bluuebunny/crossref_metadata_2025 huggingface dataset:
Older adults compensate for switch, but not mixing costs, relative to younger adults on an intrinsically cued task switching experiment
Authors: Eich Teal S. , Langfield Christopher , Sakhardande Jayant , Gazes Yunglin , Habeck Christian , Stern Yaakov
Published: April 2023

Introduction

Aging negatively impacts the ability to rapidly and successfully switch between two or more tasks that have different rules or objectives. However, previous work has shown that the context impacts the extent of this age-related impairment: while there is relative age-related invariance when participants must rapidly switch back and forth between two simple tasks (often called “switch costs”), age-related differences emerge when the contexts changes from one in which only one task must be performed to one in which multiple tasks must be performed, but a trial-level switch is not required (e.g., task repeat trials within dual task blocks, often called “mixing costs”). Here, we explored these two kinds of costs behaviorally, and also investigated the neural correlates of these effects.

Methods

Seventy-one younger adults and 175 older adults completed a task-switching experiment while they underwent fMRI brain imaging. We investigated the impact of age on behavioral performance and neural activity considering two types of potential costs: switch costs (dual-task switch trials minus dual-task non-switch trials), and mixing costs (dual-task non-switch minus single-task trials).

Results

We replicated previous behavioral findings, with greater age associated with mixing, but not switch costs. Neurally, we found age-related compensatory activations for switch costs in the dorsal lateral prefrontal cortex, pars opercularis, superior temporal gyrus, and the posterior and anterior cingulate, but age-related under recruitment for mixing costs in fronto-parietal areas including the supramarginal gyrus and pre and supplemental motor areas.

Discussion

These results suggest an age-based dissociation between executive components that contribute to task switching.
Research progress on vestibular dysfunction and visual–spatial cognition in patients with Alzheimer’s disease
Authors: Huang Yan , Xu Jiaxi , Zhang Xuehao , Liu Yuhe , Yu Enyan
Published: April 2023

Alzheimer’s disease (AD) or vestibular dysfunction may impair visual–spatial cognitive function. Recent studies have shown that vestibular dysfunction is increasingly common in patients with AD, and patients with AD with vestibular impairment show more visual–spatial cognitive impairment. By exploring the relationship and interaction mechanism among the vestibular system, visual–spatial cognitive ability, and AD, this study aims to provide new insights for the screening, diagnosis, and rehabilitation intervention of patients with AD. In contrast, routine vestibular function tests are particularly important for understanding the vestibular function of patients with AD. The efficacy of vestibular function test as a tool for the early screening of patients with AD must also be further studied. Through the visual–spatial cognitive ability test, the “spatial impairment” subtype of patients with AD, which may be significant in caring for patients with AD to prevent loss and falls, can also be determined. Additionally, the visual–spatial cognitive ability test has great benefits in preventing and alleviating cognitive decline of patients with AD.
Cytological, molecular, cytogenetic, and physiological characterization of a novel immortalized human enteric glial cell line
Authors: Zanoletti Lisa , Valdata Aurora , Nehlsen Kristina , Faris Pawan , Casali Claudio , Cacciatore Rosalia , Sbarsi Ilaria , Carriero Francesca , Arfini Davide , van Baarle Lies , De Simone Veronica , Barbieri Giulia , Raimondi Elena , May Tobias , Moccia Francesco , Bozzola Mauro , Matteoli Gianluca , Comincini Sergio , Manai Federico
Published: April 2023

Enteric glial cells (EGCs), the major components of the enteric nervous system (ENS), are implicated in the maintenance of gut homeostasis, thereby leading to severe pathological conditions when impaired. However, due to technical difficulties associated with EGCs isolation and cell culture maintenance that results in a lack of valuable in vitro models, their roles in physiological and pathological contexts have been poorly investigated so far. To this aim, we developed for the first time, a human immortalized EGC line (referred as ClK clone) through a validated lentiviral transgene protocol. As a result, ClK phenotypic glial features were confirmed by morphological and molecular evaluations, also providing the consensus karyotype and finely mapping the chromosomal rearrangements as well as HLA-related genotypes. Lastly, we investigated the ATP- and acetylcholine, serotonin and glutamate neurotransmitters mediated intracellular Ca2+ signaling activation and the response of EGCs markers (GFAP, SOX10, S100β, PLP1, and CCL2) upon inflammatory stimuli, further confirming the glial nature of the analyzed cells. Overall, this contribution provided a novel potential in vitro tool to finely characterize the EGCs behavior under physiological and pathological conditions in humans.
Reactive astrogliosis in the era of single-cell transcriptomics
Authors: Matusova Zuzana , Hol Elly M. , Pekny Milos , Kubista Mikael , Valihrach Lukas
Published: April 2023

Reactive astrogliosis is a reaction of astrocytes to disturbed homeostasis in the central nervous system (CNS), accompanied by changes in astrocyte numbers, morphology, and function. Reactive astrocytes are important in the onset and progression of many neuropathologies, such as neurotrauma, stroke, and neurodegenerative diseases. Single-cell transcriptomics has revealed remarkable heterogeneity of reactive astrocytes, indicating their multifaceted functions in a whole spectrum of neuropathologies, with important temporal and spatial resolution, both in the brain and in the spinal cord. Interestingly, transcriptomic signatures of reactive astrocytes partially overlap between neurological diseases, suggesting shared and unique gene expression patterns in response to individual neuropathologies. In the era of single-cell transcriptomics, the number of new datasets steeply increases, and they often benefit from comparisons and integration with previously published work. Here, we provide an overview of reactive astrocyte populations defined by single-cell or single-nucleus transcriptomics across multiple neuropathologies, attempting to facilitate the search for relevant reference points and to improve the interpretability of new datasets containing cells with signatures of reactive astrocytes.
Mechanism of Qihuang needle therapy in the management of tic disorders: a clinical trial protocol
Authors: Tang Yuyuan , Wu Jun'e , Xu Zhirui , Fan Baochao , Li Xiangli , Jin Bingxu , Tang Chunzhi
Published: April 2023

Background

Qihuang needle therapy is a newly developed acupuncture therapy to treat tic disorders in clinical practice. However, the mechanism to reduce tic severity remains unknown. Changes in intestinal flora and circulation metabolites are perhaps the potential pathogenesis of tic disorders. As a result, we present a protocol for a controlled clinical trial using multi-omics analysis to probe the mechanism of the Qihuang needle in managing tic disorders.

Methods

This is a matched-pairs design, controlled, clinical trial for patients with tic disorders. Participants will be allocated to either an experimental group or a healthy control group. The main acupoints are Baihui (GV20), Yintang (EX-HN3), and Jueyinshu (BL14). The experimental group will receive Qihuang needle therapy for a month, while the control group will receive no interventions.

Expected outcomes

The change in the severity of the tic disorder is set as the main outcome. Secondary outcomes include gastrointestinal severity index and recurrence rate, which will be calculated after a 12-week follow-up. Gut microbiota, measured by 16S rRNA gene sequencing; serum metabolomics, assessed via LC/MS; and serum zonulin, assessed by enzyme-linked immunosorbent assay (ELISA), will be used as biological specimen analysis outcomes. The present study will investigate the possible interactions between intestinal flora and serum metabolites and the improvement of clinical profiles, which may elucidate the mechanism of Qihuang needle therapy for tic disorders.

Trial registration

This trial is registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/). Registration number: ChiCTR2200057723, Date: 2022-04-14.
Laser interstitial thermal therapy (LITT) for pediatric patients affected by intracranial tumors
Authors: Spacca Barbara , Di Maurizio Marco , Grandoni Manuela , Tempesti Sara , Genitori Lorenzo
Published: April 2023

Introduction

The surgical treatment of brain tumors has evolved over time, offering different strategies tailored to patients and their specific lesions. Among these strategies, Laser Interstitial Thermal Therapy (LITT) is one of the most recent advances in pediatric neurooncological surgery, and its results and evolution are still under assessment.

Methods

We retrospectively analyzed data from six pediatric patients with deep-seated brain tumors treated with LITT at a single center between November 2019 and June 2022. A total of four patients underwent a stereotaxic biopsy during the same operating session. The indications and preparation for LITT, technical issues, clinical and radiological follow-up, impact on quality of life, and oncological treatment are discussed.

Results

The mean patient age eight years (ranging from 2 to 11 years). The lesion was thalamic in four patients, thalamo-peduncular in one, and occipital posterior periventricular in one. In total, two patients had been previously diagnosed with low-grade glioma (LGG). Biopsies revealed LGG in two patients, ganglioglioma grade I in one, and diffuse high-grade glioma (HGG) in one. Postoperatively, two patients presented with transient motor deficits. The mean follow-up period was 17 months (ranging from 5 to 32 months). Radiological follow-up showed a progressive reduction of the tumor in patients with LGG.

Conclusion

Laser interstitial thermal therapy is a promising, minimally invasive treatment for deep-seated tumors in children. The results of lesion reduction appear to be relevant in LGGs and continue over time. It can be used as an alternative treatment for tumors located at sites that are difficult to access surgically or where other standard treatment options have failed.
The neuroprotective effect of ascorbic acid against imidacloprid-induced neurotoxicity and the role of HO-1 in mice
Authors: Mudgal Rajat , Sharma Satyam , Singh Sanjiv , Ravichandiran V.
Published: April 2023

Imidacloprid (IMI) is not only a neurotoxic agricultural pesticide but also a possible food contaminant. The aims of this study were to (1) explore the relationship between recurrent IMI administration and neuronal toxicity in mice and (2) evaluate the potential neuroprotective effect of ascorbic acid (AA), a substance with significant free radical scavenger and having property to block the inflammatory pathways. Mice were categorized as naïve controls (administered vehicles for 28 days); the IMI-treatment animal group (administered po 45-mg/kg body weight of IMI per day for 28 days); and the IMI + AA treatment animal group (administered the same IMI dose + 200 mg/kg of AA orally for 28 days). On day 28, memory losses were assessed using the Y-maze and novel target identification behavioral tests. Mice were sacrificed 24 h after the final IMI treatments, as well as hippocampus tissues, were utilized to determine histological assessments, oxidative stress biomarkers, and Heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression levels. The findings demonstrated that IMI-treated mice had substantial impairment of spatial and non-spatial memory functions, as well as reduced antioxidant enzyme and acetylcholinesterase activity. The AA neuroprotective action was achieved through the suppression of the HO-1 expression as well as the stimulation of Nrf2 expression in hippocampal tissues. In summary, recurrent IMI exposure causes oxidative stress and neurotoxicity in mice, and the administration of AA significantly reduces the IMI toxicity possibly by the activation of the HO-1/Nrf2 pathway.
Abnormal intraepidermal nerve fiber density in disease: A scoping review
Authors: Thomas Sarah , Enders Jonathan , Kaiser Andrew , Rovenstine Luke , Heslop Lana , Hauser Will , Chadwick Andrea , Wright Douglas
Published: April 2023

Background

Intraepidermal nerve fiber density (IENFD) has become an important biomarker for neuropathy diagnosis and research. The consequences of reduced IENFD can include sensory dysfunction, pain, and a significant decrease in quality of life. We examined the extent to which IENFD is being used as a tool in human and mouse models and compared the degree of fiber loss between diseases to gain a broader understanding of the existing data collected using this common technique.

Methods

We conducted a scoping review of publications that used IENFD as a biomarker in human and non-human research. PubMed was used to identify 1,004 initial articles that were then screened to select articles that met the criteria for inclusion. Criteria were chosen to standardize publications so they could be compared rigorously and included having a control group, measuring IENFD in a distal limb, and using protein gene product 9.5 (PGP9.5).

Results

We analyzed 397 articles and collected information related to publication year, the condition studied, and the percent IENFD loss. The analysis revealed that the use of IENFD as a tool has been increasing in both human and non-human research. We found that IENFD loss is prevalent in many diseases, and metabolic or diabetes-related diseases were the most studied conditions in humans and rodents. Our analysis identified 73 human diseases in which IENFD was affected, with 71 reporting IENFD loss and an overall average IENFD change of −47%. We identified 28 mouse and 21 rat conditions, with average IENFD changes of −31.6% and −34.7%, respectively. Additionally, we present data describing sub-analyses of IENFD loss according to disease characteristics in diabetes and chemotherapy treatments in humans and rodents.

Interpretation

Reduced IENFD occurs in a surprising number of human disease conditions. Abnormal IENFD contributes to important complications, including poor cutaneous vascularization, sensory dysfunction, and pain. Our analysis informs future rodent studies so they may better mirror human diseases impacted by reduced IENFD, highlights the breadth of diseases impacted by IENFD loss, and urges exploration of common mechanisms that lead to substantial IENFD loss as a complication in disease.
Neurocysticercosis in non-endemic regions: The experience of Qatar
Authors: Haddad Naim , Shaheen Yanal , Abunaib Mohammed , Melikyan Gayane , El Sotouhy Ahmed , Wahbeh Farah , Nauman Areej , Al-Maadid Fatima , Soliman Mohamed , Mesraoua Boulenouar , Elkhider Hisham , Mahfoud Ziyad
Published: April 2023

Objective

To describe the occurrence and features of Neurocystircercosis (NCC) in Qatar.

Background

Qatar has a mixed population of natives and expats. NCC is not endemic to the region, but clinical practice suggests its occurrence in large numbers.

Design/ methods

A database was created to summarize information retrospectively collected on patients with NCC seen through the national health system (HMC) between 2013 and 2018. We identified demographic and disease related variables (clinical manifestations, investigative findings, treatment and outcome) for all patients.

Results

Out of 420 identified NCC patients, 393 (93.6%) were men, and 98.3% were immigrants from NCC endemic countries such as Nepal (63.8%) and India (29.5%). Eighty percent of patients presented with seizures, with the majority (69%) experiencing generalized tonic–clonic seizures. Five percent presented with status epilepticus. Headaches, the second most common complaint, were reported in 18% of subjects. On imaging, 50% had a single lesion while 63% included pathology at the calcified stage. The lesions were parenchymal in 99.5% of cases, predominantly in the frontal lobe (59%). Thirteen percent were diagnosed incidentally on imaging, mainly in the form of isolated calcified non enhancing lesions. Albendazole was received by 55% of patients, and phenytoin was the most prescribed anti-seizure drug (57%). When long term follow up was available, 70% of the patients presenting with seizures were completely seizure free.

Conclusion

NCC is prevalent in Qatar, mainly within the large Southeast Asian immigrant population. NCC is currently a significant contributor to the epilepsy burden in Qatar, often with a good outcome regarding seizure control. NCC with intraparenchymal single lesion shares a large proportion of our cohort.
Pre-trained deep learning models for brain MRI image classification
Authors: Krishnapriya Srigiri , Karuna Yepuganti
Published: April 2023

Brain tumors are serious conditions caused by uncontrolled and abnormal cell division. Tumors can have devastating implications if not accurately and promptly detected. Magnetic resonance imaging (MRI) is one of the methods frequently used to detect brain tumors owing to its excellent resolution. In the past few decades, substantial research has been conducted in the field of classifying brain images, ranging from traditional methods to deep-learning techniques such as convolutional neural networks (CNN). To accomplish classification, machine-learning methods require manually created features. In contrast, CNN achieves classification by extracting visual features from unprocessed images. The size of the training dataset had a significant impact on the features that CNN extracts. The CNN tends to overfit when its size is small. Deep CNNs (DCNN) with transfer learning have therefore been developed. The aim of this work was to investigate the brain MR image categorization potential of pre-trained DCNN VGG-19, VGG-16, ResNet50, and Inception V3 models using data augmentation and transfer learning techniques. Validation of the test set utilizing accuracy, recall, Precision, and F1 score showed that the pre-trained VGG-19 model with transfer learning exhibited the best performance. In addition, these methods offer an end-to-end classification of raw images without the need for manual attribute extraction.
Pre- and post-treatment of α-Tocopherol on cognitive, synaptic plasticity, and mitochondrial disorders of the hippocampus in icv-streptozotocin-induced sporadic Alzheimer’s-like disease in male Wistar rat
Authors: Nabavi Zadeh Fatemeh , Nazari Maryam , Amini Abdollah , Adeli Soheila , Barzegar Behrooz Amir , Fahanik Babaei Javad
Published: April 2023

Objective

Most dementia cases in the elderly are caused by Alzheimer’s disease (AD), a complex, progressive neurological disease. Intracerebroventricular (ICV) administration of streptozotocin (STZ) in rat’s results in aberrant brain insulin signaling, oxidative stress, and mitochondrial dysfunction that impair cognition change neural plasticity, and eventually lead to neuronal death. The current study aims to define the neuroprotective action of alpha-tocopherol in enhancing mitochondrial function and the function of synapses in memory-impaired rats brought on by icv-STZ.

Methods

Male Wistar rats were pre-treated with (α-Tocopherol 150 mg/kg) orally once daily for 7 days before and 14 days after being bilaterally injected with icv-STZ (3 mg/kg), while sham group rats received the same volume of STZ solvent. After 2 weeks of icv-STZ infusion, rats were tested for cognitive performance using a behaviors test and then were prepared electrophysiology recordings or sacrificed for biochemical and histopathological assays.

Results

The cognitive impairment was significantly minimized in the behavioral paradigms for those who had taken α-Tocopherol. In the hippocampus of icv-STZ rat brains, α-Tocopherol ocopherol effectively prevented the loss of glutathione levels and superoxide dismutase enzyme activity, lowered mitochondrial ROS and mitochondrial membrane potential, and also brought about a decrease in Aβ aggregation and neuronal death.

Conclusion

Our findings demonstrated that by lowering neurobehavioral impairments caused by icv-STZ, oxidative stress, and mitochondrial dysfunction, α-Tocopherol enhanced intracellular calcium homeostasis and corrected neurodegenerative defects in the brain. These findings examine the available approach for delaying AD connected to mitochondrial malfunction and plasticity issues.
The TSC2 c.2742+5G>A variant causes variable splicing changes and clinical manifestations in a family with tuberous sclerosis complex
Authors: Fan Kuan , Guo Yi , Song Zhi , Yuan Lamei , Zheng Wen , Hu Xiao , Gong Lina , Deng Hao
Published: April 2023

Background

Tuberous sclerosis complex (TSC) is a genetic, variably expressed, multisystem disease characterized by benign tumors. It is caused by pathogenic variants of the TSC complex subunit 1 gene (TSC1) and the TSC complex subunit 2 gene (TSC2). Genetic testing allows for early diagnosis, genetic counseling, and improved outcomes, but it did not identify a pathogenic variant in up to 25% of all TSC patients. This study aimed to identify the disease-causing variant in a Han-Chinese family with TSC.

Methods

A six-member, three-generation Han-Chinese family with TSC and three unrelated healthy women were recruited. A comprehensive medical examination, a 3-year follow-up, whole exome sequencing, Sanger sequencing, and segregation analysis were performed in the family. The splicing analysis results obtained from six in silico tools, minigene assay, and patients' lymphocyte messenger RNA were compared, and quantitative reverse transcription PCR was used to confirm the pathogenicity of the variant.

Results

Two affected family members had variable clinical manifestations including a rare bilateral cerebellar ataxia symptom. The 3-year follow-up results suggest the effects of a combined treatment of anti-epilepsy drugs and sirolimus for TSC-related epilepsy and cognitive deficits. Whole exome sequencing, Sanger sequencing, segregation analysis, splicing analysis, and quantitative reverse transcription PCR identified the TSC2 gene c.2742+5G>A variant as the genetic cause. This variant inactivated the donor splice site, a cryptic non-canonical splice site was used for different splicing changes in two affected subjects, and the resulting mutant messenger RNA may be degraded by nonsense-mediated decay. The defects of in silico tools and minigene assay in predicting cryptic splice sites were suggested.

Conclusions

This study identified a TSC2 c.2742+5G>A variant as the genetic cause of a Han-Chinese family with TSC and first confirmed its pathogenicity. These findings expand the phenotypic and genetic spectrum of TSC and may contribute to its diagnosis and treatment, as well as a better understanding of the splicing mechanism.
Cingulate protein arginine methyltransferases 1 regulates peripheral hypersensitivity via fragile X messenger ribonucleoprotein
Authors: Wu Cheng , Shang Hui-Fang , Wang Yong-Jie , Wang Jing-Hua , Zuo Zhen-Xing , Lian Yan-Na , Liu Li , Zhang Chen , Li Xiang-Yao
Published: April 2023

The deficit of fragile X messenger ribonucleoprotein (FMRP) leads to intellectual disability in human and animal models, which also leads to desensitization of pain after nerve injury. Recently, it was shown that the protein arginine methyltransferases 1 (PRMT1) regulates the phase separation of FMRP. However, the role of PRMT1 in pain regulation has been less investigated. Here we showed that the downregulation of PRMT1 in the anterior cingulate cortex (ACC) contributes to the development of peripheral pain hypersensitivity. We observed that the peripheral nerve injury decreased the expression of PRMT1 in the ACC; knockdown of the PRMT1 via shRNA in the ACC decreased the paw withdrawal thresholds (PWTs) of naïve mice. Moreover, the deficits of FMRP abolished the effects of PRMT1 on pain sensation. Furthermore, overexpression of PRMT1 in the ACC increased the PWTs of mice with nerve injury. These observations indicate that the downregulation of cingulate PRMT1 was necessary and sufficient to develop peripheral hypersensitivity after nerve injury. Thus, we provided evidence that PRMT1 is vital in regulating peripheral pain hypersensitivity after nerve injury via the FMRP.
Change in cardiometabolic risk factors in a pilot safety-net plant-based lifestyle medicine program
Authors: Albert Stephanie L. , Massar Rachel E. , Correa Lilian , Kwok Lorraine , Joshi Shivam , Shah Sapana , Boas Rebecca , Alcalá Héctor E. , McMacken Michelle
Published: April 2023

Introduction

Interventions emphasizing healthful lifestyle behaviors are proliferating in traditional health care settings, yet there is a paucity of published clinical outcomes, outside of pay-out-of-pocket or employee health programs.

Methods

We assessed weight, hemoglobin A1c (HbA1c), blood pressure, and cholesterol for 173 patients of the Plant-Based Lifestyle Medicine Program piloted in a New York City safety-net hospital. We used Wilcoxon signed-rank tests to assess changes in means, from baseline to six-months, for the full sample and within baseline diagnoses (i.e., overweight or obesity, type 2 diabetes, prediabetes, hypertension, hyperlipidemia). We calculated the percentage of patients with clinically meaningful changes in outcomes for the full sample and within diagnoses.

Findings

The full sample had statistically significant improvements in weight, HbA1c, and diastolic blood pressure. Patients with prediabetes or overweight or obesity experienced significant improvements in weight and those with type 2 diabetes had significant improvements in weight and HbA1c. Patients with hypertension had significant reductions in diastolic blood pressure and weight. Data did not show differences in non-high-density lipoprotein cholesterol (non-HDL-C), but differences in low-density lipoprotein cholesterol (LDL-C) were approaching significance for the full sample and those with hyperlipidemia. The majority of patients achieved clinically meaningful improvements on all outcomes besides systolic blood pressure.

Conclusion

Our study demonstrates that a lifestyle medicine intervention within a traditional, safety-net clinical setting improved biomarkers of cardiometabolic disease. Our findings are limited by small sample sizes. Additional large-scale, rigorous studies are needed to further establish the effectiveness of lifestyle medicine interventions in similar settings.
Monitoring EGFR-lung cancer evolution: a possible beginning of a “methylation era” in TKI resistance prediction
Authors: Fabrizio Federico Pio , Sparaneo Angelo , Muscarella Lucia Anna
Published: April 2023

The advances in scientific knowledge on biological therapies of the last two decades have impressively oriented the clinical management of non-small-cell lung cancer (NSCLC) patients. The treatment with tyrosine kinase inhibitors (TKIs) in patients harboring Epidermal Growth Factor Receptor (EGFR)-activating mutations is dramatically associated with an improvement in disease control. Anyhow, the prognosis for this selected group of patients remains unfavorable, due to the innate and/or acquired resistance to biological therapies. The methylome analysis of many tumors revealed multiple patterns of methylation at single/multiple cytosine-phosphate-guanine (CpG) sites that are linked to the modulation of several cellular pathways involved in cancer onset and progression. In lung cancer patients, ever increasing evidences also suggest that the association between DNA methylation changes at promoter/intergenic regions and the consequent alteration of gene-expression signatures could be related to the acquisition of resistance to biological therapies. Despite this intriguing hypothesis, large confirmatory studies are demanded to consolidate and finalize many preliminary observations made in this field. In this review, we will summarize the available knowledge about the dynamic role of DNA methylation in EGFR-mutated NSCLC patients.
Pelvic floor muscle exercises alleviate symptoms and improve mental health and rectal function in patients with low anterior resection syndrome
Authors: Yuanyuan Wu , Shiyin He , Lei He , Ding Ding
Published: April 2023

Background

Pelvic floor rehabilitation has been reported to be effective in improving fecal incontinence. The aim of this study was to prospectively evaluate the effectiveness of combined pelvic floor muscle exercises (PFMEs) and loperamide treatment on rectal function and mental health for low anterior resection syndrome (LARS) patients after sphincter-saving operation (SSO) for rectal cancer.

Methods

A total of 60 inpatients diagnosed with LARS were enrolled and randomly assigned to one of two groups: patients in Group A (n = 30) were treated with a PFME intervention and those in Group B (n = 30) with a control intervention for 4 weeks. High-resolution anorectal manometry (HRAM) was performed for all LARS patients. Demographic information was collected for all patients, and they subsequently also completed several questionnaires, including the Hospital Anxiety and Depression Scale (HADS), a measure of Wexner score, a measure of stool frequency per day, and the Bristol Stool Form Scale (BSFS).

Results

No significant differences between the groups were observed in baseline data. With regard to rectal function, we found significant improvements at week 4 in maximal resting pressure (MRP) (39.93 ± 5.02 vs. 28.70 ± 5.40 mmH2O, p < 0.001) and maximal squeeze pressure (MSP) (132.43 ± 8.16 mmH2O vs. 113.33 ± 9.87 mmH2O, p < 0.001) among Group A patients compared to Group B patients. Additionally, Wexner scores were significantly lower in Group A than in Group B at week 4 (8.10 ± 1.24 vs. 9.87 ± 1.29 ml, p = 0.018), as were stool frequency (6.47 ± 0.90 vs. 7.83 ± 0.93, p < 0.001) and BSFS scores (5.17 ± 0.65 vs. 6.10 ± 0.80, p = 0.020). Notably, HADS scores were also significantly lower in Group A than in Group B at week 4 (8.25 ± 2.36 vs. 10.48 ± 3.01, p < 0.001). Additionally, both anxiety scores (4.16 ± 1.38 vs. 5.33 ± 1.69, p < 0.001) and depression scores (4.09 ± 1.56 vs. 5.15 ± 1.89, p < 0.001) were significantly lower in Group A than in Group B at week 4.

Conclusion

Pelvic floor muscle exercises are an effective treatment that can alleviate symptoms and improve rectal function and mental health in patients with low anterior resection syndrome.
A new model based on gamma-glutamyl transpeptidase to lymphocyte ratio and systemic immune-inflammation index can effectively predict the recurrence of hepatocellular carcinoma after liver transplantation
Authors: Zhang Weiqi , Bi Yi , Yang Kai , Xie Yan , Li Zhaoxian , Yu Xinghui , Zhang Li , Jiang Wentao
Published: April 2023

Background

Liver transplantation (LT) is one of the most effective treatment modalities for hepatocellular carcinoma (HCC), but patients with HCC recurrence after LT always have poor prognosis. This study aimed to evaluate the predictive value of the gamma-glutamyl transpeptidase-to-lymphocyte ratio (GLR) and systemic immune-inflammation index (SII) in terms of HCC recurrence after LT, based on which we developed a more effective predictive model.

Methods

The clinical data of 325 HCC patients who had undergone LT were collected and analyzed retrospectively. The patients were randomly divided into a development cohort (n = 215) and a validation cohort (n = 110). Cox regression analysis was used to screen the independent risk factors affecting postoperative recurrence in the development cohort, and a predictive model was established based on the results of the multivariate analysis. The predictive values of GLR, SII and the model were evaluated by receiver operating characteristic (ROC) curve analysis, which determined the cut-off value for indicating patients’ risk levels. The Kaplan-Meier survival analysis and the competing-risk regression analysis were used to evaluate the predictive performance of the model, and the effectiveness of the model was verified further in the validation cohort.

Results

The recurrence-free survival of HCC patients after LT with high GLR and SII was significantly worse than that of patients with low GLR and SII (P<0.001). Multivariate Cox regression analysis identified GLR (HR:3.405; 95%CI:1.954-5.936; P<0.001), SII (HR: 2.285; 95%CI: 1.304-4.003; P=0.004), tumor number (HR:2.368; 95%CI:1.305-4.298; P=0.005), maximum tumor diameter (HR:1.906; 95%CI:1.121-3.242; P=0.017), alpha-fetoprotein level (HR:2.492; 95%CI:1.418-4.380; P=0.002) as independent risk factors for HCC recurrence after LT. The predictive model based on these risk factors had a good predictive performance in both the development and validation cohorts (area under the ROC curve=0.800, 0.791, respectively), and the performance of the new model was significantly better than that of single GLR and SII calculations (P<0.001). Survival analysis and competing-risk regression analysis showed that the predictive model could distinguish patients with varying levels of recurrence risk in both the development and validation cohorts.

Conclusions

The GLR and SII are effective indicators for evaluating HCC recurrence after LT. The predictive model based on these indicators can accurately predict HCC recurrence after LT and is expected to guide preoperative patient selection and postoperative follow-up.
Gut Metabolite Urolithin A Inhibits Osteoclastogenesis and Senile Osteoporosis by Enhancing the Autophagy Capacity of Bone Marrow Macrophages
Authors: Tao Huaqiang , Tao Yunxia , Yang Chen , Li Wenming , Zhang Wei , Li Xueyan , Gu Ye , Hong Yujing , Yang Huilin , Liu Yu , Yang Xing , Geng Dechun
Published: April 2023

Senile osteoporosis (SOP) is a systemic bone disease that is significantly associated with age and eventually leads to deteriorated bone strength and increased fracture risk. Urolithin A (Uro-A) is a gut microbiome-derived compound that is mainly produced from pomegranates and some nuts. Uro-A has attracted great attention in recent years in view of its protective effects on aging-related diseases, including muscle dysfunction, kidney disease and knee injury. However, its protective influence and possible mechanisms in senile osteoporosis remain unclear. Our study describes the beneficial effect of Uro-A on bone marrow macrophages (BMMs). The in vitro results demonstrated that Uro-A inhibited receptor activator for nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in BMMs in a concentration-dependent manner. Uro-A significantly reduced the expression of osteoclast-related genes and bone resorption. Mechanistically, we found that the autophagy ability of BMMs was significantly enhanced in the early stage of Uro-A treatment, accompanied by the activation of LC3 and Beclin 1. At the same time, this enhanced autophagy activity was maintained until the later stage after stimulation with RANKL. Furthermore, we found that the MARK signaling pathway was blocked by Uro-A treatment. In a mouse model of aging, Uro-A effectively inhibited bone loss in the proximal femur, spine and tibia of aging mice. These results indicated that Uro-A is a robust and effective treatment for preventing senile osteoporosis bone loss.
Fluoxetine degrades luminance perceptual thresholds while enhancing motivation and reward sensitivity
Authors: Gacoin Maëva , Ben Hamed Suliann
Published: April 2023

Selective serotonin reuptake inhibitors (SSRIs) increase serotonin activity in the brain. While they are mostly known for their antidepressant properties, they have been shown to improve visual functions in amblyopia and impact cognitive functions ranging from attention to motivation and sensitivity to reward. Yet, a clear understanding of the specific action of serotonin to each of bottom-up sensory and top-down cognitive control components and their interaction is still missing. To address this question, we characterize, in two adult male macaques, the behavioral effects of fluoxetine, a specific SSRI, on visual perception under varying bottom-up (luminosity, distractors) and top-down (uncertainty, reward biases) constraints while they are performing three different visual tasks. We first manipulate target luminosity in a visual detection task, and we show that fluoxetine degrades luminance perceptual thresholds. We then use a target detection task in the presence of spatial distractors, and we show that under fluoxetine, monkeys display both more liberal responses as well as a degraded perceptual spatial resolution. In a last target selection task, involving free choice in the presence of reward biases, we show that monkeys display an increased sensitivity to reward outcome under fluoxetine. In addition, we report that monkeys produce, under fluoxetine, more trials and less aborts, increased pupil size, shorter blink durations, as well as task-dependent changes in reaction times. Overall, while low level vision appears to be degraded by fluoxetine, performances in the visual tasks are maintained under fluoxetine due to enhanced top-down control based on task outcome and reward maximization.
Drug-related problems among transfusion-dependent thalassemia patients: A real-world evidence study
Authors: Chun Geok Ying , Mohd Tahir Nurul Ain , Islahudin Farida , Selvaratnam Veena , Li Shu Chuen
Published: April 2023

Introduction: Thalassemia is among the most common genetic disorders globally and many patients suffer from iron overload (IOL) complications that mainly affect the heart, liver and endocrine system. These events may be further complicated by drug-related problems (DRP), an inherent issue among patients with chronic diseases.

Objective: The study aimed to evaluate the burden, associated factors and impacts of DRP in transfusion-dependent thalassemia (TDT) patients.

Method: Eligible TDT patients under follow-up in a tertiary hospital between 01 March 2020 to 30 April 2021 were interviewed and their medical records were reviewed retrospectively to identify any DRP. DRPs were classified using the Pharmaceutical Care Network Europe (PCNE) classification version 9.1. The incidence and preventability of DRP were assessed and the associated risk factors were estimated by univariate and multivariate logistic regression.

Results: A total of 200 patients were enrolled with a median (interquartile range: IQR) age of 28 years at enrolment. Approximately 1 in 2 patients were observed to suffer from thalassemia-related complications. Throughout the study period, 308 DRPs were identified among 150 (75%) participants, with a median DRP per participant of 2.0 (IQR 1.0–3.0). Of the three DRP dimensions, treatment effectiveness was the most common DRP (55.8%) followed by treatment safety (39.6%) and other DRP (4.6%). The median serum ferritin level was statistically higher in patients with DRP compared with patients without DRP (3833.02 vs. 1104.98 μg/L, p < 0.001). Three risk factors were found to be significantly associated with the presence of DRP. Patients with frequent blood transfusion, moderate to high Medication Complexity Index (MRCI) and of Malay ethnicity were associated with higher odds of having a DRP (AOR 4.09, 95% CI: 1.83, 9.15; AOR 4.50, 95% CI: 1.89, 10.75; and AOR 3.26, 95% CI: 1.43, 7.43, respectively).

Conclusion: The prevalence of DRP was relatively high amongst TDT patients. Increased medication complexity, more severe form of the disease and Malay patients were more likely to experience DRP. Hence, more viable interventions targeted to these groups of patients should be undertaken to mitigate the risk of DRP and achieve better treatment outcomes.
Hurdles and signposts on the road to virtual control groups—A case study illustrating the influence of anesthesia protocols on electrolyte levels in rats
Authors: Gurjanov A. , Kreuchwig A. , Steger-Hartmann T. , Vaas L. A. I.
Published: April 2023

Introduction: Virtual Control Groups (VCGs) represent the concept of using historical control data from legacy animal studies to replace concurrent control group (CCG) animals. Based on the data curation and sharing activities of the Innovative Medicine Initiatives project eTRANSAFE (enhancing TRANSlational SAFEty Assessment through Integrative Knowledge Management) the ViCoG working group was established with the objectives of i) collecting suitable historical control data sets from preclinical toxicity studies, ii) evaluating statistical methodologies for building adequate and regulatory acceptable VCGs from historical control data, and iii) sharing those control-group data across multiple pharmaceutical companies. During the qualification process of VCGs a particular focus was put on the identification of hidden confounders in the data sets, which might impair the adequate matching of VCGs with the CCG.

Methods: During our analyses we identified such a hidden confounder, namely, the choice of the anesthetic procedure used in animal experiments before blood withdrawal. Anesthesia using CO2 may elevate the levels of some electrolytes such as calcium in blood, while the use of isoflurane is known to lower these values. Identification of such hidden confounders is particularly important if the underlying experimental information (e.g., on the anesthetic procedure) is not routinely recorded in the standard raw data files, such as SEND (Standard for Exchange of Non-clinical Data). We therefore analyzed how the replacement of CCGs with VCGs would affect the reproducibility of treatment-related findings regarding electrolyte values (potassium, calcium, sodium, and phosphate). The analyses were performed using a legacy rat systemic toxicity study consisting of a control and three treatment groups conducted according to pertinent OECD guidelines. In the report of this study treatment-related hypercalcemia was reported. The rats in this study were anesthetized with isoflurane.

Results: Replacing the CCGs with VCGs derived from studies comprising both anesthetics resulted in a shift of control electrolyte parameters. Instead of the originally reported hypercalcemia the use of VCG led to fallacious conclusions of no observed effect or hypocalcemia.

Discussion: Our study highlights the importance of a rigorous statistical analysis including the detection and elimination of hidden confounders prior to the implementation of the VCG concept.
Characterization of a polychromatic microfocus X-ray fluorescence imaging setup with metallic contrast agents in a microphysiological tumor model
Authors: Kumar Kunal , Fachet Melanie , Al-Maatoq Marwah , Chakraborty Amit , Khismatrao Rahul S. , Oka Shreyas V. , Staufer Theresa , Grüner Florian , Michel Thilo , Walles Heike , Hoeschen Christoph
Published: April 2023

Introduction: Accurate diagnosis and personalized treatments involving site-targeted cancer localization, drug delivery, therapeutic strategy, and disease pathways identification, rely on a precise understanding of biomarker kinetics, drug pharmacokinetics, and mechanistic behaviour of functionalized tracers through in vitro and in vivo studies. X-ray fluorescence (XRF) computed tomography (XFCT) offers a potential alternative to current 3D imaging techniques for spatiotemporal localization of nanoparticle-tracers with high spatial resolution and sensitivity. In this work, the applicability of a benchtop cone-beam system with a polychromatic X-ray source was examined with regard to physical constraints of engineered tissue models.

Methods: A tissue engineering approach based on a decellularized scaffold was used to establish a 3D breast cancer model with MDA-MB-231 cells in co-culture with primary human fibroblasts. The 3D breast cancer system, in combination with small-animal-sized phantoms, was used to demonstrate the novel integrated pre-clinical imaging approach to perform in vitro surrogate investigations and non-destructive analysis on biophantoms. These models are adopted to evaluate the functionality and optimize the setup for high-spatial-resolution, fast, and fully-3D quantitative imaging. Polychromatic X-rays from a microfocus source are used for XRF stimulation from conventional Gadolinium (Gd) and nanoparticle-based Molybdenum (MoNPs) contrast agents.

Results and Discussion: The intestinal scaffold allowed the invasion of the breast cancer cells over this barrier and therefore provides a valuable tool to study metastasis formation of tumor cells from epithelial origin. The breast cancer model was well suited for the development and validation of the proposed XRF imaging, with spatial resolution under <2 mm and contrast dose in the order of a few 100 μg/mL (∼0.3 mg/mL for Gd and ∼0.5 mg/mL for MoNPs), radiation dose in the order of a few 100 cGy (280 cGy for Gd and 94 cGy for MoNPs, with a possible reduction of an order of magnitude for Gd and 67% for MoNPs), and imaging time in the order of 10 min for Gd (33 min total) and 100 min (2.8 h total) for MoNPs, approaching in vivo conform conditions for pre-clinical studies. High-resolution XFCT for tissue-engineered cancer models would be of significant interest in biomedical research and diagnostic imaging, e.g., for an increased mechanistic understanding of molecular processes in tumor formation or early cancer detection.
In Ovo Injection of CHIR-99021 Promotes Feather Follicle Development via Modulating the Wnt Signaling Pathway and Transcriptome in Goose Embryos (Anser cygnoides)
Authors: Feng Ziqiang , Gong Haizhou , Fu Jinhong , Xu Xiaohui , Song Yupu , Yan Xiaomin , Mabrouk Ichraf , Zhou Yuxuan , Wang Yudong , Fu Xianou , Sui Yujian , Liu Tuoya , Li Chuanghang , Liu Zebei , Tian Xu , Sun Le , Guo Keying , Sun Yongfeng , Hu Jingtao
Published: April 2023

Feather performs important physiological functions in birds, and it is also one of the economic productions in goose farming. Understanding and modulating feather follicle development during embryogenesis are essential for bird biology and the poultry industry. CHIR-99021 is a potent Wnt/β-catenin signaling pathway activator associated with feather follicle development. In this study, goose embryos (Anser cygnoides) received an in ovo injection of CHIR-9902, which was conducted at the beginning of feather follicle development (E9). The results showed that feather growth and feather follicle development were promoted. The Wnt signaling pathway was activated by the inhibition of GSK-3β. Transcriptomic analyses showed that the transcription changes were related to translation, metabolism, energy transport, and stress in dorsal tissue of embryos that received CHIR-99021, which might be to adapt and coordinate the promoting effects of CHIR-99021 on feather follicle development. This study suggests that in ovo injection of CHIR-99021 is a potential strategy to improve feather follicle development and feather-related traits for goose farming and provides profiling of the Wnt signaling pathway and transcriptome in dorsal tissue of goose embryos for further understanding of feather follicle development.