bluuebunny/crossref_metadata_2025 huggingface dataset:
Rare variants in complement system genes associate with endothelial damage after pediatric allogeneic hematopoietic stem cell transplantation
Authors: Leimi Lilli , Koski Jessica R. , Kilpivaara Outi , Vettenranta Kim , Lokki A. Inkeri , Meri Seppo
Published: September 2023

Introduction

Complement system has a postulated role in endothelial problems after hematopoietic stem cell transplantation (HSCT). In this retrospective, singlecenter study we studied genetic complement system variants in patients with documented endotheliopathy. In our previous study among pediatric patients with an allogeneic HSCT (2001-2013) at the Helsinki University Children´s Hospital, Finland, we identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome (CLS), venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS) or thrombotic microangiopathy (TMA).

Methods

We performed whole exome sequencing (WES) on 109 patients having an adequate pre-transplantation DNA for the analysis to define possible variations and mutations potentially predisposing to functional abnormalities of the complement system. In our data analysis, we focused on 41 genes coding for complement components.

Results

50 patients (45.9%) had one or several, nonsynonymous, rare germline variants in complement genes. 21/66 (31.8%) of the variants were in the terminal pathway. Patients with endotheliopathy had variants in different complement genes: in the terminal pathway (C6 and C9), lectin pathway (MASP1) and receptor ITGAM (CD11b, part of CR3). Four had the same rare missense variant (rs183125896; Thr279Ala) in the C9 gene. Two of these patients were diagnosed with endotheliopathy and one with capillary leak syndrome-like problems. The C9 variant Thr279Ala has no previously known disease associations and is classified by the ACMG guidelines as a variant of uncertain significance (VUS). We conducted a gene burden test with gnomAD Finnish (fin) as the reference population. Complement gene variants seen in our patient population were investigated and Total Frequency Testing (TFT) was used for execution of burden tests. The gene variants seen in our patients with endotheliopathy were all significantly (FDR < 0.05) enriched compared to gnomAD. Overall, 14/25 genes coding for components of the complement system had an increased burden of missense variants among the patients when compared to the gnomAD Finnish population (N=10 816).

Discussion

Injury to the vascular endothelium is relatively common after HSCT with different phenotypic appearances suggesting yet unidentified underlying mechanisms. Variants in complement components may be related to endotheliopathy and poor prognosis in these patients.
Lower levels of FOXP3 are associated with prolonged inflammatory responses in kidney transplant recipients
Authors: Saleh Qais W. , Mohammadnejad Afsaneh , Tepel Martin
Published: September 2023

Background

Immunosuppressive treatment of kidney transplant recipients is mainly aimed at pro-inflammatory T effector cells, yet they also target the immunosuppressive T regulatory cells. Here, we test the hypothesis that low levels of the master gene regulator of T regulatory cells, forkhead box P3 (FOXP3) splice variants, are associated with prolonged inflammatory responses to stimuli.

Methods

From blood samples obtained the first – and 29th day post-transplant, we extracted peripheral blood mononuclear cells and measured mRNA levels of Total FOXP3, pre-mature RNA FOXP3 (pre-mRNA FOXP3), full length FOXP3 (FOXP3fl) and, FOXP3 splice variant excluding exon two (FOXP3d2). We defined the primary outcome as the number of days in which C reactive protein (CRP) was above 50 mg/L. CRP levels were gathered in two periods, the first from the second to 29 days post-transplant, and the second from 30 to 57 days post-transplant. The association was tested using adjusted negative binomial regression.

Results

From 507 included kidney transplant recipients, 382 recipients had at least one CRP measurement >50 mg/L in the first period, median duration of elevated CRP was 4 days [interquartile range (IQR) 2 to 6]. In the second period, 69 recipients had at least one CRP measurement >50 mg/L, median duration of elevated CRP was 3 days [IQR 2 to 5]. In the first period, we found a significant association between lower levels of Total FOXP3 and prolonged duration of CRP elevation, incidence rate ratio 0.61 (95% confidence interval 0.46-0.80), p<0.01.

Conclusion

Lower levels of total FOXP3 mRNA levels in peripheral blood of kidney transplant recipients are associated with prolonged duration of inflammatory responses regardless of the underlying stimuli.
An integrated overview of the immunosuppression features in the tumor microenvironment of pancreatic cancer
Authors: Guo Jinglong , Wang Siyue , Gao Qi
Published: September 2023

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. It is characterized by a complex and immunosuppressive tumor microenvironment (TME), which is primarily composed of tumor cells, stromal cells, immune cells, and acellular components. The cross-interactions and -regulations among various cell types in the TME have been recognized to profoundly shape the immunosuppression features that meaningfully affect PDAC biology and treatment outcomes. In this review, we first summarize five cellular composition modules by integrating the cellular (sub)types, phenotypes, and functions in PDAC TME. Then we discuss an integrated overview of the cross-module regulations as a determinant of the immunosuppressive TME in PDAC. We also briefly highlight TME-targeted strategies that potentially improve PDAC therapy.
Regulatory T cells are associated with the tumor immune microenvironment and immunotherapy response in triple-negative breast cancer
Authors: Huang Pengfei , Zhou Xinyue , Zheng Minying , Yu Yongjun , Jin Gongsheng , Zhang Shiwu
Published: September 2023

Introduction

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high risk of distant metastasis, an extremely poor prognosis, and a high risk of death. Regulatory T cells (Tregs) contribute to the formation of a tumor immunosuppressive microenvironment, which plays an important role in the progression and treatment resistance of TNBC.

Methods

A public single-cell sequencing dataset demonstrated increased infiltration of Tregs in TNBC tissues relative to normal breast tissue. Weighted gene co-expression network analysis was used to identify Treg infiltration-related modules for METABRIC TNBC samples. Subsequently, we obtained two Treg infiltration-associated clusters of TNBC by applying consensus clustering and further constructed a prognostic model based on this Treg infiltration-associated gene module. The ability of the selected gene in the prognostic model, thymidine kinase-1 (TK1), to promote the progression of TNBC was evaluated in vitro.

Results

We concluded that two Treg infiltration-associated clusters had different prognoses and sensitivities to drugs commonly used in breast cancer treatment, and multi-omics analysis revealed that the two clusters had different copy number variations of key tumor progression genes. The 7-gene risk score based on TNBC Treg infiltration was a reliable prognostic indicator both in the training and validation cohorts. Moreover, patients with TNBC with high Treg infiltration-related scores lacked the activation of immune activation pathways and exhibited resistance to anti-PD1 immunotherapy. Knocking down TK1 led to impaired proliferation, migration, and invasion of TNBC cells in vitro. In addition, specimens from patients with TNBC with high TK1 expression showed significantly higher Treg infiltration in tumors. Results of spatial transcriptome analysis showed that TK1 positive cells mainly localize in tumor area, and Treg cell infiltration in TNBC tissues was associated with high expression of TK1. Pan-cancer analysis also demonstrated that TK1 is associated with poor prognosis and activation of proliferation pathways in multiple cancers.

Discussion

We established a prognostic model related to Treg infiltration and this model can be used to establish a clinically relevant classification of TNBC progression. Additionally, our work revealed the underestimable potential of TK1 as a tumor biomarker and immunotherapeutic target.
Camera-based automated monitoring of flying insects in the wild (Camfi). II. flight behaviour and long-term population monitoring of migratory Bogong moths in Alpine Australia
Authors: Wallace Jesse Rudolf Amenuvegbe , Dreyer David , Reber Therese Maria Joanna , Khaldy Lana , Mathews-Hunter Benjamin , Green Ken , Zeil Jochen , Warrant Eric
Published: September 2023

Introduction

The Bogong moth Agrotis infusa is well known for its remarkable annual round-trip migration from its breeding grounds across eastern and southern Australia to its aestivation sites in the Australian Alps, to which it provides an important annual influx of nutrients. Over recent years, we have benefited from a growing understanding of the navigational abilities of the Bogong moth. Meanwhile, the population of Bogong moths has been shrinking. Recently, the ecologically and culturally important Bogong moth was listed as endangered by the IUCN Red List, and the establishment of a program for long-term monitoring of its population has been identified as critical for its conservation.

Methods

Here, we present the results of two years of monitoring of the Bogong moth population in the Australian Alps using recently developed methods for automated wildlife-camera monitoring of flying insects, named Camfi. While in the Alps, some moths emerge from the caves in the evening to undertake seemingly random flights, filling the air with densities in the dozens per cubic metre. The purpose of these flights is unknown, but they may serve an important role in Bogong moth navigation.

Results

We found that these evening flights occur throughout summer and are modulated by daily weather factors. We present a simple heuristic model of the arrival to and departure from aestivation sites by Bogong moths, and confirm results obtained from fox-scat surveys which found that aestivating Bogong moths occupy higher elevations as the summer progresses. Moreover, by placing cameras along two elevational transects below the summit of Mt. Kosciuszko, we found that evening flights were not random, but were systematically oriented in directions relative to the azimuth of the summit of the mountain. Finally, we present the first recorded observations of the impact of bushfire smoke on aestivating Bogong moths – a dramatic reduction in the size of a cluster of aestivating Bogong moths during the fire, and evidence of a large departure from the fire-affected area the day after the fire.

Discussion

Our results highlight the challenges of monitoring Bogong moths in the wild and support the continued use of automated camera-based methods for that purpose.
Heatwaves hinder mussel invasion by weakening byssus production
Authors: Xu Xin , Yang Ke , Liu Yong , Deng Yuewen , Zhao Liqiang
Published: September 2023

Heatwaves and bioinvasion are among the most pressing ecological issues worldwide. The highly invasive South American mussels (Mytella strigata) can construct extremely dense byssal mats in intertidal habitats they invade, causing serious threats to local biodiversity and ecosystems. Yet, little is known about whether intensifying heatwaves might facilitate their invasions. Here, we investigated how the byssus production of M. strigata responds to heatwaves scenarios that have frequently occurred in recent years in the South China Sea. Compared with those grown at ambient temperature, mussels exposed to simulation heatwaves secreted significantly lowered number, length, and diameter of byssal threads, and exhibited significant impairments in the adhesion of byssus. Differential expressions of key genes involved in byssus production (e.g., foot protein gene, cell apoptosis gene, extracellular matrix-receptor interaction gene, and neuroactive ligand-receptor interaction gene) offered deeper insights into heatwaves-induced physiological changes in byssal gland. These results can provide an improved understanding of responses of mussel byssus production to intensifying heatwaves and take a major leap forward in examining the dispersal of highly invasive species in a rapidly warming ocean.
Effect of live-storage period and temperature on oxygen consumption rate in the cold-water sea cucumber Parastichopus tremulus
Authors: Landes Anja M. , Sunde Jan , Christophersen Gyda
Published: September 2023

Sea cucumbers are of great significance in marine ecosystems all over the world. The red sea cucumber Parastichopus tremulus is also considered commercially interesting but very little information is available on its ecology and physiology. This study aimed at investigating this North Atlantic species` oxygen demand in relation to live-storage period and temperature in an attempt to deliver some physiological puzzle pieces useful in a potential aquacultural context. Oxygen consumption rate (OCR) was measured in P. tremulus stored in a flow-through system for up to one year, and in recirculation systems at different temperatures (4, 8 and 12°C) for up to four weeks. Throughout the experimental period, biometric data were collected from the different treatment groups and a condition index (CI) calculated. The results showed that long-term storage affected OCR and CI, which increased and decreased with time, respectively. Storage at 4°C resulted in significantly lower OCR and higher CI compared to 8 and 12°C after four weeks, suggesting that 4°C may be best for maintaining body mass during short-term storage, whereas storage at 8 and 12°C may require supplementary feeding to avoid biomass loss. Data presented in this study may be useful for a range of applications, for example in a prospective aquaculture setting, for optimizing live seafood storage, but also for impact assessment and management of wild stocks.
Additional role of ECC in the detection and treatment of cervical HSIL
Authors: Sijing Li , Ying Jia , Jing Wu , Xiaoge Li , Ming Luo , Zhaoning Duan
Published: September 2023

Objective

To probe into the additional role of ECC in the detection of cervical HSIL. The primary objective was to risk-stratify HSIL patients according to ECC so as to provide clinical suggestions for subsequent treatment.

Methods

Retrospective analysis of medical records for patients with HSIL. All patients underwent both ECC and cervical biopsy. According to the results of colposcopic targeted biopsy and ECC, the patients were divided into three groups: (1) ECC negative group (those whose colposcopic targeted biopsy indicated HSIL, but ECC indicated LSIL or chronic inflammation); (2) Only the ECC positive group (those whose ECC suggested HSIL, but colposcopic targeted biopsy showed LSIL or chronic inflammation); (3) ECC and biopsy positive group (those whose ECC and targeted biopsy were both HSIL). Chi-square test was used to analyze the differences of lesion residue and biopsy results after LEEP amongst the three groups.

Results

A total of 1,146 medical records were analyzed. The diagnostic accuracy of ECC combined with colposcopic targeted biopsy for HSIL was higher than that of colposcopic biopsy alone (72.43% vs. 67.54%). When ECC indicated HSIL, the coincidence rate of ECC combined with colposcopic targeted biopsy and the histological pathology of LEEP was 86.25%, and the proportion of residual lesions after LEEP was 41.43%. When ECC and targeted biopsy both indicated HSIL, HSIL or worse lesions were confirmed in 90.68% of patients after surgery. Of these, 10.77% were confirmed as cervical invasive carcinoma. Moreover, the positive rate of LEEP resection margin and postoperative ECC in these patients was 43.48%.

Conclusion

ECC can improve the detection rate of cervical HSIL and reduce missed diagnosis. Also ECC can help clinicians predict the proportion of residual lesions after LEEP. This provides the gynecologists with a reference for the need to increase the depth of the procedure and the need to perform ECC for the residual cervical canal.
Effectiveness and safety of an atropine/midazolam and target controlled infusion propofol-based moderate sedation protocol during percutaneous endoscopic transgastric jejunostomy procedures in Parkinson’s disease: a real-life retrospective observational study
Authors: Gravina Antonietta Gerarda , Pellegrino Raffaele , De Micco Rosa , Dellavalle Mirco , Grasso Anna , Palladino Giovanna , Satolli Sara , Ciaravola Massimo , Federico Alessandro , Tessitore Alessandro , Romano Marco , Ferraro Fausto
Published: September 2023

Patients with Parkinson’s disease (PD), often elderly with various comorbidities, may require a continuous intestinal infusion of carbidopa/levodopa gel by the placement of a percutaneous endoscopic gastrostomy (PEG) with a jejunal tube (PEG-J) to improve their motor outcome and quality of life. However, it is unclear what is the best procedural sedation protocol for PEG-J procedures. Fifty patients with PD and indication for PEG-J procedure (implantation, replacement, removal) underwent, from 2017 to 2022, a sedation protocol characterized by premedication with atropine (0.01 mg/Kg i.v.), midazolam (0.015–0.03 mg/Kg i.v.) and induction with bolus propofol (0.5–1 mg/Kg i.v.) as well as, finally, sedation with continuous infusion propofol (2–5 mg/Kg/h i.v.) by Target Controlled Infusion (TCI) technique. Ninety-eight per cent of patients experienced no intraprocedural or peri-procedural adverse events. All the procedures were technically successful. A good discharge time was recorded. The vital parameters recorded during the procedure did not vary significantly. A PEG-J procedure conducted within 30 min showed a significant advantage over end-tidal carbon dioxide (EtCO2). Indeed, the latter showed some predictive behavior (OR: 1.318, 95% CI 1.075–1.615, p = 0.008). In the real world, this sedation protocol showed a good safety and effectiveness profile, even with reduced doses of midazolam and a TCI propofol technique in moderate sedation.
Less, but not gone—gluten-free diet effects on fatigue in celiac disease: a prospective controlled study
Authors: Skjellerudsveen Berit Mære , Omdal Roald , Hetta Anne Kristine , Kvaløy Jan Terje , Aabakken Lars , Skoie Inger Marie , Grimstad Tore
Published: September 2023

Introduction

Fatigue is a frequent complaint in patients with celiac disease. A gluten-free diet is the only established treatment for celiac disease, but how this diet influences fatigue is uncertain. We aimed to investigate fatigue prevalence, severity, and associated factors in patients with celiac disease, at diagnosis and at 1 year after commencing a gluten-free diet.

Methods

78 patients with serologically and histologically verified celiac disease, 78 age- and sex-matched healthy subjects. Primary endpoints were Fatigue Visual Analog Scale (fVAS), Fatigue Severity Scale (FSS), and inverted Vitality subscale of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36vs). Clinically relevant fatigue was defined as: FSS score ≥ 4, fVAS score ≥ 50 mm, or inverted SF-36vs score ≥ 65. Higher scores represented more fatigue.

Results

Fatigue was reduced after a 12-month gluten-free diet. Median scores changed from 3.8 (interquartile range [IQR]: 2.2 to 4.8) to 1.9 (IQR: 1.4 to 3.5) for FSS, from 44.5 (IQR: 18.8 to 66.0) to 15.5 (IQR: 7.8 to 43.3) for fVAS, and from 65 (IQR: 40 to 75) to 35 (IQR: 25 to 55) for inverted SF-36vs (p < 0.001 for all). Fatigue prevalence also declined after treatment. However, scores were significantly higher in patients compared to control subjects. Higher fatigue scores were associated with depression and pain, but not with signs of disease activity or nutritional deficiency.

Conclusion

At diagnosis, patients with celiac disease frequently had severe fatigue. Fatigue declined after a gluten-free diet, but it remained higher than that observed in healthy subjects.

Clinical trial registration

ClinicalTrials.gov, Identifier NCT01551563.
Temporal stability and community assembly mechanisms in healthy broiler cecum
Authors: Ameer Aqsa , Cheng Youqi , Saleem Farrukh , Uzma  , McKenna Aaron , Richmond Anne , Gundogdu Ozan , Sloan William T. , Javed Sundus , Ijaz Umer Zeeshan
Published: September 2023

In recent years, there has been an unprecedented advancement in in situ analytical approaches that contribute to the mechanistic understanding of microbial communities by explicitly incorporating ecology and studying their assembly. In this study, we have analyzed the temporal profiles of the healthy broiler cecal microbiome from day 3 to day 35 to recover the stable and varying components of microbial communities. During this period, the broilers were fed three different diets chronologically, and therefore, we have recovered signature microbial species that dominate during each dietary regime. Since broilers were raised in multiple pens, we have also parameterized these as an environmental condition to explore microbial niches and their overlap. All of these analyses were performed in view of different parameters such as body weight (BW-mean), feed intake (FI), feed conversion ratio (FCR), and age (days) to link them to a subset of microbes that these parameters have a bearing upon. We found that gut microbial communities exhibited strong and statistically significant specificity for several environmental variables. Through regression models, genera that positively/negatively correlate with the bird’s age were identified. Some short-chain fatty acids (SCFAs)-producing bacteria, including Izemoplasmatales, Gastranaerophilales, and Roseburia, have a positive correlation with age. Certain pathogens, such as Escherichia-Shigella, Sporomusa, Campylobacter, and Enterococcus, negatively correlated with the bird’s age, which indicated a high disease risk in the initial days. Moreover, the majority of pathways involved in amino acid biosynthesis were also positively correlated with the bird’s age. Some probiotic genera associated with improved performance included Oscillospirales; UCG-010, Shuttleworthia, Bifidobacterium, and Butyricicoccaceae; UCG-009. In general, predicted antimicrobial resistance genes (piARGs) contributed at a stable level, but there was a slight increase in abundance when the diet was changed. To the best of the authors’ knowledge, this is one of the first studies looking at the stability, complexity, and ecology of natural broiler microbiota development in a temporal setting.
Glutamate-pantothenate pathway promotes antibiotic resistance of Edwardsiella tarda
Authors: Yan Bei-bei , Dong Xue-sa , Wang Jun-peng , Li Xiao-ying , An Li , Wang Xi-rong , Zhang Long-gang , Meng Qing-lei , Wang Chao
Published: September 2023

Although cellular metabolic states have been shown to modulate bacterial susceptibility to antibiotics, the interaction between glutamate (Glu) and chloramphenicol (CAP) resistance remains unclear because of the specificity of antibiotics and bacteria. We found that the level of Glu was upregulated in the CAP-resistant strain of Edwardsiella tarda according to a comparative metabolomics approach based on LC–MS/MS. Furthermore, we verified that exogenous metabolites related to Glu, the tricarboxylic acid (TCA) cycle, and glutathione (GSH) metabolism could promote CAP resistance in survival assays. If GSH metabolism or the TCA cycle is inhibited by L-buthionine sulfoximine or propanedioic acid, the promotion of CAP resistance by Glu in the corresponding pathway disappears. According to metabolomic analysis, exogenous Glu could change pantothenate metabolism, affecting GSH biosynthesis and the TCA cycle. These results showed that the glutamate-pantothenate pathway could promote CAP resistance by being involved in the synthesis of GSH, entering the TCA cycle by direct deamination, or indirectly affecting the metabolism of the two pathways by pantothenate. These results extend our knowledge of the effect of Glu on antibiotic resistance and suggest that the potential effect, which may aggravate antibiotic resistance, should be considered before Glu and GSH administration in the clinic.
Insights into the role of three Endonuclease III enzymes for oxidative stress resistance in the extremely radiation resistant bacterium Deinococcus radiodurans
Authors: Rollo Filipe , Martins Guilherme D. , Gouveia André G. , Ithurbide Solenne , Servant Pascale , Romão Célia V. , Moe Elin
Published: September 2023

The extremely radiation and desiccation resistant bacterium Deinococcus radiodurans possesses three genes encoding Endonuclease III-like enzymes (DrEndoIII1, DrEndoIII2, DrEndoIII3). In vitro enzymatic activity measurements revealed that DrEndoIII2 is the main Endonuclease III in this organism, while DrEndoIII1 and 3 possess unusual and, so far, no detectable EndoIII activity, respectively. In order to understand the role of these enzymes at a cellular level, DrEndoIII knockout mutants were constructed and subjected to various oxidative stress related conditions. The results showed that the mutants are as resistant to ionizing and UV-C radiation as well as H2O2 exposure as the wild type. However, upon exposure to oxidative stress induced by methyl viologen, the knockout strains were more resistant than the wild type. The difference in resistance may be attributed to the observed upregulation of the EndoIII homologs gene expression upon addition of methyl viologen. In conclusion, our data suggest that all three EndoIII homologs are crucial for cell survival in stress conditions, since the knockout of one of the genes tend to be compensated for by overexpression of the genes encoding the other two.
Detection and quantification of antiviral drug tenofovir using silver nanoparticles and surface enhanced Raman spectroscopy (SERS) with spatially resolved hotspot selection
Authors: Butler Marguerite R. , Hrncirova Jana , Jacot Terry A. , Dutta Sucharita , Clark Meredith R. , Doncel Gustavo F. , Cooper John B.
Published: September 2023

This study introduces a convenient and ultra-sensitive method of detection and quantification of the antiviral drug, tenofovir (TFV), by surface-enhanced Raman spectroscopy (SERS). Novel spatially resolved instrumentation for spectral acquisition and subsequent statistical analysis for hot spot selection was developed for convenient quantification of TFV in an aqueous matrix. Methods of statistical analysis include the use of partial least squares (PLS) regression vector analysis and spectral ranking by quality indices computed using CHAOS theory. Hydroxylamine-reduced Ag colloidal nanoparticles evaporated to dryness on an aluminum well-plate were used as the SERS substrate. To our knowledge, quantification of TFV down to 25 ng/mL by SERS, comprising clinically relevant concentrations, has not been previously reported. Furthermore, in this work we propose a novel method of quantification of aqueous TFV standards by SERS using statistical treatment of data by PLS and CHAOS theory. Based on these data, we propose future studies to develop a method of TFV detection and quantification in biological samples, beneficial to clinicians for rapid assessment of drug adherence during the treatment and prevention of viral diseases.
Case report: Fatal ischemic stroke induced by unruptured traumatic intracranial vertebral artery dissection
Authors: Wen Shuheng , Unuma Kana , Inaji Motoki , Makino Yohsuke , Nagano Shutaro , Harada Kazuki , Arai Nobutaka , Uemura Koichi
Published: September 2023

Intracranial vertebral artery dissection (IVAD) is rare and potentially fatal due to the risk of secondary subarachnoid hemorrhage once ruptured. Unruptured traumatic IVAD is even rarer and can result in ischemic stroke, yet mostly benign when timely diagnosed. Herein, we present an uncommon case of a patient who underwent a fatal ischemic stroke induced by unruptured traumatic IVAD. The patient was symptomatic soon after being physically assaulted but left untreated until acute deterioration for multiple brain infarctions occurred, secondary to IVAD-induced cerebellar stroke. Fifteen days later, he died, regardless of an urgently performed thrombectomy. Multiple serial histologic examinations revealed an unruptured dissection of the intracranial vertebral artery with a slit-like tear of the intimal and medial layers, considered to be the culprit lesion. The 15-day prolonged onset of stroke was rare in traumatic IVADs. Furthermore, the slit-like tear of the intimal layer in our case may support the initial intimal laceration hypothesis for VAD pathogenesis. Since limited pathohistological information is available regarding ischemic IVAD, we believe this rare case will be beneficial in understanding the pathophysiology of ischemic IVAD.
Treatment of non-epileptic episodes of anxious, fearful behavior in adolescent juvenile neuronal ceroid lipofuscinosis (CLN3 disease)
Authors: Ostergaard John R.
Published: September 2023

Background

Recurrent non-epileptic episodes of frightened facial and body expression occur in more than half of post-adolescent patients with juvenile neuronal ceroid lipofuscinosis (JNCL, CLN3 disease). Clinically, the episodes look similar to the attacks of paroxysmal sympathetic hyperactivity (PSH) commonly seen following traumatic brain injury (TBI). The episodes occur when the patients are exposed to separation, hear loud sounds or are otherwise bothered by discomfort and as in PSH following TBI, the attacks are difficult to prevent and/or treat.

Aim and methods

Based on present knowledge of triggering factors, the neural anxiety/fear circuit, its afferent and efferent pathways and documented CLN3 disease-impact on these tracks, the current study discusses a rational approach how to prevent and/or treat the attacks.

Results

Patients with JNCL have a disturbed somatosensory modulation leading to a reduced threshold of pain; a degeneration within the neural anxiety/fear circuit leading to an imbalance of central network inhibition and excitation pathways; and finally, an, with advancing age, increasing autonomic imbalance leading to a significant dominance of the sympathetic neural system.

Discussion

Theoretically, there are three points of attack how to prevent or treat the episodes: (1) increase in threshold of discomfort impact; (2) modulation of imbalance of central network inhibition and excitation, and (3) restoring the balance between the sympathetic and parasympathetic neural systems prompted by a parasympathetic withdrawal. As to (1) and (2), prevention should have the greatest priority. As regards (3), research of transcutaneous vagal stimulation treatment in JNCL is warranted.
SIGMAR1 variants in ALS–PD complex cases: a case report of a novel mutation and literature review
Authors: Li Haining , Xuan Tingting , Xu Ting , Yang Juan , Cheng Jiang , Wang Zhenhai
Published: September 2023

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons, with occasional involvement of the extrapyramidal system. Mutations in the sigma non-opioid intracellular receptor 1 (SIGMAR1) gene have been identified as one of the causes of ALS. Here, we present a case of a 49-year-old man diagnosed with ALS–Parkinson’s disease (PD) complex. The patient exhibited bradykinesia and tremor, and whole-exome sequencing revealed homozygous mutations in the SIGMAR1 gene (c.446-2A > T). In addition, we conducted an investigation into the clinical and molecular phenotype of previously reported variants of SIGMAR1 associated with ALS. This case report aims to raise awareness among physicians regarding atypical phenotypes of amyotrophic lateral sclerosis and to encourage further research on the factors leading to SIGMAR1 mutations in patients.
Markov chains as a proxy for the predictive memory representations underlying mismatch negativity
Authors: Schröger Erich , Roeber Urte , Coy Nina
Published: September 2023

Events not conforming to a regularity inherent to a sequence of events elicit prediction error signals of the brain such as the Mismatch Negativity (MMN) and impair behavioral task performance. Events conforming to a regularity lead to attenuation of brain activity such as stimulus-specific adaptation (SSA) and behavioral benefits. Such findings are usually explained by theories stating that the information processing system predicts the forthcoming event of the sequence via detected sequential regularities. A mathematical model that is widely used to describe, to analyze and to generate event sequences are Markov chains: They contain a set of possible events and a set of probabilities for transitions between these events (transition matrix) that allow to predict the next event on the basis of the current event and the transition probabilities. The accuracy of such a prediction depends on the distribution of the transition probabilities. We argue that Markov chains also have useful applications when studying cognitive brain functions. The transition matrix can be regarded as a proxy for generative memory representations that the brain uses to predict the next event. We assume that detected regularities in a sequence of events correspond to (a subset of) the entries in the transition matrix. We apply this idea to the Mismatch Negativity (MMN) research and examine three types of MMN paradigms: classical oddball paradigms emphasizing sound probabilities, between-sound regularity paradigms manipulating transition probabilities between adjacent sounds, and action-sound coupling paradigms in which sounds are associated with actions and their intended effects. We show that the Markovian view on MMN yields theoretically relevant insights into the brain processes underlying MMN and stimulates experimental designs to study the brain’s processing of event sequences.
A tactile twist: decoding the phenomena of mechanical itch and alloknesis
Authors: Follansbee Taylor , Dong Xinzhong
Published: September 2023

Itch is a sensation in the skin which provokes the desire to scratch. In the past few decades there has been a significant elucidation of the immune and neural pathways which underly the sensation of itch. An interesting divergence in the itch pathway relates to the type of stimulation used to evoke an itchy sensation. Commonly, chemical mediators of itch such as histamine are injected into the skin where they activate their cognate receptors on sensory neurons. Another way to evoke itch, particularly in patients with chronic itch, is to use light mechanical stimulation. Investigation into these pathways utilizing the mouse model have shown that the neuronal pathways which underly chemical itch are distinct from those which mediate itch in response to mechanical stimulation. Specific populations of primary sensory neurons, spinal interneurons and transmission neurons have been identified which suggests a labeled line for itch transmission. Additionally, Piezo channels, which underly mechanosensation, were discovered to play an important role in the mechanical itch pathway. Given these novel findings relating to the mechanical itch pathway, the purpose of this review is to summarize the reports from human subjects and animal studies to highlight the advances in our understanding of mechanical itch and alloknesis.
Altered intestinal barrier contributes to cognitive impairment in old mice with constipation after sevoflurane anesthesia
Authors: Zhao Tianyun , Lu Junming , Qin Jingwen , Chen Yanxin , Shi Ziwen , Wei Wei , Xiong Peng , Ma Daqing , Song Xingrong
Published: September 2023

Background

Elderly patients have a high risk of developing postoperative cognitive dysfunction (POCD). Gastrointestinal disorders, such as constipation, in the elderly population may be involved in the pathogenesis of neurological disorders by promoting inflammatory responses due to a ‘leaky gut’. General anesthetic sevoflurane may impair gastrointestinal function in elderly patients to trigger neurological complications following surgery. Therefore, we hypothesized that elderly individuals with gastrointestinal dysfunction may be more vulnerable to sevoflurane and consequently develop POCD.

Methods

Aged mice were randomly divided into four groups: control (CTRL), CTRL+sevoflurane (Sev), slow transit constipation (STC), and STC + Sev. Mice in the STC and STC + Sev groups were intra-gastrically administrated loperamide (3 mg/kg, twice a day for 7 days) to induce a slow transit constipation (STC) model determined with fecal water content and the time of first white fecal pellet, whereas mice in the other groups received the similar volume of saline. One week later, mice in the CTRL+Sev group and STC + Sev group received 2% sevoflurane for 2 h. The gut permeability evaluated with 4-kDa fluorescein isothiocyanate (FITC)-dextran, serum cytokines, microglia density, TLR4/NF-κB signaling expression, and POCD-like behavioral changes were determined accordingly.

Results

The loperamide-induced STC mice had decreased fecal water content and prolonged time of first white fecal pellet. Sevoflurane exposure caused significantly increased gut permeability and serum cytokines, as well as the activation of microglia and the TLR4/NF-κB signaling pathway in the prefrontal cortex of the aged STC mice. Sevoflurane also caused cognitive impairment and emotional phenotype abnormality in aged STC mice.

Conclusion

Aged STC mice were more vulnerable to sevoflurane anesthesia and consequently developed POCD-like behavioral changes. Our data suggest that gastrointestinal disorders including constipation may contribute to the development of POCD.
Therapeutic potential of bixin on inflammation: a mini review
Authors: Shadisvaaran Saminathan , Chin Kok-Yong , Mohd-Said Shahida , Leong Xin-Fang
Published: September 2023

Chronic inflammation is the underlying mechanism for many diseases. Thus, inflammatory signaling pathways are valuable targets for new treatment modalities. Natural products have gained interest as a potential source of bioactive compounds which provide health benefits in combating inflammatory-related diseases. Recent reports have linked the medicinal values of Bixa orellana L. with its anti-inflammatory activities. Therefore, this review aims to examine the therapeutic potential of bixin, a major bioactive constituent found in the seeds of B. orellana, on inflammatory-related diseases based on existing in vitro and in vivo evidence. Additionally, the anti-inflammatory mechanism of bixin via signaling pathways is explored and possible toxic effects are addressed. The findings suggest that bixin may ameliorate inflammation via inhibition of toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and thioredoxin-interacting protein/NOD-like receptor protein 3 (TXNIP/NLRP3) inflammasome mechanisms. More well-planned clinical studies should be performed to verify its effectiveness and safety profile.
Research on application of radiomics in glioma: a bibliometric and visual analysis
Authors: Chen Chunbao , Du Xue , Yang Lu , Liu Hongjun , Li Zhou , Gou Zhangyang , Qi Jian
Published: September 2023

Background

With the continuous development of medical imaging informatics technology, radiomics has become a new and evolving field in medical applications. Radiomics aims to be an aid to support clinical decision making by extracting quantitative features from medical images and has a very wide range of applications. The purpose of this study was to perform a bibliometric and visual analysis of scientific results and research trends in the research application of radiomics in glioma.

Methods

We searched the Web of Science Core Collection (WOScc) for publications related to glioma radiomics. A bibliometric and visual analysis of online publications in this field related to countries/regions, authors, journals, references and keywords was performed using CiteSpace and R software.

Results

A total of 587 relevant literature published from 2012 to September 2022 were retrieved in WOScc, and finally a total of 484 publications were obtained according to the filtering criteria, including 393 (81.20%) articles and 91 (18.80%) reviews. The number of relevant publications increases year by year. The highest number of publications was from the USA (171 articles, 35.33%) and China (170 articles, 35.12%). The research institution with the highest number of publications was Chinese Acad Sci (24), followed by Univ Penn (22) and Fudan Univ (21). WANG Y (27) had the most publications, followed by LI Y (22), and WANG J (20). Among the 555 co-cited authors, LOUIS DN (207) and KICKINGEREDER P (207) were the most cited authors. FRONTIERS IN ONCOLOGY (42) was the most published journal and NEURO-ONCOLOGY (412) was the most co-cited journal. The most frequent keywords in all publications included glioblastoma (187), survival (136), classification (131), magnetic resonance imaging (113), machine learning (100), tumor (82), and feature (79), central nervous system (66), IDH (57), and radiomics (55). Cluster analysis was performed on the basis of keyword co-occurrence, and a total of 16 clusters were formed, indicating that these directions are the current hotspots of radiomics research applications in glioma and may be the future directions of continuous development.

Conclusion

In the past decade, radiomics has received much attention in the medical field and has been widely used in clinical research applications. Cooperation and communication between countries/regions need to be enhanced in future research to promote the development of radiomics in the field of medicine. In addition, the application of radiomics has improved the accuracy of pre-treatment diagnosis, efficacy prediction and prognosis assessment of glioma and helped to promote the development into precision medicine, the future still faces many challenges.
Serum metabolomics analysis of biomarkers and metabolic pathways in patients with colorectal cancer associated with spleen-deficiency and qi-stagnation syndrome or damp-heat syndrome: a prospective cohort study
Authors: Zou Min , Zhang Yan-Sheng , Feng Jin-Kai , Tu Hao , Gui Ming-Bin , Wang Ya-Nan , Yang Zi-Jie , Yang Zeng-Qiang , Xu Ming , Wu Wei-Qiang , Gao Feng
Published: September 2023

Objective

To profile the serum metabolites and metabolic pathways in colorectal cancer (CRC) patients associated with spleen-deficiency and qi-stagnation syndrome (SDQSS) or damp-heat syndrome (DHS).

Methods

From May 2020 to January 2021, CRC patients diagnosed with traditional Chinese medicine (TCM) syndromes of SDQSS or DHS were enrolled. The clinicopathological data of the SDQSS and DHS groups were compared. The serum samples were analyzed by liquid chromatography-mass spectrometry (LC-MS). The variable importance in the projection >1, fold change ≥3 or ≤0.333, and P value ≤0.05 were used to identify differential metabolites between the two groups. Furthermore, areas under the receiver operating characteristic (ROC) curve > 0.9 were applied to select biomarkers with good predictive performance. The enrichment metabolic pathways were searched through the database of Kyoto Encyclopedia of Genes and Genomes.

Results

60 CRC patients were included (30 SDQSS and 30 DHS). The level of alanine aminotransferase was marginally significantly higher in the DHS group than the SDQSS group (P = 0.051). The other baseline clinicopathological characteristics were all comparable between the two groups. 23 differential serum metabolites were identified, among which 16 were significantly up-regulated and 7 were significantly down-regulated in the SDQSS group compared with the DHS group. ROC curve analysis showed that (S)-3-methyl-2-oxopentanoic acid, neocembrene, 1-aminocyclopropanecarboxylic acid, 3-methyl-3-hydroxypentanedioate, and nicotine were symbolic differential metabolites with higher predictive power. The top five enrichment signalling pathways were valine, leucine and isoleucine biosynthesis; lysosome; nicotine addiction; fructose and mannose metabolism; and pertussis.

Conclusion

Our study identifies the differential metabolites and characteristic metabolic pathways among CRC patients with SDQSS or DHS, offering the possibility of accurate and objective syndrome differentiation and TCM treatment for CRC patients.
A real-time contouring feedback tool for consensus-based contour training
Authors: Nelson Christopher L. , Nguyen Callistus , Fang Raymond , Court Laurence E. , Cardenas Carlos E. , Rhee Dong Joo , Netherton Tucker J. , Mumme Raymond P. , Gay Skylar , Gay Casey , Marquez Barbara , El Basha Mohammad D. , Zhao Yao , Gronberg Mary , Hernandez Soleil , Nealon Kelly A. , Martel Mary K. , Yang Jinzhong
Published: September 2023

Purpose

Variability in contouring structures of interest for radiotherapy continues to be challenging. Although training can reduce such variability, having radiation oncologists provide feedback can be impractical. We developed a contour training tool to provide real-time feedback to trainees, thereby reducing variability in contouring.

Methods

We developed a novel metric termed localized signed square distance (LSSD) to provide feedback to the trainee on how their contour compares with a reference contour, which is generated real-time by combining trainee contour and multiple expert radiation oncologist contours. Nine trainees performed contour training by using six randomly assigned training cases that included one test case of the heart and left ventricle (LV). The test case was repeated 30 days later to assess retention. The distribution of LSSD maps of the initial contour for the training cases was combined and compared with the distribution of LSSD maps of the final contours for all training cases. The difference in standard deviations from the initial to final LSSD maps, ΔLSSD, was computed both on a per-case basis and for the entire group.

Results

For every training case, statistically significant ΔLSSD were observed for both the heart and LV. When all initial and final LSSD maps were aggregated for the training cases, before training, the mean LSSD ([range], standard deviation) was –0.8 mm ([–37.9, 34.9], 4.2) and 0.3 mm ([–25.1, 32.7], 4.8) for heart and LV, respectively. These were reduced to –0.1 mm ([–16.2, 7.3], 0.8) and 0.1 mm ([–6.6, 8.3], 0.7) for the final LSSD maps during the contour training sessions. For the retention case, the initial and final LSSD maps of the retention case were aggregated and were –1.5 mm ([–22.9, 19.9], 3.4) and –0.2 mm ([–4.5, 1.5], 0.7) for the heart and 1.8 mm ([–16.7, 34.5], 5.1) and 0.2 mm ([-3.9, 1.6],0.7) for the LV.

Conclusions

A tool that uses real-time contouring feedback was developed and successfully used for contour training of nine trainees. In all cases, the utility was able to guide the trainee and ultimately reduce the variability of the trainee’s contouring.