bluuebunny/crossref_metadata_2025 huggingface dataset:
Defective Mitochondrial Dynamics and Protein Degradation Pathways Underlie Cadmium-Induced Neurotoxicity and Cell Death in Huntington’s Disease Striatal Cells
Authors: Kamitsuka Paul J. , Ghanem Marwan M. , Ziar Rania , McDonald Sarah E. , Thomas Morgan G. , Kwakye Gunnar F.
Published: April 2023

Exposure to heavy metals, including cadmium (Cd), can induce neurotoxicity and cell death. Cd is abundant in the environment and accumulates in the striatum, the primary brain region selectively affected by Huntington’s disease (HD). We have previously reported that mutant huntingtin protein (mHTT) combined with chronic Cd exposure induces oxidative stress and promotes metal dyshomeostasis, resulting in cell death in a striatal cell model of HD. To understand the effect of acute Cd exposure on mitochondrial health and protein degradation pathways, we hypothesized that expression of mHTT coupled with acute Cd exposure would cooperatively alter mitochondrial bioenergetics and protein degradation mechanisms in striatal STHdh cells to reveal novel pathways that augment Cd cytotoxicity and HD pathogenicity. We report that mHTT cells are significantly more susceptible to acute Cd-induced cell death as early as 6 h after 40 µM CdCl2 exposure compared with wild-type (WT). Confocal microscopy, biochemical assays, and immunoblotting analysis revealed that mHTT and acute Cd exposure synergistically impair mitochondrial bioenergetics by reducing mitochondrial potential and cellular ATP levels and down-regulating the essential pro-fusion proteins MFN1 and MFN2. These pathogenic effects triggered cell death. Furthermore, Cd exposure increases the expression of autophagic markers, such as p62, LC3, and ATG5, and reduces the activity of the ubiquitin–proteasome system to promote neurodegeneration in HD striatal cells. Overall, these results reveal a novel mechanism to further establish Cd as a pathogenic neuromodulator in striatal HD cells via Cd-triggered neurotoxicity and cell death mediated by an impairment in mitochondrial bioenergetics and autophagy with subsequent alteration in protein degradation pathways.
Identification and Functional Analysis of Tartrate-Resistant Acid Phosphatase Type 5b (TRAP5b) in Oreochromis niloticus
Authors: Lei Yang , Fu Shengli , Yang Yanjian , Chen Jianlin , Li Bingxi , Guo Zheng , Ye Jianmin
Published: April 2023

Tartrate-resistant acid phosphatase type 5 (TRAP5) is an enzyme that is highly expressed in activated macrophages and osteoclasts and plays important biological functions in mammalian immune defense systems. In the study, we investigated the functions of tartrate-resistant acid phosphatase type 5b from Oreochromis niloticus (OnTRAP5b). The OnTRAP5b gene has an open reading frame of 975 bp, which encodes a mature peptide consisting of 302 amino acids with a molecular weight of 33.448 kDa. The OnTRAP5b protein contains a metallophosphatase domain with metal binding and active sites. Phylogenetic analysis revealed that OnTRAP5b is clustered with TRAP5b of teleost fish and shares a high amino acid sequence similarity with other TRAP5b in teleost fish (61.73–98.15%). Tissues expression analysis showed that OnTRAP5b was most abundant in the liver and was also widely expressed in other tissues. Upon challenge with Streptococcus agalactiae and Aeromonas hydrophila in vivo and in vitro, the expression of OnTRAP5b was significantly up-regulated. Additionally, the purified recombinant OnTRAP5b ((r)OnTRAP5) protein exhibited optimal phosphatase activity at pH 5.0 and an ideal temperature of 50 °C. The Vmax, Km, and kcat of purified (r)OnTRAP5b were found to be 0.484 μmol × min−1 × mg−1, 2.112 mM, and 0.27 s−1 with respect to pNPP as a substrate, respectively. Its phosphatase activity was differentially affected by metal ions (K+, Na+, Mg2+, Ca2+, Mn2+, Cu2+, Zn2+, and Fe3+) and inhibitors (sodium tartrate, sodium fluoride, and EDTA). Furthermore, (r)OnTRAP5b was found to promote the expression of inflammatory-related genes in head kidney macrophages and induce reactive oxygen expression and phagocytosis. Moreover, OnTRAP5b overexpression and knockdown had a significant effect on bacterial proliferation in vivo. When taken together, our findings suggest that OnTRAP5b plays a significant role in the immune response against bacterial infection in Nile tilapia.
Differential Expression of ATM, NF-KB, PINK1 and Foxo3a in Radiation-Induced Basal Cell Carcinoma
Authors: Jenni Rim , Chikhaoui Asma , Nabouli Imen , Zaouak Anissa , Khanchel Fatma , Hammami-Ghorbel Houda , Yacoub-Youssef Houda
Published: April 2023

Research in normal tissue radiobiology is in continuous progress to assess cellular response following ionizing radiation exposure especially linked to carcinogenesis risk. This was observed among patients with a history of radiotherapy of the scalp for ringworm who developed basal cell carcinoma (BCC). However, the involved mechanisms remain largely undefined. We performed a gene expression analysis of tumor biopsies and blood of radiation-induced BCC and sporadic patients using reverse transcription-quantitative PCR. Differences across groups were assessed by statistical analysis. Bioinformatic analyses were conducted using miRNet. We showed a significant overexpression of the FOXO3a, ATM, P65, TNF-α and PINK1 genes among radiation-induced BCCs compared to BCCs in sporadic patients. ATM expression level was correlated with FOXO3a. Based on receiver-operating characteristic curves, the differentially expressed genes could significantly discriminate between the two groups. Nevertheless, TNF-α and PINK1 blood expression showed no statistical differences between BCC groups. Bioinformatic analysis revealed that the candidate genes may represent putative targets for microRNAs in the skin. Our findings may yield clues as to the molecular mechanism involved in radiation-induced BCC, suggesting that deregulation of ATM-NF-kB signaling and PINK1 gene expression may contribute to BCC radiation carcinogenesis and that the analyzed genes could represent candidate radiation biomarkers associated with radiation-induced BCC.
Effect of Genetic Factors, Age and Sex on Levels of Circulating Extracellular Vesicles and Platelets
Authors: Orrù Valeria , Virdis Francesca , Marongiu Michele , Serra Valentina , Schlessinger David , Devoto Marcella , Cucca Francesco , Fiorillo Edoardo
Published: April 2023

Extracellular vesicles (EVs) mediate cell interactions in biological processes, such as receptor activation or molecule transfer. Estimates of variation by age and sex have been limited by small sample size, and no report has assessed the contribution of genetic factors to levels of EVs. Here, we evaluated blood levels of 25 EV and 3 platelet traits in 974 individuals (933 genotyped) and reported the first genome-wide association study (GWAS) on levels of these traits. EV levels all decreased with age, whereas the trend for their surface markers was more heterogeneous. Platelets and CD31dim platelet EVs significantly increased in females compared to males, although CD31 expression on both platelets and platelet EVs decreased in females. Levels of the other EV subsets were similar between sexes. GWAS revealed three statistically significant genetic signals associated with EV levels in the F10 and GBP1 genes and in the intergenic region between LRIG1 and KBTBD8. These add to a signal in the 3′UTR of RHOF associated with CD31 expression on platelets that was previously found to be associated with other platelet traits. These findings suggest that EV formation is not a simple, constant adjunct of metabolism but is under both age-related and genetic control that can be independent of the regulation of the levels of the cells from which the EVs derive.
Pathophysiology and Neuroimmune Interactions Underlying Parkinson’s Disease and Traumatic Brain Injury
Authors: Lillian Alyssa , Zuo Wanhong , Laham Linda , Hilfiker Sabine , Ye Jiang-Hong
Published: April 2023

Parkinson’s disease (PD) is a progressive neurodegenerative disorder clinically defined by motor instability, bradykinesia, and resting tremors. The clinical symptomatology is seen alongside pathologic changes, most notably the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of α-synuclein and neuromelanin aggregates throughout numerous neural circuits. Traumatic brain injury (TBI) has been implicated as a risk factor for developing various neurodegenerative diseases, with the most compelling argument for the development of PD. Dopaminergic abnormalities, the accumulation of α-synuclein, and disruptions in neural homeostatic mechanisms, including but not limited to the release of pro-inflammatory mediators and the production of reactive oxygen species (ROS), are all present following TBI and are closely related to the pathologic changes seen in PD. Neuronal iron accumulation is discernable in degenerative and injured brain states, as is aquaporin-4 (APQ4). APQ4 is an essential mediator of synaptic plasticity in PD and regulates edematous states in the brain after TBI. Whether the cellular and parenchymal changes seen post-TBI directly cause neurodegenerative diseases such as PD is a point of considerable interest and debate; this review explores the vast array of neuroimmunological interactions and subsequent analogous changes that occur in TBI and PD. There is significant interest in exploring the validity of the relationship between TBI and PD, which is a focus of this review.
Development of a Novel, Automated High-Throughput Device for Performing the Comet Assay
Authors: Karbaschi Mahsa , Ji Yunhee , Mujawar Mubarak A. , Mendoza Mario , Marquez Juan S. , Sonawane Apurva , Shah Pratikkumar , Ross Chris , Bhansali Shekhar , Cooke Marcus S.
Published: April 2023

A comet assay is a trusted and widely used method for assessing DNA damage in individual eukaryotic cells. However, it is time-consuming and requires extensive monitoring and sample manipulation by the user. This limits the throughput of the assay, increases the risk of errors, and contributes to intra- and inter-laboratory variability. Here, we describe the development of a device which automates high throughput sample processing for a comet assay. This device is based upon our patented, high throughput, vertical comet assay electrophoresis tank, and incorporates our novel, patented combination of assay fluidics, temperature control, and a sliding electrophoresis tank to facilitate sample loading and removal. Additionally, we demonstrated that the automated device performs at least as well as our “manual” high throughput system, but with all the advantages of a fully “walkaway” device, such as a decreased need for human involvement and a decreased assay run time. Our automated device represents a valuable, high throughput approach for reliably assessing DNA damage with the minimal operator involvement, particularly if combined with the automated analysis of comets.
DNA Demethylation of Myogenic Genes May Contribute to Embryonic Leg Muscle Development Differences between Wuzong and Shitou Geese
Authors: Zhang Xumeng , Li Yong , Zhu Chenyu , Li Fada , Liu Zhiyuan , Li Xiujin , Shen Xu , Wu Zhongping , Fu Mengsi , Xu Danning , Tian Yunbo , Huang Yunmao
Published: April 2023

Skeletal muscle development from embryonic stages to hatching is critical for poultry muscle growth, during which DNA methylation plays a vital role. However, it is not yet clear how DNA methylation affects early embryonic muscle development between goose breeds of different body size. In this study, whole genome bisulfite sequencing (WGBS) was conducted on leg muscle tissue from Wuzong (WZE) and Shitou (STE) geese on embryonic day 15 (E15), E23, and post-hatch day 1. It was found that at E23, the embryonic leg muscle development of STE was more intense than that of WZE. A negative correlation was found between gene expression and DNA methylation around transcription start sites (TSSs), while a positive correlation was observed in the gene body near TTSs. It was also possible that earlier demethylation of myogenic genes around TSSs contributes to their earlier expression in WZE. Using pyrosequencing to analyze DNA methylation patterns of promoter regions, we also found that earlier demethylation of the MyoD1 promoter in WZE contributed to its earlier expression. This study reveals that DNA demethylation of myogenic genes may contribute to embryonic leg muscle development differences between Wuzong and Shitou geese.
Comet Assay Profiling of FLASH-Induced Damage: Mechanistic Insights into the Effects of FLASH Irradiation
Authors: Cooper Christian R. , Jones Donald J. L. , Jones George D. D. , Petersson Kristoffer
Published: April 2023

Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate ‘FLASH’ irradiation in vivo, with an associated reduction in damage burden being reported in vitro. Towards this, two key radiochemical mechanisms have been proposed: radical–radical recombination (RRR) and transient oxygen depletion (TOD), with both being proposed to lead to reduced levels of induced damage. Previously, we reported that FLASH induces lower levels of DNA strand break damage in whole-blood peripheral blood lymphocytes (WB-PBL) ex vivo, but our study failed to distinguish the mechanism(s) involved. A potential outcome of RRR is the formation of crosslink damage (particularly, if any organic radicals recombine), whilst a possible outcome of TOD is a more anoxic profile of induced damage resulting from FLASH. Therefore, the aim of the current study was to profile FLASH-induced damage via the Comet assay, assessing any DNA crosslink formation as a putative marker of RRR and/or anoxic DNA damage formation as an indicative marker of TOD, to determine the extent to which either mechanism contributes to the “FLASH effect”. Following FLASH irradiation, we see no evidence of any crosslink formation; however, FLASH irradiation induces a more anoxic profile of induced damage, supporting the TOD mechanism. Furthermore, treatment of WB-PBLs pre-irradiation with BSO abrogates the reduced strand break damage burden mediated by FLASH exposures. In summary, we do not see any experimental evidence to support the RRR mechanism contributing to the reduced damage burden induced by FLASH. However, the observation of a greater anoxic profile of damage following FLASH irradiation, together with the BSO abrogation of the reduced strand break damage burden mediated by FLASH, lends further support to TOD being a driver of the reduced damage burden plus a change in the damage profile mediated by FLASH.
Aberrant Dopamine System Function in the Ferrous Amyloid Buthionine (FAB) Rat Model of Alzheimer’s Disease
Authors: Perez Stephanie M. , Boley Angela M. , McCoy Alexandra M. , Lodge Daniel J.
Published: April 2023

Antipsychotics increase the risk of death in elderly patients with Alzheimer’s disease (AD). Thus, there is an immediate need for novel therapies to treat comorbid psychosis in AD. Psychosis has been attributed to a dysregulation of the dopamine system and is associated with aberrant regulation by the hippocampus. Given that the hippocampus is a key site of pathology in AD, we posit that aberrant regulation of the dopamine system may contribute to comorbid psychosis in AD. A ferrous amyloid buthionine (FAB) rodent model was used to model a sporadic form of AD. FAB rats displayed functional hippocampal alterations, which were accompanied by decreases in spontaneous, low-frequency oscillations and increases in the firing rates of putative pyramidal neurons. Additionally, FAB rats exhibited increases in dopamine neuron population activity and augmented responses to the locomotor-inducing effects of MK-801, as is consistent with rodent models of psychosis-like symptomatology. Further, working memory deficits in the Y-maze, consistent with an AD-like phenotype, were observed in FAB rats. These data suggest that the aberrant hippocampal activity observed in AD may contribute to dopamine-dependent psychosis, and that the FAB model may be useful for the investigation of comorbid psychosis related to AD. Understanding the pathophysiology that leads to comorbid psychosis in AD will ultimately lead to the discovery of novel targets for the treatment of this disease.
The Effect of Silencing the Genes Responsible for the Level of Sphingosine-1-phosphate on the Apoptosis of Colon Cancer Cells
Authors: Markowski Adam R. , Żbikowski Arkadiusz , Zabielski Piotr , Chlabicz Urszula , Sadowska Patrycja , Pogodzińska Karolina , Błachnio-Zabielska Agnieszka U.
Published: April 2023

Sphingosine-1-phosphate (S1P) and ceramides (Cer) are engaged in key events of signal transduction, but their involvement in the pathogenesis of colorectal cancer is not conclusive. The aim of our study was to investigate how the modulation of sphingolipid metabolism through the silencing of the genes involved in the formation (SPHK1) and degradation (SGPL1) of sphingosine-1-phosphate would affect the sphingolipid profile and apoptosis of HCT-116 human colorectal cancer cells. Silencing of SPHK1 expression decreased S1P content in HCT-116 cells, which was accompanied by an elevation in sphingosine, C18:0-Cer, and C18:1-Cer, increase in the expression and activation of Caspase-3 and -9, and augmentation of apoptosis. Interestingly, silencing of SGLP1 expression increased cellular content of both the S1P and Cer (C16:0-; C18:0-; C18:1-; C20:0-; and C22:0-Cer), yet inhibited activation of Caspase-3 and upregulated protein expression of Cathepsin-D. The above findings suggest that modulation of the S1P level and S1P/Cer ratio regulates both cellular apoptosis and CRC metastasis through Cathepsin-D modulation. The cellular ratio of S1P/Cer seems to be a crucial component of the above mechanism.
Fundamental Properties and Clinical Application of 3D-Printed Bioglass Porcelain Fused to Metal Dental Restoration
Authors: Yun Yangan , Kang Hyeon , Kim Eun-Chae , Park Sangwon , Lee Yong-Seok , Yun Kwidug
Published: April 2023

The purpose of this study is to evaluate the mechanical properties and clinical fitness of 3D-printed bioglass porcelain fused to metal (PFM) dental crowns. To evaluate the mechanical properties, tensile strength, Vickers microhardness, shear bond strength, and surface roughness tests of the SLM printed Co-Cr alloy was conducted. A right mandibular 1st molar tooth was prepared for a single dental crown (n = 10). For a three-unit metal crown and bridge, the right mandibular first premolar and first molar were prepared. Bioglass porcelain was fired to fabricate PFM dental restorations. A clinical gap was observed and measured during each of the four times porcelain was fired. A statistical analysis was conducted. The SLM technique showed the largest statistically significant tensile strength and a 0.2% yield strength value. The milling technique had the lowest statistically significant compressive strength value. The shear bond strength and surface roughness showed no statistically significant difference between the fabricated method. There was a statistically significant change in marginal discrepancy according to the porcelain firing step. The casting technique showed the greatest statistically significant margin discrepancy value. The SLM method showed better fitness than the traditional casting method and showed better mechanical properties as a dental material.
Whole-Transcriptome Sequencing of Antler Tissue Reveals That circRNA2829 Regulates Chondrocyte Proliferation and Differentiation via the miR-4286-R+1/FOXO4 Axis
Authors: Yao Haibo , Jiang Renfeng , Chen Danyang , Li Yanjun , Song Mengmeng , Sun Zitong , Long Guohui , Wu Lei , Hu Wei
Published: April 2023

The antler is the unique mammalian organ found to be able to regenerate completely and periodically after loss, and the continuous proliferation and differentiation of mesenchymal cells and chondrocytes together complete the regeneration of the antler. Circular non-coding RNAs (circRNAs) are considered to be important non-coding RNAs that regulate body development and growth. However, there are no reports on circRNAs regulating the antler regeneration process. In this study, full-transcriptome high-throughput sequencing was performed on sika deer antler interstitial and cartilage tissues, and the sequencing results were verified and analyzed. The competing endogenous RNA (ceRNA) network related to antler growth and regeneration was further constructed, and the differentially expressed circRNA2829 was screened out from the network to study its effect on chondrocyte proliferation and differentiation. The results indicated that circRNA2829 promoted cell proliferation and increased the level of intracellular ALP. The analysis of RT-qPCR and Western blot demonstrated that the mRNA and protein expression levels of genes involved in differentiation rose. These data revealed that circRNAs play a crucial regulatory role in deer antler regeneration and development. CircRNA2829 might regulate the antler regeneration process through miR-4286-R+1/FOXO4.
Comparison of Cardiorespiratory Fitness between Patients with Mitral Valve Prolapse and Healthy Peers: Findings from Serial Cardiopulmonary Exercise Testing
Authors: Chung Jin-Hui , Tsai Yi-Ju , Lin Ko-Long , Weng Ken-Pen , Huang Ming-Hsuan , Chen Guan-Bo , Tuan Sheng-Hui
Published: April 2023

Individuals with mitral valve prolapse (MVP) have exercise intolerance even without mitral valve regurgitation. Mitral valve degeneration may progress with aging. We aimed to evaluate the influence of MVP on the cardiopulmonary function (CPF) of individuals with MVP through serial follow-ups from early to late adolescence. Thirty patients with MVP receiving at least two cardiopulmonary exercise tests (CPETs) using a treadmill (MVP group) were retrospectively analyzed. Age-, sex-, and body mass index-matched healthy peers, who also had serial CPETs, were recruited as the control group. The average time from the first CPET to the last CPET was 4.28 and 4.06 years in the MVP and control groups, respectively. At the first CPET, the MVP group had a significantly lower peak rate pressure product (PRPP) than the control group (p = 0.022). At the final CEPT, the MVP group had lower peak metabolic equivalent (MET, p = 0.032) and PRPP (p = 0.031). Moreover, the MVP group had lower peak MET and PRPP as they aged, whereas healthy peers had higher peak MET (p = 0.034) and PRPP (p = 0.047) as they aged. Individuals with MVP had poorer CPF than healthy individuals as they develop from early to late adolescence. It is important for individuals with MVP to receive regular CPET follow-ups.
Oral and Vaginal Hormonal Contraceptives Induce Similar Unfavorable Metabolic Effects in Women with PCOS: A Randomized Controlled Trial
Authors: Mosorin Maria-Elina , Piltonen Terhi , Rantala Anni , Kangasniemi Marika , Korhonen Elisa , Bloigu Risto , Tapanainen Juha , Morin-Papunen Laure
Published: April 2023

This clinical trial aims to compare hormonal and metabolic changes after a 9-week continuous use of oral or vaginal combined hormonal contraceptives (CHCs) in women with polycystic ovary syndrome (PCOS). We recruited 24 women with PCOS and randomized them to use either combined oral (COC, n = 13) or vaginal (CVC, n = 11) contraception. At baseline and 9 weeks, blood samples were collected and a 2 h glucose tolerance test (OGTT) was performed to evaluate hormonal and metabolic outcomes. After treatment, serum sex hormone binding globulin (SHBG) levels increased (p < 0.001 for both groups) and the free androgen index (FAI) decreased in both study groups (COC p < 0.001; CVC p = 0.007). OGTT glucose levels at 60 min (p = 0.011) and AUCglucose (p = 0.018) increased in the CVC group. Fasting insulin levels (p = 0.037) increased in the COC group, and insulin levels at 120 min increased in both groups (COC p = 0.004; CVC p = 0.042). There was a significant increase in triglyceride (p < 0.001) and hs-CRP (p = 0.032) levels in the CVC group. Both oral and vaginal CHCs decreased androgenicity and tended to promote insulin resistance in PCOS women. Larger and longer studies are needed to compare the metabolic effects of different administration routes of CHCs on women with PCOS.
Secondary Tumors of the Pancreas: A Multicenter Analysis of Clinicopathological and Endosonographic Features
Authors: Spadaccini Marco , Conti Bellocchi Maria Cristina , Mangiavillano Benedetto , Fantin Alberto , Rahal Daoud , Manfrin Erminia , Gavazzi Francesca , Bozzarelli Silvia , Crinò Stefano Francesco , Terrin Maria , Di Leo Milena , Bonifacio Cristiana , Facciorusso Antonio , Realdon Stefano , Cristofori Chiara , Auriemma Francesco , Fugazza Alessandro , Frulloni Luca , Hassan Cesare , Repici Alessandro , Carrara Silvia
Published: April 2023

Many tumors may secondarily involve the pancreas; however, only retrospective autopic and surgical series are available. We retrospectively collected data from all consecutive patients with histologically confirmed secondary tumors of the pancreas referred to five Italian centers between 2010 and 2021. We described clinical and pathological features, therapeutic approach and treatment outcomes. EUS characteristics of the lesions and the tissue acquisition procedures (needle, passages, histology) were recorded. A total of 116 patients (males/females 69/47; mean age 66.7) with 236 histologically confirmed pancreatic metastases were included; kidney was the most common primary site. EUS was performed to confirm the diagnosis in 205 lesions which presented as predominantly solitary (59), hypoechoic (95) and hypervascular (60), with a heterogeneous (n = 54) pattern and well-defined borders (n = 52). EUS-guided tissue acquisition was performed in 94 patients with an overall accuracy of 97.9%. Histological evaluation was possible in 88.3% of patients, obtaining final diagnosis in all cases. When cytology alone was performed, the final diagnosis was obtained in 83.3% of cases. A total of 67 patients underwent chemo/radiation therapy, and surgery was attempted in 45 (38.8%) patients. Pancreatic metastases are a possible event in the natural history of solid tumors, even long after the diagnosis of the primary site. EUS-guided fine needle biopsy may be suggested to implement the differential diagnosis.
Maternal Preconception Body Mass Index Overtakes Age as a Risk Factor for Gestational Diabetes Mellitus
Authors: Mirabelli Maria , Tocci Vera , Donnici Alessandra , Giuliano Stefania , Sarnelli Paola , Salatino Alessandro , Greco Marta , Puccio Luigi , Chiefari Eusebio , Foti Daniela Patrizia , Brunetti Antonio
Published: April 2023

Introduction—The purpose of this study was to determine the relative impact of modifiable and non-modifiable risk factors in the development of gestational diabetes mellitus (GDM), with a particular focus on maternal preconception body mass index (BMI) and age, two important determinants of insulin resistance. Understanding the factors that contribute most to the current escalation of GDM rates in pregnant women could help to inform prevention and intervention strategies, particularly in areas where this female endocrine disorder has an elevated prevalence. Methods—A retrospective, contemporary, large population of singleton pregnant women from southern Italy who underwent 75 g OGTT for GDM screening was enrolled at the Endocrinology Unit, “Pugliese Ciaccio” Hospital, Catanzaro. Relevant clinical data were collected, and the characteristics of women diagnosed with GDM or with normal glucose tolerance were compared. The effect estimates of maternal preconception BMI and age as risk factors for GDM development were calculated through correlation and logistic regression analysis by adjusting for potential confounders. Results—Out of the 3856 women enrolled, 885 (23.0%) were diagnosed with GDM as per IADPSG criteria. Advanced maternal age (≥35 years), gravidity, reproductive history of spontaneous abortion(s), previous GDM, and thyroid and thrombophilic diseases, all emerged as non-modifiable risk factors of GDM, whereas preconception overweight or obesity was the sole potentially modifiable risk factor among those investigated. Maternal preconception BMI, but not age, had a moderate positive association with fasting glucose levels at the time of 75 g OGTT (Pearson coefficient: 0.245, p < 0.001). Abnormalities in fasting glucose drove the majority (60%) of the GDM diagnoses in this study. Maternal preconception obesity almost tripled the risk of developing GDM, but even being overweight resulted in a more pronounced increased risk of developing GDM than advanced maternal age (adjusted OR for preconception overweight: 1.63, 95% CI 1.320–2.019; adjusted OR for advanced maternal age: 1.45, 95% CI 1.184–1.776). Conclusions—Excess body weight prior to conception leads to more detrimental metabolic effects than advanced maternal age in pregnant women with GDM. Thus, in areas in which GDM is particularly common, such as southern Italy, measures aiming to counteracting maternal preconception overweight and obesity may be efficient in reducing GDM prevalence.
Revascularization and Medical Therapy for Chronic Coronary Syndromes: Lessons Learnt from Recent Trials, a Literature Review
Authors: Pham Vincent , Moroni Alice , Gall Emmanuel , Benedetti Alice , Zivelonghi Carlo , Picard Fabien
Published: April 2023

Stable coronary artery disease (CAD) has recently been replaced by a new entity described as chronic coronary syndrome (CCS). This new entity has been developed based on a better understanding of the pathogenesis, the clinical characteristics, and the morbi-mortality associated to this condition as part of the dynamic spectrum of CAD. This has significant implications in the clinical management of CCS patients, that ranges from lifestyle adaptation, medical therapy targeting all the elements contributing to CAD progression (i.e., platelet aggregation, coagulation, dyslipidaemia, and systemic inflammation), to invasive strategies (i.e., revascularization). CCS is the most frequent presentation of coronary artery disease which is the first cardiovascular disease worldwide. Medical therapy is the first line therapy for these patients; however, revascularization and especially percutaneous coronary intervention remains beneficial for some of them. European and American guidelines on myocardial revascularization were released in 2018 and 2021, respectively. These guidelines provide different scenarios to help physicians choose the optimal therapy for CCS patients. Recently, several trials focusing on CCS patients have been published. We sought to synthetize the place of revascularization in CCS patients according to the latest guidelines, the lessons learnt from recent trials on revascularization and medical therapy, and future perspectives.
Sex-Related Aspects in Diabetic Kidney Disease—An Update
Authors: Loeffler Ivonne , Ziller Nadja
Published: April 2023

Differences between the sexes exist in many diseases, and in most cases, being a specific sex is considered a risk factor in the development and/or progression. This is not quite so clear in diabetic kidney disease (DKD), the development and severity of which depends on many general factors, such as the duration of diabetes mellitus, glycemic control, and biological risk factors. Similarly, sex-specific factors, such as puberty or andro-/menopause, also determine the microvascular complications in both the male and female sex. In particular, the fact that diabetes mellitus itself influences sex hormone levels, which in turn seem to be involved in renal pathophysiology, highlights the complexity of the question of sex differences in DKD. The major objective of this review is to summarize and simplify the current knowledge on biological sex-related aspects in the development/progression but also treatment strategies of human DKD. It also highlights findings from basic preclinical research that may provide explanations for these differences.
Effectiveness of Percutaneous Flexor Tenotomies for the Prevention and Management of Toe-Related Diabetic Foot Ulcers: A Systematic Review
Authors: Calvo-Wright María M. , López-Moral Mateo , García-Álvarez Yolanda , García-Madrid Marta , Álvaro-Afonso Francisco J. , Lázaro-Martínez José Luis
Published: April 2023

There is a high prevalence of digital deformities in diabetic patients, particularly claw toe, which can result in ulceration, often located at the tip of the toe. These lesions are challenging to off-load with conventional devices and frequently lead to infection and high amputation rates. Recent guidelines recommend considering flexor tenotomies to manage these ulcerations and prevent complications. This review, which analyzed 11 studies, aimed to assess the effect of flexor tenotomies on the healing and prevention of diabetic foot ulcers (DFUs) at the toe tip. Satisfactory results were found, with a healing rate of 92% to 100% and a mean healing time of 2–4 weeks. Few mild complications were observed, and the recurrence rate was very low. Transfer lesions were the most prevalent, but simultaneous tenotomy of all toes can eliminate this risk. Flexor tenotomies are a simple, effective, and safe procedure for the treatment and management of DFUs located at the apex of the toes and should be considered part of the standard of care for diabetic feet.
Textural Features of MR Images Correlate with an Increased Risk of Clinically Significant Cancer in Patients with High PSA Levels
Authors: Gibala Sebastian , Obuchowicz Rafal , Lasek Julia , Schneider Zofia , Piorkowski Adam , Pociask Elżbieta , Nurzynska Karolina
Published: April 2023

Background: Prostate cancer, which is associated with gland biology and also with environmental risks, is a serious clinical problem in the male population worldwide. Important progress has been made in the diagnostic and clinical setups designed for the detection of prostate cancer, with a multiparametric magnetic resonance diagnostic process based on the PIRADS protocol playing a key role. This method relies on image evaluation by an imaging specialist. The medical community has expressed its desire for image analysis techniques that can detect important image features that may indicate cancer risk. Methods: Anonymized scans of 41 patients with laboratory diagnosed PSA levels who were routinely scanned for prostate cancer were used. The peripheral and central zones of the prostate were depicted manually with demarcation of suspected tumor foci under medical supervision. More than 7000 textural features in the marked regions were calculated using MaZda software. Then, these 7000 features were used to perform region parameterization. Statistical analyses were performed to find correlations with PSA-level-based diagnosis that might be used to distinguish suspected (different) lesions. Further multiparametrical analysis using MIL-SVM machine learning was used to obtain greater accuracy. Results: Multiparametric classification using MIL-SVM allowed us to reach 92% accuracy. Conclusions: There is an important correlation between the textural parameters of MRI prostate images made using the PIRADS MR protocol with PSA levels > 4 mg/mL. The correlations found express dependence between image features with high cancer markers and hence the cancer risk.
Advances in Translational Regenerative Therapies
Authors: Kiwanuka Harriet , Wang Alice T. , Orgill Dennis P.
Published: April 2023

Regenerative medicine aims to replace damaged cells and tissues following injury [...]
Auditory Steady-State Response and Hearing Impairment in Survivors of Childhood Bacterial Meningitis in Luanda, Angola
Authors: Karppinen Mariia , Rugemalira Emilie , Savonius Okko , Cruzeiro Manuel Leite , Aarnisalo Antti , Jutila Topi , Pelkonen Tuula
Published: April 2023

Survivors of childhood bacterial meningitis (BM) often develop hearing impairment (HI). In low- and middle-income countries (LMICs), BM continues to be a significant cause of hearing disability. We assessed hearing among BM survivors using auditory steady-state responses (ASSR), providing frequency-specific estimated audiograms, and examined whether ASSR would provide a greater understanding of BM-induced HI. Survivors from two prospective BM trials (ISRCTN62824827; NCT01540838) from Luanda Children’s Hospital were examined in a follow-up visit with a median duration of 26 months after BM. The hearing of 50 BM survivors and 19 control children was evaluated using ASSR and auditory brainstem response (ABR) after interview and neurological and otorhinolaryngological examinations. The median age of survivors was 80 (IQR 86) months. We diagnosed HI (better ear hearing ≥ 26 dB) in 9/50 (18%) children. Five of the fifty survivors (10%) and 14/100 ears (14%) had profound HI (>80 dB). Severe-to-profound HI affected all frequencies steadily, affecting only the ears of BM survivors (18/100 vs. 0/38, p = 0.003). When looking only at the severely or profoundly affected ears, young age, low Glascow coma score, pneumococcal aetiology, and ataxia were associated with a worse hearing outcome.
Risk of Gastric Cancer among Patients with Newly Diagnosed Ulcerative Colitis: A Nationwide Population-Based Study
Authors: Kim Hee Man , Kim Jihoon , Kim Hyunil , Park Soon Chang , Lee Jung Kuk , Kang Dae Ryong , Kim Su Young , Kim Hyun-Soo
Published: April 2023

Background: Few studies have investigated the risk of gastric cancer (GC) in ulcerative colitis (UC), and the results have been inconsistent. This study aimed to assess the risk of gastric cancer in newly diagnosed UC patients. Methods: Based on claims data from Korean National Health Insurance from January 2006 to December 2015, we identified 30,546 patients with UC and randomly selected 88,829 non-UC individuals as controls, who were matched by age and sex. Multivariate Cox proportional hazards regression was used to calculate adjusted hazard ratios (HRs) for gastric cancer events, with covariates taken into account. Results: During the study period, a total of 77 (0.25%) patients with UC and 383 (0.43%) non-UC individuals were diagnosed with GC. After multivariable adjustment, the HR for GC was 0.60 (95% CI: 0.47–0.77) in patients with UC, using non-UC individuals as the reference group. When stratified by age, the adjusted HRs for GC in UC patients were 0.19 (95% CI: 0.04–0.98) for those aged 20–39 years at the time of UC diagnosis, 0.65 (95% CI: 0.45–0.94) for 40–59, and 0.60 (95% CI: 0.49–0.80) for ≥60 as compared to non-UC individuals in the corresponding age groups. When stratified by sex, the adjusted HR for GC was 0.54 (95% CI: 0.41–0.73) in male UC patients of all ages. Within UC patients, a multivariable analysis revealed that the HR for GC was 12.34 (95% CI: 2.23–68.16) for those aged ≥ 60 years at the time of diagnosis of UC. Conclusions: Patients with UC had a decreased GC risk compared with non-UC individuals in South Korea. Within the UC population, advancing age (≥60 years) was identified as a significant risk factor for GC.
A Randomized Placebo-Controlled Study of a Transcranial Photobiomodulation Helmet in Parkinson’s Disease: Post-Hoc Analysis of Motor Outcomes
Authors: McGee Claire , Liebert Ann , Bicknell Brian , Pang Vincent , Isaac Vivian , McLachlan Craig S. , Kiat Hosen , Herkes Geoffrey
Published: April 2023

Emerging evidence is increasingly supporting the use of transcranial photobiomodulation (tPBM) to improve symptoms of neurodegenerative diseases, including Parkinson’s disease (PD). The objective of this study was to analyse the safety and efficacy of tPBM for PD motor symptoms. The study was a triple blind, randomized placebo-controlled trial with 40 idiopathic PD patients receiving either active tPBM (635 nm plus 810 nm LEDs) or sham tPBM for 24 min per day (56.88J), six days per week, for 12 weeks. The primary outcome measures were treatment safety and a 37-item MDS-UPDRS-III (motor domain) assessed at baseline and 12 weeks. Individual MDS-UPDRS-III items were clustered into sub-score domains (facial, upper-limb, lower-limb, gait, and tremor). The treatment produced no safety concerns or adverse events, apart from occasional temporary and minor dizziness. There was no significant difference in total MDS-UPDRS-III scores between groups, presumably due to the placebo effect. Additional analyses demonstrated that facial and lower-limb sub-scores significantly improved with active treatment, while gait and lower-limb sub-scores significantly improved with sham treatment. Approximately 70% of participants responded to active treatment (≥5 decrease in MDS-UPDRS-III score) and improved in all sub-scores, while sham responders improved in lower-limb sub-scores only. tPBM appears to be a safe treatment and improved several PD motor symptoms in patients that responded to treatment. tPBM is proving to be increasingly attractive as a possible non-pharmaceutical adjunct therapy.
Inflammatory Cells Can Alter the Levels of H3K9ac and γH2AX in Dysplastic Cells and Favor Tumor Phenotype
Authors: Barbeiro Camila de Oliveira , Fernandes Darcy , Palaçon Mariana Paravani , Castilho Rogerio Moraes , de Almeida Luciana Yamamoto , Bufalino Andreia
Published: April 2023

Oral potentially malignant disorders (OPMD) are clinical presentations that carry an increased risk of cancer development. Currently, epithelial dysplasia grade is based on architectural and cytological epithelial changes and is used to predict the malignant transformation of these lesions. However, predicting which OPMD will progress to a malignant tumor is very challenging. Inflammatory infiltrates can favor cancer development, and recent studies suggest that this association with OPMD lesions may be related to the etiology and/or aggressive clinical behavior of these lesions. Epigenetic changes such as histone modifications may mediate chronic inflammation and also favor tumor cells in immune resistance and evasion. This study aimed to evaluate the relationship between histone acetylation (H3K9ac) and DNA damage in the context of dysplastic lesions with prominent chronic inflammation. Immunofluorescence of “low-risk” and “high-risk” OPMD lesions (n = 24) and inflammatory fibrous hyperplasia (n = 10) as the control group was performed to assess histone acetylation levels and DNA damage through the phosphorylation of H2AX (γH2AX). Cell co-culture assays with PBMCs and oral keratinocyte cell lines (NOK-SI, DOK, and SCC-25) were performed to assess proliferation, adhesion, migration, and epithelial–mesenchymal transition (EMT). Oral dysplastic lesions showed a hypoacetylation of H3K9 and low levels of γH2AX compared to control. The contact of dysplastic oral keratinocytes with PBMCs favored EMT and the loss of cell–cell adhesion. On the other hand, p27 levels increased and cyclin E decreased in DOK, indicating cell cycle arrest. We conclude that the presence of chronic inflammation associated to dysplastic lesions is capable of promoting epigenetic alterations, which in turn can favor the process of malignant transformation.
Biogeophysical Effects of Land-Use and Land-Cover Changes in South Asia: An Analysis of CMIP6 Models
Authors: Santos Juliana Freitas , Schickhoff Udo , ul Hasson Shabeh , Böhner Jürgen
Published: April 2023

The identification of the biogeophysical effects due to land-use, land-cover, and land- management changes (LULCC) is yet to be clearly understood. A range of factors, such as the inclusion of an interactive ocean model component, representation of land management, transient LULCC, and accountability for atmospheric feedback, potentially shifts how models may detect the impacts of the land surface on the climate system. Previous studies on the biogeophysical effects of LULCC in South Asia have either neglected one of those factors or are single model results. Therefore, we analyzed the outputs from 11 models, participants of the Coupled Model Intercomparison Project in its Sixth Phase (CMIP6), which derived from experiments with and without LULCC and compared the two simulations with respect to changes in near-surface temperature and total precipitation means. The CMIP6 simulations, to a certain extent, accounted for the elements previously overlooked. We examined the grid cells that robustly indicated a climatic impact from LULCC. Additionally, we investigated the atmospheric feedback and the dominant fluxes with their associated land surface variables involved in the changes in temperature and precipitation. Our results indicated that the biogeophysical effects from LULCC favored surface net cooling and surface net drying over the robust areas at all seasons. The surface net cooling was strongly influenced by the decrease in available energy and the increase in latent heat and total evapotranspiration. Surface net drying was highly promoted by local hydrological processes, especially in areas outside the monsoon core. The study also revealed that non-local sources might influence precipitation in some parts of South Asia, although this was inconclusive. Our research presented similar results to previous studies but with different magnitudes, which highlighted the added value of CMIP6-GCMs simulations but also their pitfalls.
Impact of Bedside Balloon Atrial Septostomy in Neonates with Transposition of the Great Arteries in a Neonatal Intensive Care Unit in Romania
Authors: Cirstoveanu Catalin , Georgescu Carmina , Bizubac Mihaela , Heriseanu Carmen , Vasile Corina , Margarint Irina , Filip Cristina
Published: April 2023

(1) Background: Transposition of the great arteries (TGA) is the most common congenital heart disease, accounting for 5–7% of all cardiac anomalies, with a prevalence of 0.2–0.3 per 1000 live births. (2) Aim: Our main objectives were to evaluate the clinical safety of balloon atrial septostomy in neonates and the possible complications. Furthermore, we tried to establish whether the procedure should be performed in all TGA patients with small atrial septal defects, regardless of oxygen saturation, within a center where corrective surgery cannot be performed on an emergency basis due to the lack of a permanent cardiac surgery team for arterial switch surgery. (2) Methods: We conducted an observational, retrospective, single tertiary-care center study between January 2008 and April 2022, which included 92 neonates with TGA transferred to our institution for specialized treatment. (3) Results: The median age at the time of the Rashkind procedure was four days. The rate of immediate complications after balloon atrial septostomy (BAS) was high (34.3%), but most were transient (metabolic acidosis and arterial hypotension—21.8%). Twenty patients with TGA managed in our hospital underwent definitive and corrective surgical intervention (arterial switch operation) at a median age of 13 days. Most patients (82.6%) were term neonates, but 16 were born preterm. (4) Conclusions: Urgent balloon atrial septostomy is often the only solution to restore adequate systemic perfusion. Bedside balloon atrial septostomy is a safe, effective, and initial palliative intervention in neonates with TGA, which can be performed in the neonatal unit.