian teratomatous appendiceal-like mucocele with LAMN has been reported as a cause of PMP.

Case presentation

A 25-year old female with infertility was diagnosed with an isolated left ovarian tumor in a context of PMP. Histological examination revealed an ovarian teratoma containing an appendiceal-like structure with mucocele and LAMN, without any associated lesion of the appendix on full histological analysis. Molecular characterization of the ovarian lesion showed co-KRAS and GNAS mutations, as described in PMP of appendiceal origin, while only KRAS mutations are reported in primitive ovarian mucinous tumor.

Conclusions

Detection of co-KRAS and GNAS mutations in our case of ovarian teratomatous appendiceal-like mucocele with LAMN shows that when PMP derives from a mucinous ovarian lesion (with histological proof of none-appendiceal involvement), it is probably of a digestive teratomatous origin, emphasizing the need to actively search for tetatomatous signs in a context of ovarian PMP.
Lateral pillar is the key in supporting pre-collapse osteonecrosis of the femoral head: a finite element model analysis of propensity-score matched cohorts
Authors: Bahk Ji Hoon , Jo Woo-Lam , Kim Seung-Chan , Kwon Soon-Yong , Lim Young Wook
Published: December 2021

Background

This study was designed as a cohort study using propensity-score matching to age, gender, and body mass index (BMI) for finite element model (FEM) analysis from pre-collapse CT images of collapsed and non-collapsed hips. Through FEM analysis, a global graphical output around the hip joint can provide simple impression of stress distribution: concentration or dispersion.

Methods

A total of 32 hips with ARCO stage 2 or 3 ONFH who were on follow up for over a one-year period were retrospectively reviewed. 16 hips with no interval progression of collapse were set as the study group, then 16 hips with progression of collapse which required arthroplasty were set as the control group using propensity-score matching. FEM was generated through Mechanical Finder for each patient, then 4500 N of load was applied to 1000 mm2 area at the top of iliac crest to analyze the models in terms of equivalents for yield stress.

Results

Age, sex, and BMI had no significant differences between the two groups, while location (p = 0.015) was lateral, and size (p = 0.015) was significantly greater in the collapsed group. Non-collapsed hips mostly exhibited stress dispersion allocated to medial and lateral pillars, while collapsed hips exhibited stress concentration focused on the lateral pillar and the primary compression trabecula. (p = 0.001).

Conclusion

Through FEM analysis, stress concentration to the lateral pillar and the primary compression trabeculae can be used to predict future collapse in ONFH with high probability. Results provide a simple and intuitive, yet valuable information to aid surgeons. Therefore, especially for young patients, holding out the lateral pillar through joint preserving procedures might be the key in preventing further collapse.