bluuebunny/crossref_metadata_2025 huggingface dataset:
Terminally differentiated effector memory T cells associate with cognitive and AD-related biomarkers in an aging-based community cohort
Authors: Winford Edric , Lutshumba Jenny , Martin Barbara J. , Wilcock Donna M. , Jicha Gregory A. , Nikolajczyk Barbara S. , Stowe Ann M. , Bachstetter Adam D.
Published: June 2024

Background and purpose

The immune response changes during aging and the progression of Alzheimer’s disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called TEMRA) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in TEMRAs are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline. This study aimed to examine whether TEMRAs are associated with cognition and plasma biomarkers of AD, neurodegeneration, and neuroinflammation in a community-based cohort of older adults.

Methods

Study participants from a University of Kentucky Alzheimer’s Disease Research Center (UK-ADRC) community-based cohort of aging and dementia were used to test our hypothesis. There were 84 participants, 44 women and 40 men. Participants underwent physical examination, neurological examination, medical history, cognitive testing, and blood collection to determine plasma biomarker levels (Aβ42/Aβ40 ratio, total tau, Neurofilament Light chain (Nf-L), Glial Fibrillary Acidic Protein (GFAP)) and to isolate peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze PBMCs from study participants for effector and memory T cell populations, including CD4+ and CD8+ central memory T cells (TCM), Naïve T cells, effector memory T cells (TEM), and effector memory CD45RA+ T cells (TEMRA) immune cell markers.

Results

CD8+ TEMRAs were positively correlated with Nf-L and GFAP. We found no significant difference in CD8+ TEMRAs based on cognitive scores and no associations between CD8+ TEMRAs and AD-related biomarkers. CD4+ TEMRAs were associated with cognitive impairment on the MMSE. Gender was not associated with TEMRAs, but it did show an association with other T cell populations.

Conclusion

These findings suggest that the accumulation of CD8+ TEMRAs may be a response to neuronal injury (Nf-L) and neuroinflammation (GFAP) during aging or the progression of AD and ADRD. As our findings in a community-based cohort were not clinically-defined AD participants but included all ADRDs, this suggests that TEMRAs may be associated with changes in systemic immune T cell subsets associated with the onset of pathology.
Lab-on-a-chip: an advanced technology for the modernization of traditional Chinese medicine
Authors: Lu Zenghui , Yuan Yue , Han Qiang , Wang Yu , Liang Qionglin
Published: June 2024

Benefiting from the complex system composed of various constituents, medicament portions, species, and places of origin, traditional Chinese medicine (TCM) possesses numerous customizable and adaptable efficacies in clinical practice guided by its theories. However, these unique features are also present challenges in areas such as quality control, screening active ingredients, studying cell and organ pharmacology, and characterizing the compatibility between different Chinese medicines. Drawing inspiration from the holistic concept, an integrated strategy and pattern more aligned with TCM research emerges, necessitating the integration of novel technology into TCM modernization. The microfluidic chip serves as a powerful platform for integrating technologies in chemistry, biology, and biophysics. Microfluidics has given rise to innovative patterns like lab-on-a-chip and organoids-on-a-chip, effectively challenging the conventional research paradigms of TCM. This review provides a systematic summary of the nature and advanced utilization of microfluidic chips in TCM, focusing on quality control, active ingredient screening/separation, pharmaceutical analysis, and pharmacological/toxicological assays. Drawing on these remarkable references, the challenges, opportunities, and future trends of microfluidic chips in TCM are also comprehensively discussed, providing valuable insights into the development of TCM.
Clinical application of voriconazole in pediatric patients: a systematic review
Authors: Hu Lin , Huang Juanjuan , Li Yanfei , He Gefei
Published: June 2024

The purpose of this study was to review the literature on the clinical use of voriconazole (VRC) in pediatric patients. MEDLINE, Embase, PubMed, Web of Science, and Cochrane Library were searched from January 1, 2000, to August 15, 2023 for relevant clinical studies on VRC use in pediatric patients. Data were collected based on inclusion and exclusion criteria, and a systematic review was performed on recent research related to the use of VRC in pediatric patients. This systematic review included a total of 35 observational studies among which there were 16 studies investigating factors influencing VRC plasma trough concentrations (Ctrough) in pediatric patients, 14 studies exploring VRC maintenance doses required to achieve target range of Ctrough, and 11 studies focusing on population pharmacokinetic (PPK) research of VRC in pediatric patients. Our study found that the Ctrough of VRC were influenced by both genetic and non-genetic factors. The optimal dosing of VRC was correlated with age in pediatric patients, and younger children usually required higher VRC doses to achieve target Ctrough compared to older children. Establishing a PPK model for VRC can assist in achieving more precise individualized dosing in children.
Advanced waveform analysis of diaphragm surface EMG allows for continuous non-invasive assessment of respiratory effort in critically ill patients at different PEEP levels
Authors: Warnaar R. S. P. , Cornet A. D. , Beishuizen A. , Moore C. M. , Donker D. W. , Oppersma E.
Published: June 2024

Background

Respiratory effort should be closely monitored in mechanically ventilated ICU patients to avoid both overassistance and underassistance. Surface electromyography of the diaphragm (sEMGdi) offers a continuous and non-invasive modality to assess respiratory effort based on neuromuscular coupling (NMCdi). The sEMGdi derived electrical activity of the diaphragm (sEAdi) is prone to distortion by crosstalk from other muscles including the heart, hindering its widespread use in clinical practice. We developed an advanced analysis as well as quality criteria for sEAdi waveforms and investigated the effects of clinically relevant levels of PEEP on non-invasive NMCdi.

Methods

NMCdi was derived by dividing end-expiratory occlusion pressure (Pocc) by sEAdi, based on three consecutive Pocc manoeuvres at four incremental (+ 2 cmH2O/step) PEEP levels in stable ICU patients on pressure support ventilation. Pocc and sEAdi quality was assessed by applying a novel, automated advanced signal analysis, based on tolerant and strict cut-off criteria, and excluding inadequate waveforms. The coefficient of variations (CoV) of NMCdi after basic manual and automated advanced quality assessment were evaluated, as well as the effect of an incremental PEEP trial on NMCdi.

Results

593 manoeuvres were obtained from 42 PEEP trials in 17 ICU patients. Waveform exclusion was primarily based on low sEAdi signal-to-noise ratio (Ntolerant = 155, 37%, Nstrict = 241, 51% waveforms excluded), irregular or abrupt cessation of Pocc (Ntolerant = 145, 35%, Nstrict = 145, 31%), and high sEAdi area under the baseline (Ntolerant = 94, 23%, Nstrict = 79, 17%). Strict automated assessment allowed to reduce CoV of NMCdi to 15% from 37% for basic quality assessment. As PEEP was increased, NMCdi decreased significantly by 4.9 percentage point per cmH2O.

Conclusion

Advanced signal analysis of both Pocc and sEAdi greatly facilitates automated and well-defined identification of high-quality waveforms. In the critically ill, this approach allowed to demonstrate a dynamic NMCdi (Pocc/sEAdi) decrease upon PEEP increments, emphasising that sEAdi-based assessment of respiratory effort should be related to PEEP dependent diaphragm function. This novel, non-invasive methodology forms an important methodological foundation for more robust, continuous, and comprehensive assessment of respiratory effort at the bedside.
Phosphoproteomic profiling of early rheumatoid arthritis synovium reveals active signalling pathways and differentiates inflammatory pathotypes
Authors: Çubuk Cankut , Lau Rachel , Cutillas Pedro , Rajeeve Vinothini , John Christopher R. , Surace Anna E. A. , Hands Rebecca , Fossati-Jimack Liliane , Lewis Myles J. , Pitzalis Costantino
Published: June 2024

Background

Kinases are intracellular signalling mediators and key to sustaining the inflammatory process in rheumatoid arthritis (RA). Oral inhibitors of Janus Kinase family (JAKs) are widely used in RA, while inhibitors of other kinase families e.g. phosphoinositide 3-kinase (PI3K) are under development. Most current biomarker platforms quantify mRNA/protein levels, but give no direct information on whether proteins are active/inactive. Phosphoproteome analysis has the potential to measure specific enzyme activation status at tissue level.

Methods

We validated the feasibility of phosphoproteome and total proteome analysis on 8 pre-treatment synovial biopsies from treatment-naive RA patients using label-free mass spectrometry, to identify active cell signalling pathways in synovial tissue which might explain failure to respond to RA therapeutics.

Results

Differential expression analysis and functional enrichment revealed clear separation of phosphoproteome and proteome profiles between lymphoid and myeloid RA pathotypes. Abundance of specific phosphosites was associated with the degree of inflammatory state. The lymphoid pathotype was enriched with lymphoproliferative signalling phosphosites, including Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted novel kinases not previously linked to RA, such as Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotype. Several phosphosites correlated with clinical features, such as Disease-Activity-Score (DAS)-28, suggesting that phosphosite analysis has potential for identifying novel biomarkers at tissue-level of disease severity and prognosis.

Conclusions

Specific phosphoproteome/proteome signatures delineate RA pathotypes and may have clinical utility for stratifying patients for personalised medicine in RA.
Reduced field-of-view DWI based on deep learning reconstruction improving diagnostic accuracy of VI-RADS for evaluating muscle invasion
Authors: Zhang Xinxin , Xu Xiaojuan , Wang Yichen , Zhang Jie , Hu Mancang , Zhang Jin , Zhang Lianyu , Wang Sicong , Li Yi , Zhao Xinming , Chen Yan
Published: June 2024

Objectives

To investigate whether reduced field-of-view (rFOV) diffusion-weighted imaging (DWI) with deep learning reconstruction (DLR) can improve the accuracy of evaluating muscle invasion using VI-RADS.

Methods

Eighty-six bladder cancer participants who were evaluated by conventional full field-of-view (fFOV) DWI, standard rFOV (rFOVSTA) DWI, and fast rFOV with DLR (rFOVDLR) DWI were included in this prospective study. Tumors were categorized according to the vesical imaging reporting and data system (VI-RADS). Qualitative image quality scoring, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and ADC value were evaluated. Friedman test with post hoc test revealed the difference across the three DWIs. Receiver operating characteristic analysis was performed to calculate the areas under the curve (AUCs).

Results

The AUC of the rFOVSTA DWI and rFOVDLR DWI were higher than that of fFOV DWI. rFOVDLR DWI reduced the acquisition time from 5:02 min to 3:25 min, and showed higher scores in overall image quality with higher CNR and SNR, compared to rFOVSTA DWI (p < 0.05). The mean ADC of all cases of rFOVSTA DWI and rFOVDLR DWI was significantly lower than that of fFOV DWI (all p < 0.05). There was no difference in mean ADC value and the AUC for evaluating muscle invasion between rFOVSTA DWI and rFOVDLR DWI (p > 0.05).

Conclusions

rFOV DWI with DLR can improve the diagnostic accuracy of fFOV DWI for evaluating muscle invasion. Applying DLR to rFOV DWI reduced the acquisition time and improved overall image quality while maintaining ADC value and diagnostic accuracy.

Critical relevance statement

The diagnostic performance and image quality of full field-of-view DWI, reduced field-of-view (rFOV) DWI with and without DLR were compared. DLR would benefit the wide clinical application of rFOV DWI by reducing the acquisition time and improving the image quality.

Key Points

Deep learning reconstruction (DLR) can reduce scan time and improve image quality.

Reduced field-of-view (rFOV) diffusion-weighted imaging (DWI) with DLR showed better diagnostic performances than full field-of-view DWI.

There was no difference of diagnostic accuracy between rFOV DWI with DLR and standard rFOV DWI.

Graphical Abstract
Dixon MRI-based quantitative parameters of extraocular muscles, intraorbital fat, and lacrimal glands for staging thyroid-associated ophthalmopathy
Authors: Pu Xiong-Ying , Chen Lu , Hu Hao , Wu Qian , Jiang Wen-Hao , Lu Jin-Ling , Chen Huan-Huan , Xu Xiao-Quan , Wu Fei-Yun
Published: June 2024

Objective

To investigate the value of Dixon magnetic resonance imaging (MRI)-based quantitative parameters of extraocular muscles (EOMs), intraorbital fat (IF), and lacrimal glands (LGs) in staging patients with thyroid-associated ophthalmopathy (TAO).

Methods

Two hundred patients with TAO (211 active and 189 inactive eyes) who underwent Dixon MRI for pretreatment evaluation were retrospectively enrolled and divided into training (169 active and 151 inactive eyes) and validation (42 active and 38 inactive eyes) cohorts. The maximum, mean, and minimum values of the signal intensity ratio (SIR), fat fraction (FF), and water fraction (WF) of EOMs, IF, and LGs were measured and compared between the active and inactive groups in the training cohort. Binary logistic regression analysis, receiver operating characteristic curve analysis, and the Delong test were used for further statistical analyses, as appropriate.

Results

Compared with inactive TAOs, active TAOs demonstrated significantly greater EOM-SIRmax, EOM-SIRmean, EOM-SIRmin, IF-SIRmax, IF-SIRmean, LG-SIRmax, LG-SIRmean, EOM-WFmean, EOM-WFmin, IF-WFmax, IF-WFmean, and LG-WFmean and lower EOM-FFmax, EOM-FFmean, IF-FFmean, IF-FFmin, and LG-FFmean values (all p < 0.05). The EOM-SIRmean, LG-SIRmean, and LG-FFmean values were independently associated with active TAO (all p < 0.05). The combination of the EOM-SIRmean, LG-SIRmean, and LG-FFmean values showed better performance than the EOM-SIRmean value alone in staging TAO in both the training (AUC, 0.820 vs 0.793; p = 0.016) and validation (AUC, 0.751 vs 0.733, p = 0.341) cohorts.

Conclusion

Dixon MRI-based parameters of EOMs, LGs, and IF are useful for differentiating active from inactive TAO. The integration of multiple parameters can further improve staging performance.

Critical relevance statement

In this study, the authors explored the combined value of quantitative parameters of EOMs, IF, and LGs derived from Dixon MRI in staging TAO patients, which can support the establishment of a proper therapeutic plan.

Key Points

The quantitative parameters of EOMs, LGs, and IF are useful for staging TAO.

The EOM-SIRmean, LG-SIRmean, and LG-FFmean values were found to independently correlate with active TAO.

Joint evaluation of orbital tissue improved the ability to assess TAO activity.

Graphical Abstract
Non-Gaussian diffusion metrics with whole-tumor histogram analysis for bladder cancer diagnosis: muscle invasion and histological grade
Authors: Fan Zhichang , Guo Junting , Zhang Xiaoyue , Chen Zeke , Wang Bin , Jiang Yueluan , Li Yan , Wang Yongfang , Yang Guoqiang , Wang Xiaochun
Published: June 2024

Purpose

To investigate the performance of histogram features of non-Gaussian diffusion metrics for diagnosing muscle invasion and histological grade in bladder cancer (BCa).

Methods

Patients were prospectively allocated to MR scanner1 (training cohort) or MR2 (testing cohort) for conventional diffusion-weighted imaging (DWIconv) and multi-b-value DWI. Metrics of continuous time random walk (CTRW), diffusion kurtosis imaging (DKI), fractional-order calculus (FROC), intravoxel incoherent motion (IVIM), and stretched exponential model (SEM) were simultaneously calculated using multi-b-value DWI. Whole-tumor histogram features were extracted from DWIconv and non-Gaussian diffusion metrics for logistic regression analysis to develop diffusion models diagnosing muscle invasion and histological grade. The models’ performances were quantified by area under the receiver operating characteristic curve (AUC).

Results

MR1 included 267 pathologically-confirmed BCa patients (median age, 67 years [IQR, 46–82], 222 men) and MR2 included 83 (median age, 65 years [IQR, 31–82], 73 men). For discriminating muscle invasion, CTRW achieved the highest testing AUC of 0.915, higher than DWIconv’s 0.805 (p = 0.014), and similar to the combined diffusion model’s AUC of 0.885 (p = 0.076). For differentiating histological grade of non-muscle-invasion bladder cancer, IVIM outperformed a testing AUC of 0.897, higher than DWIconv’s 0.694 (p = 0.020), and similar to the combined diffusion model’s AUC of 0.917 (p = 0.650). In both tasks, DKI, FROC, and SEM failed to show diagnostic superiority over DWIconv (p > 0.05).

Conclusion

CTRW and IVIM are two potential non-Gaussian diffusion models to improve the MRI application in assessing muscle invasion and histological grade of BCa, respectively.

Critical relevance statement

Our study validates non-Gaussian diffusion imaging as a reliable, non-invasive technique for early assessment of muscle invasion and histological grade in BCa, enhancing accuracy in diagnosis and improving MRI application in BCa diagnostic procedures.

Key Points

Muscular invasion largely determines bladder salvageability in bladder cancer patients.

Evaluated non-Gaussian diffusion metrics surpassed DWIconv in BCa muscle invasion and histological grade diagnosis.

Non-Gaussian diffusion imaging improved MRI application in preoperative diagnosis of BCa.

Graphical Abstract
Soft tissue vascular tumor-like lesions in adults: imaging and pathological analysis pitfalls per ISSVA classification
Authors: Marcelin C. , Dubois J. , Kokta V. , Giroux M. F. , Danino M. A. , Mottard S. , Soulez G.
Published: June 2024

Objectives

To compare the magnetic resonance imaging (MRI) and Doppler ultrasound (DUS) findings with the pathological findings of soft tissue vascular tumors (STVTs) according to the 2018 ISSVA (International Society for the Study of Vascular Anomalies) classification to differentiate vascular tumors from vascular malformations.

Methods

This retrospective study included patients with STVTs who underwent contrast-enhanced MRI and pathological analysis at our hospital between 2010 and 2020. The presumptive diagnosis based on the on-site imaging and histological analysis was compared with imaging and histological analysis conducted off-site utilizing the ISSVA criteria.

Results

This study included 31 patients with 31 vascular tumors located in the head and neck (n = 3), trunk (n = 2), and extremities (n = 26). The off-site pathological analysis confirmed benign vascular tumors in 54.8% of cases (non-involuting congenital hemangioma: 35.5%; epithelioid hemangioma: 13%; pyogenic granuloma: 3%; and spindle cell hemangioma: 3%). Based on the off-site histological analysis, 25.8% were reclassified as having a vascular malformation whereas three had other benign lesions. Only phleboliths were associated with a vascular malformation (p = 0.03). The concordance between off-site MRI and pathological findings was fair (k = 0.3902 (0.0531–0.7274)), whereas that between on-site and off-site pathological analyses was poor (k = −0.0949 (−0.4661 to 0.2763)).

Conclusion

Benign vascular tumors have non-specific imaging features on imaging with some overlap with atypical vascular malformations. Therefore, histological analysis is recommended. Imaging and pathological analyses should be performed in accordance with the ISSVA classification to minimize inter-observer discrepancies.

Critical relevance statement

Imaging features of benign vascular tumors on MRI are non-specific, leading to discrepancies with pathological findings and potential overlap with atypical vascular malformations. Imaging and histological analyses should be performed in accordance with ISSVA guidelines to improve patient management.

Key Points

The imaging features of benign vascular tumors are non-specific.

Histological analysis is recommended for soft tissue vascular tumors in adults.

Analyses of soft tissue vascular tumors should be performed in accordance with ISSVA guidelines.

Graphical Abstract
Fetal liver CD34+ contain human immune and endothelial progenitors and mediate solid tumor rejection in NOG mice
Authors: Celhar Teja , Li Xinyi , Zhao Yunqian , Tay Hui Chien , Lee Andrea , Liew Hui Hua , Shepherdson Edwin Kunxiang , Rajarethinam Ravisankar , Fan Yiping , Mak Anselm , Chan Jerry Kok Yen , Singhal Amit , Takahashi Takeshi
Published: June 2024

Background

Transplantation of CD34+ hematopoietic stem and progenitor cells (HSPC) into immunodeficient mice is an established method to generate humanized mice harbouring a human immune system. Different sources and methods for CD34+ isolation have been employed by various research groups, resulting in customized models that are difficult to compare. A more detailed characterization of CD34+ isolates is needed for a better understanding of engraftable hematopoietic and potentially non-hematopoietic cells. Here we have performed a direct comparison of CD34+ isolated from cord blood (CB-CD34+) or fetal liver (FL-CD34+ and FL-CD34+CD14−) and their engraftment into immunocompromised NOD/Shi-scid Il2rgnull (NOG) mice.

Methods

NOG mice were transplanted with either CB-CD34+, FL-CD34+ or FL-CD34+CD14− to generate CB-NOG, FL-NOG and FL-CD14−-NOG, respectively. After 15–20 weeks, the mice were sacrificed and human immune cell reconstitution was assessed in blood and several organs. Liver sections were pathologically assessed upon Haematoxylin and Eosin staining. To assess the capability of allogenic tumor rejection in CB- vs. FL-reconstituted mice, animals were subcutaneously engrafted with an HLA-mismatched melanoma cell line. Tumor growth was assessed by calliper measurements and a Luminex-based assay was used to compare the cytokine/chemokine profiles.

Results

We show that CB-CD34+ are a uniform population of HSPC that reconstitute NOG mice more rapidly than FL-CD34+ due to faster B cell development. However, upon long-term engraftment, FL-NOG display increased numbers of neutrophils, dendritic cells and macrophages in multiple tissues. In addition to HSPC, FL-CD34+ isolates contain non-hematopoietic CD14+ endothelial cells that enhance the engraftment of the human immune system in FL-NOG mice. We demonstrate that these CD14+CD34+ cells are capable of reconstituting Factor VIII-producing liver sinusoidal endothelial cells (LSEC) in FL-NOG. However, CD14+CD34+ also contribute to hepatic sinusoidal dilatation and immune cell infiltration, which may culminate in a graft-versus-host disease (GVHD) pathology upon long-term engraftment. Finally, using an HLA-A mismatched CDX melanoma model, we show that FL-NOG, but not CB-NOG, can mount a graft-versus-tumor (GVT) response resulting in tumor rejection.

Conclusion

Our results highlight important phenotypical and functional differences between CB- and FL-NOG and reveal FL-NOG as a potential model to study hepatic sinusoidal dilatation and mechanisms of GVT.
The impact of hypoxia preconditioning on mesenchymal stem cells performance in hypertensive kidney disease
Authors: Sohi Gurparneet Kaur , Farooqui Naba , Mohan Arjunmohan , Rajagopalan Kamalnath Sankaran , Xing Li , Zhu Xiang Y. , Jordan Kyra , Krier James D. , Saadiq Ishran M. , Tang Hui , Hickson LaTonya J. , Eirin Alfonso , Lerman Lilach O. , Herrmann Sandra M.
Published: June 2024

Background

Autologous mesenchymal stem cells (MSCs) have emerged as a therapeutic option for many diseases. Hypertensive kidney disease (HKD) might impair MSCs’ reparative ability by altering the biomolecular properties, but the characteristics of this impairment are unclear. In our previous pre-clinical studies, we found hypoxic preconditioning (HPC) enhanced angiogenesis and suppressed senescence gene expression. Thus, we hypothesize that HPC would improve human MSCs by enhancing their functionality and angiogenesis, creating an anti-inflammatory and anti-senescence environment.

Methods

MSC samples (n = 12 each) were collected from the abdominal fat of healthy kidney donors (HC), hypertensive patients (HTN), and patients with hypertensive kidney disease (HKD). MSCs were harvested and cultured in Normoxic (20% O2) or Hypoxic (1% O2) conditions. MSC functionality was measured by proliferation assays and cytokine released in conditioned media. Senescence was evaluated by senescence-associated beta-galactosidase (SA-beta-gal) activity. Additionally, transcriptome analysis using RNA-sequencing and quantitative PCR (qPCR) were performed.

Results

At baseline, normoxic HTN-MSCs had higher proliferation capacity compared to HC. However, HPC augmented proliferation in HC. HPC did not affect the release of pro-angiogenic protein VEGF, but increased EGF in HC-MSC, and decreased HGF in HC and HKD MSCs. Under HPC, SA-β-gal activity tended to decrease, particularly in HC group. HPC upregulated mostly the pro-angiogenic and inflammatory genes in HC and HKD and a few senescence genes in HKD.

Conclusions

HPC has a more favorable functional effect on HC- than on HKD-MSC, reflected in increased proliferation and EGF release, and modest decrease in senescence, whereas it has little effect on HTN or HKD MSCs.
Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice
Authors: Florczyk-Soluch Urszula , Polak Katarzyna , Jelinkova Sarka , Bronisz-Budzyńska Iwona , Sabo Reece , Bolisetty Subhashini , Agarwal Anupam , Werner Ewa , Józkowicz Alicja , Stępniewski Jacek , Szade Krzysztof , Dulak Józef
Published: June 2024

Background

Adult muscle-resident myogenic stem cells, satellite cells (SCs), that play non-redundant role in muscle regeneration, are intrinsically impaired in Duchenne muscular dystrophy (DMD). Previously we revealed that dystrophic SCs express low level of anti-inflammatory and anti-oxidative heme oxygenase-1 (HO-1, HMOX1). Here we assess whether targeted induction of HMOX1 affect SC function and alleviates hallmark symptoms of DMD.

Methods

We generated double-transgenic mouse model (mdx;HMOX1Pax7Ind) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1Pax7Ind and control mdx mice were subjected to 5-day TX injections (75 mg/kg b.w.) followed by acute exercise protocol with high-speed treadmill (12 m/min, 45 min) and downhill running to worsen skeletal muscle phenotype and reveal immediate effects of HO-1 on muscle pathology and SC function.

Results

HMOX1 induction caused a drop in SC pool in mdx;HMOX1Pax7Ind mice (vs. mdx counterparts), while not exaggerating the effect of physical exercise. Upon physical exercise, the proliferation of SCs and activated CD34− SC subpopulation, was impaired in mdx mice, an effect that was reversed in mdx;HMOX1Pax7Ind mice, however, both in vehicle- and TX-treated animals. This corresponded to the pattern of HO-1 expression in skeletal muscles. At the tissue level, necrotic events of selective skeletal muscles of mdx mice and associated increase in circulating levels of muscle damage markers were blunted in HO-1 transgenic animals which showed also anti-inflammatory cytokine profile (vs. mdx).

Conclusions

Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.
Soluble CD14 produced by bovine mammary epithelial cells modulates their response to full length LPS
Authors: Védrine Mégane , Gilbert Florence B. , Maman Sarah , Klopp Christophe , Gitton Christophe , Rainard Pascal , Germon Pierre
Published: June 2024

Bovine mastitis remains a major disease in cattle world-wide. In the mammary gland, mammary epithelial cells (MEC) are sentinels equipped with receptors allowing them to detect and respond to the invasion by bacterial pathogens, in particular Escherichia coli. Lipopolysaccharide (LPS) is the major E. coli motif recognized by MEC through its interaction with the TLR4 receptor and the CD14 co-receptor. Previous studies have highlighted the role of soluble CD14 (sCD14) in the efficient recognition of LPS molecules possessing a full-length O-antigen (LPSS). We demonstrate here that MEC are able to secrete CD14 and are likely to contribute to the presence of sCD14 in milk. We then investigated how sCD14 modulates and is required for the response of MEC to LPSS. This study highlights the key role of sCD14 for the full activation of the Myd88-independent pathway by LPSS. We also identified several lncRNA that are activated in MEC in response to LPS, including one lncRNA showing homologies with the mir-99a-let-7c gene (MIR99AHG). Altogether, our results show that a full response to LPS by mammary epithelial cells requires sCD14 and provide detailed information on how milk sCD14 can contribute to an efficient recognition of LPS from coliform pathogens.
Consumption of antibiotics in Brazil - an analysis of sales data between 2014 and 2019
Authors: Lopes Luciane Cruz , Motter Fabiane R. , Carvalho-Soares Mônica Da Luz
Published: June 2024

Background

Antibiotic consumption is a driver for the increase of antimicrobial resistance. The objective of this study is to analyze variations in antibiotic consumption and its appropriate use in Brazil from 2014 to 2019.

Methods

We conducted a time series study using the surveillance information system database (SNGPC) from the Brazilian Health Regulatory Agency. Antimicrobials sold in retail pharmacies were evaluated. All antimicrobials recorded for systemic use identified by the active ingredient were eligible. Compounded products and formulations for topic use (dermatological, gynecological, and eye/ear treatments) were excluded. The number of defined daily doses (DDDs)/1,000 inhabitants/day for each antibiotic was attributed. The number of DDDs per 1,000 inhabitants per day (DDIs) was used as a proxy for consumption. Results were stratified by regions and the average annual percentage change in the whole period studied was estimated. We used the WHO Access, Watch, and Reserve (AWaRe) framework to categorize antimicrobial drugs.

Results

An overall increase of 30% in consumption from 2014 to 2019 was observed in all Brazilian regions. Amoxicillin, azithromycin and cephalexin were the antimicrobials more consumed, with the Southeast region responsible for more than 50% of the antibiotic utilization. Among all antimicrobials analyzed 45.0% were classified as watch group in all Brazilian regions.

Conclusion

We observed a significant increase in antibiotics consumption from 2014 to 2019 in Brazil restricted to the Northeast and Central West regions. Almost half of the antibiotics consumed in Brazil were classified as watch group, highlighting the importance to promote rational use in this country.
Prevalence and predictors of self-medication with antibiotics in Ethiopia: a systematic review and meta-analysis
Authors: Ayenew Wondim , Tessema Tewodros Ayalew , Anagaw Yeniewa Kerie , Siraj Ebrahim Abdela , Zewdie Segenet , Simegn Wudneh , Limenh Liknaw Workie , Tafere Chernet , Yayehrad Ashagrachew Tewabe
Published: June 2024

Introduction

Antibiotic self-medication is a global public health concern contributing to antibiotic resistance. This systematic review and meta-analysis aim to assess the prevalence of antibiotic self-medication and its associated factors in Ethiopia.

Methods

A comprehensive search of electronic databases was conducted from MEDLINE (PubMed), Scopus, Google Scholar and Web of Science to identify relevant studies published between 2000 and 2024. Adult households, undergraduate university students and health care professionals who had taken antibiotics without a prescription in the household setting were included in this review. The primary outcome of this review is antibiotic self- medication. The random-effects model was used to estimate pooled prevalence rates. The outcome measure was analyzed with STATA version 17 software.

Results

A total of nine studies were included in the Meta-analysis, comprising a sample size of 5908 participants. The pooled prevalence of antibiotic self-medication among Ethiopians was found to be 46.14 with 95% Confidence Interval [35.71, 56.57]. The most frequently used classes of self-medicated antibiotics were penicillins, followed by tetracyclines. Community pharmacies were the source of information that individuals utilized. The most common reported reasons for antibiotic self-medication include previous experience of treating a similar illness, to save cost, lack of time and avoiding waiting time for medical services. Participants having less than high school educational level was the most commonly reported factor associated with self-medication antibiotics.

Conclusion

Antibiotic self-medication is a prevalent practice in Ethiopia. This underscores the need for targeted interventions such as educating people about the risks associated with using antibiotics without medical guidance, which results in a reduction in antibiotic resistance.
Surveillance of close contacts of patients with infectious tuberculosis: a prospective cohort study
Authors: Ma Zichun , Duan Shujuan , Wang Wei , Liu Rongmei , Li Shanshan , Shang Yuanyuan , Zhang Xuxia , Yuan Jinfeng , Gao Mengqiu , Pang Yu
Published: June 2024

Background

A long-term follow-up of close contacts to monitor their infection status is essential to formulate a promising screening strategy. The study aimed to assess the dynamics of tuberculosis (TB) infection using Interferon-γ release assay (IGRA) and determine risk factors associated with TB infection.

Methods

Definite TB patients were interviewed and their household contacts were screened for TB infection by IGRA during 12-month longitudinal investigation.

Results

We included in our analyses 184 household contacts of 92 index TB patients. 87 individuals (47.3%) in contact group progressed to TB infection, of whom 86 developed into IGRA positive within 24 weeks. Close contacts with a higher age and comorbidities are easier to exhibit TB infection. Analysis showed that risk factors for becoming IGRA-positive individuals included residence, older age, comorbidities, BCG scar and high bacterial load. Contacts with BCG scar had a lower IGRA-positive rate.

Conclusion

IGRA conversion generally occurs within 24 weeks after exposure. The TB transmission happens since subclinical TB stage and the presence of BCG scar is an independent protective factor reducing risk of TB infection among close contacts. Repeated IGRA tests are sensible to conducted among close contacts at 24 weeks after exposure to identify the IGRA-positive individuals.
Development of a postoperative visual function rehabilitation compliance assessment scale for children with congenital cataract: a reliability and validity study
Authors: Zhang Yanan , Xie Wanhua , Xiang Daoman
Published: June 2024

Objective

To develop a comprehensive compliance assessment scale for postoperative visual function rehabilitation in children with congenital cataracts and to assess its reliability and validity.

Method

Drawing on the Interactive Model of Health Behavior, we conducted a literature review and semi-structured interviews to create a pool of 36 items. The items underwent rigorous evaluation through the Delphi method, face validity checks, and item analysis, leading to a reduction to 18 items. To assess the scale's reliability and validity, we collected data from 225 parents of children with congenital cataracts. We employed SPSS version 25.0 for data analysis and evaluated construct validity using exploratory factor analysis, content validity, internal consistency reliability, and test–retest reliability.

Results

The compliance scale for postoperative visual function rehabilitation in children with congenital cataracts comprises 5 dimensions and 18 items. Exploratory factor analysis extracted 5 common factors, with a cumulative variance contribution rate of 68.178%. Item-level content validity index ranged from 0.730 to 1.000, and the content validity index of the scale was 0.963. The total Cronbach's alpha coefficient, split-half reliability, and test–retest reliability of the scale were 0.855, 0.778, and 0.859, respectively.

Conclusions

The compliance assessment scale for postoperative visual function rehabilitation in children with congenital cataracts demonstrates acceptable reliability and validity. It serves as a valuable reference for developing standardized nursing programs for these children in clinical practice.
Gasdermin E benefits CD8+T cell mediated anti-immunity through mitochondrial damage to activate cGAS-STING-interferonβ axis in colorectal cancer
Authors: Luo Bixian , Zhang Shun , Yu Xinbo , Tan Dan , Wang Ying , Wang Mingliang
Published: June 2024

Background

Pyroptosis belongs to a unique type of programmed cell death among which GSDME is reported to exert anti-tumor immunity. However, the underlying mechanisms of how to boost tumor-infiltrating lymphocytes and whether it could benefit the efficacy of ICIs are still unknown.

Methods

CRC samples were used to analyze its relationship with CD8+T cells. GSDME in mouse CRC cell lines CT26/MC38 was overexpressed. The infiltration of CD8+T cells in grafted tumors was determined by multiplex flow cytometric analysis and immunohistochemistry. Transcriptomic analysis was performed in cell lines to define key signatures related to its overexpression. The mechanism of how mtDNA was released by GSDME-induced mitochondrial damage and activated cGAS-STING pathway was observed. Whether GSDME benefited ICIs and the relationships with the genotypes of CRC patients were investigated.

Results

It had favorable prognostic value in CRC and was positively associated with increased number and functionality of CD8+T cells both in human samples and animal models. This was due to mitochondrial damage and activation of cGAS-STING-IFNβ pathway for the recruitment of CD8+T cells. Mechanically, GSDME overexpression enhanced N-GSDME level, leading to the mitochondrial damage and mtDNA was released into cytosol. Finally, GSDME benefited with ICIs and exhibited positive relationships with MSI in CRC patients.

Conclusion

We presented the mechanism of GSDME in anti-tumor immunity through activating cGAS-STING-IFNβ axis mediated by mitochondrial damage, leading to more infiltration of CD8+T cells with synergistic efficacy with ICIs.
Rainbow code of biodeterioration to cultural heritage objects
Authors: Avdanina Daria A. , Zhgun Alexander A.
Published: June 2024

The vast majority of cultural heritage objects consist of materials that can be subjected to biodeterioration. Currently, there is significant number of publications showing which materials are capable of destroying certain organisms, and what conservation and restoration procedures are required. However, there is neither a clear classification of these diverse events nor their visual representation. In our review, for the first time, an attempt is made to compare the type of biodeterioration, based on the destruction of a particular material, with a specific color of the rainbow. In this regard, a cultural heritage objects made of a single material are designated as one color icon; and those made of composite materials are designated as pictogram consisting of several icons of corresponding colors. For example, a stone sculpture, in accordance with the rainbow code, is assigned a gray color, which was introduced to visualize stone materials. The drum corresponds to a pictogram consisting of violet (corresponds to leather) and brown (corresponds to wood). A work of easel painting on canvas corresponds to a pictogram consisting of a red color icon (corresponds to canvas) and a gold color icon (corresponds to painting materials). We used cold color shades to denote basic inorganic materials, and cold color shades to denote organic materials. The proposed rainbow code for biodetermination is an open platform that can be expanded by adding new colors for new materials introduced, and allows to translate potentially any cultural heritage object into a pictogram with colors that correspond to the materials used in its manufacture. Such a graphical interpretation can help both systematize the storage conditions of museum exhibits and facilitate understanding of the processes of biodeterioration of composite materials.

Graphical Abstract
The extraordinary universe of Peter Apian: technical investigation of five copies of a 16th-century astronomical book
Authors: Fiorillo Flavia , Cheese Edward , Öberg Strådal Sara , Reynolds Suzanne
Published: June 2024

In 1540, in Ingolstadt, Germany, the influential astronomer and printer Peter Apian produced the Astronomicum Caesareum: a printed and hand-coloured astronomical book visualising the Ptolemaic universe through the use of diagrams and wheelcharts, worthy of his imperial patron, Charles V. About 130 copies have survived to this day, with varying degrees of paper quality and level of decoration, and only eleven volumes are considered deluxe copies. We thoroughly analysed one deluxe volume held at the Fitzwilliam Museum, Cambridge, and compared the results with four (one deluxe and three standard) other copies from institutions in the UK. A non-invasive analytical protocol was applied, including extensive microscopy, fibre-optic reflectance spectroscopy (FORS), X-ray spectroscopy (XRF), macroscale XRF (MA-XRF) and Raman spectroscopy. The most interesting pages were chosen based on art-historical evidence and the variety of the colour palette, including on volvelles (wheelcharts) and coats of arms. Following a systematic approach, we analysed the same pages in each volume, gathering information on the colour palette in all the volumes. The type of paper and the presence of watermarks were also documented. A wide range of materials was identified in the five copies, including red, purple and yellow organic dyes, lead white, verdigris, vermilion, azurite, indigo, smalt, and lead–tin yellow. Mosaic gold was used to embellish certain paint passages in the deluxe volumes and metals (gold and silver) were applied on some pages. The comprehensive findings were essential to identify specific traits related to Apian’s workshop, to differentiate deluxe from standard copies, to suggest an order of production of the copies, and to provide new information on this landmark book and more generally in an under-researched field of study.
Inhibition of astroglial hemichannels prevents synaptic transmission decline during spreading depression
Authors: Tichauer Juan E. , Lira Matías , Cerpa Waldo , Orellana Juan A. , Sáez Juan C. , Rovegno Maximiliano
Published: June 2024

Background

Spreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is repetitive and produces a metabolic overload that increases secondary damage. However, the mechanisms associated with the initiation and propagation of SD are unknown. Multiple lines of evidence indicate that persistent and uncontrolled opening of hemichannels could participate in the pathogenesis and progression of several neurological disorders including acute brain injuries. Here, we explored the contribution of astroglial hemichannels composed of connexin-43 (Cx43) or pannexin-1 (Panx1) to SD evoked by high-K+ stimulation in brain slices.

Results

Focal high-K+ stimulation rapidly evoked a wave of SD linked to increased activity of the Cx43 and Panx1 hemichannels in the brain cortex, as measured by light transmittance and dye uptake analysis, respectively. The activation of these channels occurs mainly in astrocytes but also in neurons. More importantly, the inhibition of both the Cx43 and Panx1 hemichannels completely prevented high K+-induced SD in the brain cortex. Electrophysiological recordings also revealed that Cx43 and Panx1 hemichannels critically contribute to the SD-induced decrease in synaptic transmission in the brain cortex and hippocampus.

Conclusions

Targeting Cx43 and Panx1 hemichannels could serve as a new therapeutic strategy to prevent the initiation and propagation of SD in several acute brain injuries.
Balance Control is Sequentially Correlated with Proprioception, Joint Range of Motion, Strength, Pain, and Plantar Tactile Sensation Among Older Adults with Knee Osteoarthritis
Authors: Shen Peixin , Li Simin , Li Li , Fong Daniel T. P. , Mao Dewei , Song Qipeng
Published: June 2024

Background

Patients with knee osteoarthritis (KOA) are at high risk for falls, which is attributed to their impaired balance control. Identifying factors associated with balance control facilitates the development of precise KOA rehabilitation programs. This study was to investigate the correlations of balance control with proprioception, plantar tactile sensation (PTS), pain, joint range of motion (ROM), and strength among older adults with and without KOA, as well as the magnitudes and sequence of correlation of these factors to balance control.

Methods

A total of 240 older adults with (n = 124, female: 84, age: 68.8 ± 4.0 years) and without (n = 116, female: 64, age: 67.9 ± 3.5 years) KOA were recruited and assigned to the KOA and control groups. Their proprioception, PTS, pain, ROM, and strength were measured. Pearson or Spearman correlations were used to test whether they were significantly related to their Berg Balance Scale (BBS), and factor analysis and multivariate linear regression were used to determine the degrees of correlation between each factor and the BBS.

Results

Compared to the control group, the KOA group had lower BBS score, larger proprioception and PTS thresholds, smaller ROM, and less strength (p: 0.008, < 0.001–0.016, < 0.001–0.005, < 0.001–0.014, and < 0.001–0.002, respectively). In the KOA group, the BBS was weakly to moderately correlated with proprioception, PTS, pain, ROM, and strength (r: 0.332–0.501, 0.197–0.291, 0.340, 0.212–0.508, and 0.236–0.336, respectively). While in the control group, the BBS was correlated with proprioception and strength (r: 0.207–0.379, and 0.212–0.410). In the KOA group, BBS = 54.41+ (0.668*strength) - (0.579*PTS) - (1.141*proprioception) + (1.054* ROM) - (0.339*pain). While in the control group, BBS = 53.85+ (0.441*strength) - (0.677*proprioception).

Conclusion

Worse proprioception and PTS, smaller ROM, and less strength were detected among older adults with KOA, and their proprioception, PTS, pain, ROM, and strength were all related to balance control. Proprioception had the strongest correlations, followed by ROM, strength, pain, and PTS. Precise KOA rehabilitation programs may be proposed following the sequence of improving the five factors.