bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive impairment in the population-based ural very old study
Authors: Bikbov Mukharram M. , Kazakbaeva Gyulli M. , Iakupova Ellina M. , Panda-Jonas Songhomitra , Fakhretdinova Albina A. , Tuliakova Azaliia M. , Rusakova Iuliia A. , Jonas Jost B.
Published: July 2022

Background

Despite its marked importance in public health, the prevalence of cognitive impairment (CI) and its associated factors have only rarely been examined in old populations in general or in Russia at all.

Objective

To assess CI prevalence and its determinants in a very elderly population in Russia.

Materials and methods

The population-based Ural Very Old Study, conducted in rural and urban region in Bashkortostan/Russia, included 1,526 (81.1%) out of 1,882 eligible individuals aged 85+ years. A series of medical examinations including the Mini-Mental State Examination (MMSE) for the assessment of CI was performed.

Results

Mini-Mental State Examination data were available for 1,442 (94.5%) individuals (mean age: 88.3 ± 2.9 years; range: 85–103 years). The median MMSE score was 24 (interquartile range: 19, 27). Prevalence of any CI (MMSE score < 24 points) was 701/1,442 [48.6%; 95% confidence interval (CI): 46.0, 51.2]. Prevalence of mild, moderate and severe CI (MMSE score 19–23 points, 10–18 points, and ≤9 points, respectively) was 357/1,442 (24.8%; 95% CI: 22.5, 27.0), 246/1,442 (17.1%; 95% CI: 15.1, 19.0), and 98/1,442 (6.8%; 95% CI: 5.5, 8.1), resp. A lower MMSE score correlated (regression coefficient r2: 0.31) with older age (beta: −0.13; P < 0.001), rural region of habitation (beta: 0.15; P < 0.001), lower level of education (beta: 0.19; P < 0.001), higher depression score (beta: −0.33; P < 0.001) (or alternatively, higher prevalence of hearing loss (beta: −0.10; P = 0.001), worse visual acuity (beta: −0.10; P = 0.001), and lower physical activity (beta: 0.06; P = 0.04).

Conclusion

In this elderly study population from rural and urban Russia, prevalence of any, mild, moderate and severe CI was 48.6, 24.8, 17.1, and 6.8%, resp. Besides medical and lifestyle factors, vision and hearing impairment were major factors associated with CI.
Ovarian steroid hormones: A long overlooked but critical contributor to brain aging and Alzheimer’s disease
Authors: Jett Steven , Schelbaum Eva , Jang Grace , Boneu Yepez Camila , Dyke Jonathan P. , Pahlajani Silky , Diaz Brinton Roberta , Mosconi Lisa
Published: July 2022

Ovarian hormones, particularly 17β-estradiol, are involved in numerous neurophysiological and neurochemical processes, including those subserving cognitive function. Estradiol plays a key role in the neurobiology of aging, in part due to extensive interconnectivity of the neural and endocrine system. This aspect of aging is fundamental for women’s brains as all women experience a drop in circulating estradiol levels in midlife, after menopause. Given the importance of estradiol for brain function, it is not surprising that up to 80% of peri-menopausal and post-menopausal women report neurological symptoms including changes in thermoregulation (vasomotor symptoms), mood, sleep, and cognitive performance. Preclinical evidence for neuroprotective effects of 17β-estradiol also indicate associations between menopause, cognitive aging, and Alzheimer’s disease (AD), the most common cause of dementia affecting nearly twice more women than men. Brain imaging studies demonstrated that middle-aged women exhibit increased indicators of AD endophenotype as compared to men of the same age, with onset in perimenopause. Herein, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining cognition in women, with evidence implicating menopause-related declines in 17β-estradiol in cognitive aging and AD risk. We will review research focused on the role of endogenous and exogenous estrogen exposure as a key underlying mechanism to neuropathological aging in women, with a focus on whether brain structure, function and neurochemistry respond to hormone treatment. While still in development, this research area offers a new sex-based perspective on brain aging and risk of AD, while also highlighting an urgent need for better integration between neurology, psychiatry, and women’s health practices.
Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease
Authors: Wang Hongjie , Devadoss Dinesh , Nair Madhavan , Chand Hitendra S. , Lakshmana Madepalli K.
Published: July 2022

Alzheimer’s disease (AD) is complex and highly heterogeneous. Less than 10% of AD cases are early-onset (EOAD) caused by autosomal dominantly inherited mutations in amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), each of which can increase Aβ generation and, thus, amyloid plaques. The remaining 90% of cases of AD are late-onset (LOAD) or sporadic. Intense research efforts have led to identification of many genes that increase the risk of AD. An IQ motif containing protein K (IQCK) was recently identified by several investigators as an Alzheimer’s disease risk gene. However, how IQCK increases AD risk is completely unknown. Since IQCK is a novel gene, there is limited information on its physiological characterization. To understand its role in AD, it is first important to determine its subcellular localization, whether and where it is expressed in the brain, and what type of brain cells express the IQCK protein. Therefore, in this study, we show by immunocytochemical (ICC) staining that IQCK is expressed in both the nucleus and the cytoplasm of SH-SY5Y neuroblastoma cells as well as HeLa cells but not in either HMC3 microglial or CHO cells. By immunohistochemistry (IHC), we also show that IQCK is expressed in both mouse and human neurons, including neuronal processes in vivo in the mouse brain. IHC data also show that the IQCK protein is widely expressed throughout the mouse brain, although regional differences were noted. IQCK expression was highest in the brainstem (BS), followed by the cerebellum (CB) and the cortex (CX), and it was lowest in the hippocampus (HP). This finding was consistent with data from an immunoblot analysis of brain tissue homogenates. Interestingly, we found IQCK expression in neurons, astrocytes, and oligodendrocytes using cell-specific antibodies, but IQCK was not detected in microglial cells, consistent with negative in vitro results in HMC3 cells. Most importantly, we found that actin-normalized IQCK protein levels were increased by 2 folds in AD brains relative to normal control (NC) brains. Furthermore, the IQCK protein was found in amyloid plaques, suggesting that IQCK may play a pathogenic role in either Aβ generation or amyloid plaque deposition in AD.
Phase-dependent Brain Activation of the Frontal and Parietal Regions During Walking After Stroke - An fNIRS Study
Authors: Lim Shannon B. , Yang Chieh-ling , Peters Sue , Liu-Ambrose Teresa , Boyd Lara A. , Eng Janice J.
Published: July 2022

Background

Recovery of walking post-stroke is highly variable. Accurately measuring and documenting functional brain activation characteristics during walking can help guide rehabilitation. Previous work in this area has been limited to investigations of frontal brain regions and have not utilized recent technological and analytical advances for more accurate measurements. There were three aims for this study: to characterize the hemodynamic profile during walking post-stroke, to investigate regional changes in brain activation during different phases of walking, and to related brain changes to clinical measures.

Methods

Functional near-infrared spectroscopy (fNIRS) along the pre-frontal, premotor, sensorimotor, and posterior parietal cortices was used on twenty individuals greater than six months post-stroke. Individual fNIRS optodes were digitized and used to estimate channel locations on each participant and short separation channels were used to control for extracerebral hemodynamic changes. Participants walked at their comfortable pace several times along a hallway while brain activation was recorded. Exploratory cluster analysis was conducted to determine if there was a link between brain activation and clinical measures.

Results

Sustained activation was observed in the pre-frontal cortex with the ipsilesional hemisphere showing greater activation compared to the contralesional side. Sensorimotor cortex was active during the early, acceleration stage of walking only. Posterior parietal cortex showed changes in activation during the later, steady-state stage of walking. Faster gait speeds also related to increased activation in contralesional sensorimotor and posterior parietal cortices. Exploratory analysis clustered participants into two distinct groups based on their brain activation profiles and generally showed that individuals with greater activation tended to have better physical outcomes.

Conclusions

These findings can guide future research for obtaining adequate power and determining factors that can be used as effect modifiers to reduce inter-subject variability. Overall, this is the first study to report specific oxygenated and deoxygenated hemoglobin changes in frontal to parietal regions during walking in the stroke population. Our results shed light on the importance of measuring brain activation across the cortex and show the importance of pre-frontal, sensorimotor, and posterior parietal cortices in walking after a stroke.
Protocol and Preliminary Results of the Establishment of Intracranial Aneurysm Database for Artificial Intelligence Application Based on CTA Images
Authors: You Wei , Sun Yong , Feng Junqiang , Wang Zhiliang , Li Lin , Chen Xiheng , Lv Jian , Tang Yudi , Deng Dingwei , Wei Dachao , Gui Siming , Liu Xinke , Liu Peng , Jin Hengwei , Ge Huijian , Zhang Yanling
Published: July 2022

Background and Purpose

Unruptured intracranial aneurysms (UIAs) are increasingly being detected in clinical practice. Artificial intelligence (AI) has been increasingly used to assist diagnostic techniques and shows encouraging prospects. In this study, we reported the protocol and preliminary results of the establishment of an intracranial aneurysm database for AI application based on computed tomography angiography (CTA) images.

Methods

Through a review of picture archiving and communication systems, we collected CTA images of patients with aneurysms between January 2010 and March 2021. The radiologists performed manual segmentation of all diagnosed aneurysms on subtraction CTA as the basis for automatic aneurysm segmentation. Then, AI will be applied to two stages of aneurysm treatment, namely, automatic aneurysm detection and segmentation model based on the CTA image and the aneurysm risk prediction model.

Results

Three medical centers have been included in this study so far. A total of 3,190 cases of CTA examinations with 4,124 aneurysms were included in the database. All identified aneurysms from CTA images that enrolled in this study were manually segmented on subtraction CTA by six readers. We developed a structure of 3D-Unet for aneurysm detection and segmentation in CTA images. The algorithm was developed and tested using a total of 2,272 head CTAs with 2,938 intracranial aneurysms. The recall and false positives per case (FP/case) of this model for detecting aneurysms were 0.964 and 2.01, and the Dice values for aneurysm segmentation were 0.783.

Conclusion

This study introduces the protocol and preliminary results of the establishment of the intracranial aneurysm database for AI applications based on CTA images. The establishment of a multicenter database based on CTA images of intracranial aneurysms is the basis for the application of AI in the diagnosis and treatment of aneurysms. In addition to segmentation, AI should have great potential for aneurysm treatment and management in the future.
Altered resting-state functional connectivity of insula in children with primary nocturnal enuresis
Authors: Zhong Shaogen , Shen Jiayao , Wang Mengxing , Mao Yi , Du Xiaoxia , Ma Jun
Published: July 2022

Objective

Primary nocturnal enuresis (PNE) is a common developmental condition in school-aged children. The objective is to better understand the pathophysiology of PNE by using insula-centered resting-state functional connectivity (rsFC).

Methods

We recruited 66 right-handed participants in our analysis, 33 with PNE and 33 healthy control (HC) children without enuresis matched for gender and age. Functional and structural MRI data were obtained from all the children. Seed-based rsFC was used to examine differences in insular functional connectivity between the PNE and HC groups. Correlation analyses were carried out to explore the relationship between abnormal insula-centered functional connectivity and clinical characteristics in the PNE group.

Results

Compared with HC children, the children with PNE demonstrated decreased left and right insular rsFC with the right medial superior frontal gyrus (SFG). In addition, the bilateral dorsal anterior insula (dAI) seeds also indicated the reduced rsFC with right medial SFG. Furthermore, the right posterior insula (PI) seed showed the weaker rsFC with the right medial SFG, while the left PI seed displayed the weaker rsFC with the right SFG. No statistically significant correlations were detected between aberrant insular rsFC and clinical variables (e.g., micturition desire awakening, bed-wetting frequency, and bladder volume) in results without global signal regression (GSR) in the PNE group. However, before and after setting age as a covariate, significant and positive correlations between bladder volume and the rsFC of the left dAI with right medial SFG and the rsFC of the right PI with right medial SFG were found in results with GSR in the PNE group.

Conclusion

To the best of our knowledge, this study explored the rsFC patterns of the insula in children with PNE for the first time. These results uncovered the abnormal rsFC of the insula with the medial prefrontal cortex without and with GSR in the PNE group, suggesting that dysconnectivity of the salience network (SN)-default mode network (DMN) may involve in the underlying pathophysiology of children with PNE. However, the inconsistent associations between bladder volume and dysconnectivity of the SN-DMN in results without and with GSR need further studies.
A Century Searching for the Neurons Necessary for Wakefulness
Authors: Grady Fillan S. , Boes Aaron D. , Geerling Joel C.
Published: July 2022

Wakefulness is necessary for consciousness, and impaired wakefulness is a symptom of many diseases. The neural circuits that maintain wakefulness remain incompletely understood, as do the mechanisms of impaired consciousness in many patients. In contrast to the influential concept of a diffuse “reticular activating system,” the past century of neuroscience research has identified a focal region of the upper brainstem that, when damaged, causes coma. This region contains diverse neuronal populations with different axonal projections, neurotransmitters, and genetic identities. Activating some of these populations promotes wakefulness, but it remains unclear which specific neurons are necessary for sustaining consciousness. In parallel, pharmacological evidence has indicated a role for special neurotransmitters, including hypocretin/orexin, histamine, norepinephrine, serotonin, dopamine, adenosine and acetylcholine. However, genetically targeted experiments have indicated that none of these neurotransmitters or the neurons producing them are individually necessary for maintaining wakefulness. In this review, we emphasize the need to determine the specific subset of brainstem neurons necessary for maintaining arousal. Accomplishing this will enable more precise mapping of wakefulness circuitry, which will be useful in developing therapies for patients with coma and other disorders of arousal.
Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine
Authors: Maksemous Neven , Blayney Claire D. , Sutherland Heidi G. , Smith Robert A. , Lea Rod A. , Tran Kim Ngan , Ibrahim Omar , McArthur Jeffrey R. , Haupt Larisa M. , Cader M. Zameel , Finol-Urdaneta Rocio K. , Adams David J. , Griffiths Lyn R.
Published: July 2022

Familial hemiplegic migraine (FHM) is a severe neurogenetic disorder for which three causal genes, CACNA1A, SCN1A, and ATP1A2, have been implicated. However, more than 80% of referred diagnostic cases of hemiplegic migraine (HM) are negative for exonic mutations in these known FHM genes, suggesting the involvement of other genes. Using whole-exome sequencing data from 187 mutation-negative HM cases, we identified rare variants in the CACNA1I gene encoding the T-type calcium channel Cav3.3. Burden testing of CACNA1I variants showed a statistically significant increase in allelic burden in the HM case group compared to gnomAD (OR = 2.30, P = 0.00005) and the UK Biobank (OR = 2.32, P = 0.0004) databases. Dysfunction in T-type calcium channels, including Cav3.3, has been implicated in a range of neurological conditions, suggesting a potential role in HM. Using patch-clamp electrophysiology, we compared the biophysical properties of five Cav3.3 variants (p.R111G, p.M128L, p.D302G, p.R307H, and p.Q1158H) to wild-type (WT) channels expressed in HEK293T cells. We observed numerous functional alterations across the channels with Cav3.3-Q1158H showing the greatest differences compared to WT channels, including reduced current density, right-shifted voltage dependence of activation and inactivation, and slower current kinetics. Interestingly, we also found significant differences in the conductance properties exhibited by the Cav3.3-R307H and -Q1158H variants compared to WT channels under conditions of acidosis and alkalosis. In light of these data, we suggest that rare variants in CACNA1I may contribute to HM etiology.
Probiotic Lactobacillus rhamnosus GR-1 supplementation attenuates Pb-induced learning and memory deficits by reshaping the gut microbiota
Authors: Gu Xiaozhen , Bi Nanxi , Wang Tian , Huang Chengqing , Wang Rongrong , Xu Yi , Wang Hui-Li
Published: July 2022

Lead (Pb) exposure during early life has been associated with an increased risk of neurodevelopmental disorders, including learning and memory deficits. The intestinal flora, via the microbiome–gut–brain axis, could play a significant role in the nervous system. However, the effects of probiotics on ameliorating Pb-induced learning and memory deficits are still unclear. In this study, we showed that adolescent Pb exposure (150 ppm) for 2 months impaired spatial learning and memory ability, accompanied by the decreasing diversity of gut microbiota, and the decreasing abundance of Lactobacillus at the genus level. Surprisingly, administration of the Lactobacillus rhamnosus GR-1 (1010 organisms/rat/day), not L. rhamnosus LGG or Lactobacillus reuteri RC-14, reversed learning and memory deficits induced by Pb exposure. Meanwhile, administration of the L. rhamnosus GR-1 increased the diversity of the gut microbiota composition and partially normalized the genus level of Lactobacillus, Parabacteroides, Enterococcus, and Akkermansia in Pb-exposed rats. Notably, supplementation of L. rhamnosus GR-1 decreased the gut permeability of Pb-exposed rats, reduced proinflammatory cytokines [interleukin-1β (IL-1β) and IL-6] expression, and promoted anti-inflammatory cytokines [granulocyte colony-stimulating factor (G-CSF)] expression. Interestingly, neural cell treatment with G-CSF rescued Pb-induced neurotoxicity. In general, L. rhamnosus GR-1 supplementation recovered the Pb-induced loss of intestinal bacteria (Lactobacillus), which may have reversed the damage to learning and memory ability. Collectively, our findings demonstrate an unexpectedly pivotal role of L. rhamnosus GR-1 in Pb-induced cognitive deficits and identify a potential probiotic therapy for cognitive dysfunction during early life.
Prevalence, correlates, and gender disparities related to eating disordered behaviors among health science students and healthcare practitioners in Lebanon: Findings of a national cross sectional study
Authors: Hoteit Maha , Mohsen Hala , Bookari Khlood , Moussa Ghadir , Jurdi Najwa , Yazbeck Nour
Published: July 2022

Background

The raised prevalence of eating disorders (ED) amongst health science students and health professionals is of mounting concern. This study aims to determine the prevalence and correlates of eating disorders risk amongst a sample of Lebanese health science students and healthcare practitioners of both genders.

Methods

This cross-sectional study enrolled a convenient sample of 1,000 participants (mean age: 23 ± 5.4; females: 74.9%) from faculties of health sciences, clinics, pharmacies, and hospitals. The validated Eating Attitudes Test (EAT-26) was used to screen for eating disorders. Anthropometric data were self-reported by respondents to assess their nutritional status.

Results

The risk of eating disorders was prevalent in 22.5% of participants. Females were at higher risk of ED compared to males p = 0.03. Eating disorders risk did not differ between students and practitioners (p = 0.3). The highest proportion of high-risk participants were students studying nutrition and practitioners (40.9%), outracing their counterparts in nursing (18.7%), medicine (17.8%), pharmacy (17.7%), and midwifery (4.9%) sciences (p = 0.02). Most high-risk participants had normal body weight (60.4%), and 28.9% were overweight (p = 0.001). Female gender, nutrition profession, and dieting were associated with increasing the odd of ED. Particularly, dieting increased the risk around five times. Further, each 3 participants over 10 were facing binge eating behavior.

Conclusion

This study uncovers an undervalued profession-related-health-disorder in Lebanese health science students and healthcare practitioners. Specific attention should be given to EDs in professional educational programmes across healthcare disciplines.
Predictive Value of the Log Odds of Negative Lymph Nodes/T Stage as a Novel Prognostic Factor in Bladder Cancer Patients After Radical Cystectomy
Authors: Chen Tao , Zhan Xiangpeng , Chen Xinpeng , Jiang Ming , Wan Hao , Fu Bin , Chen Luyao
Published: July 2022

Background

The effect of lymph node resection on the prognosis of bladder cancer (BLCA) patients receiving radical cystectomy should not be ignored. Our aim was to explore the prognostic value of the log odds of negative lymph nodes/T stage (LONT) and construct a more effective nomogram based on LONT to predict cancer-specific survival (CSS) in postoperative BLCA patients.

Methods

Patients diagnosed with BLCA after radical cystectomy between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were enrolled. We randomly split (7:3) these patients into the primary cohort and internal validation cohort. 86 patients from the First Affiliated Hospital of Nanchang University were collected as the external validation set. Univariate and multivariate cox regression analyses were carried out to seek prognostic factors of postoperative BLCA patients. According to these significantly prognostic factors, a simple-to-use nomogram was established for predicting CSS. Their performances were evaluated by using calibration curves, the concordance index (C-index), the receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). In addition, different risk groups were tested by Kaplan-Meier curves and log-rank tests.

Result

Whether in cancer-specific survival (CSS) or overall survival (OS), LONT was an independent and significant prognostic factor. Through further screening, the ultimate nomogram of CSS was composed of nine independent prognostic factors including LONT, age, race, tumor size, histologic type, T stage, N stage, summary stage and chemotherapy. The C-index of nomogram in the primary cohort, internal and external validation cohort were 0.734, 0.720 and 0.728, respectively. The AUC of predicting CSS at 3 and 5 years were 0.783 and 0.774 in the primary cohort and 0.781 and 0.781 in the validation cohort. The results of calibration and DCA showed good concordance and clinical applicability. Significant differences (P < 0.05) were displayed in CSS among different risk groups.

Conclusion

LONT was regarded as a novel and reliable prognostic factor. Compared with the AJCC staging system, the established nomogram based on LONT can more effectively predict the prognosis of BLCA patients after radical cystectomy.
A Cross-Comparison of High-Throughput Platforms for Circulating MicroRNA Quantification, Agreement in Risk Classification, and Biomarker Discovery in Non-Small Cell Lung Cancer
Authors: Gargiuli Chiara , De Cecco Loris , Mariancini Andrea , Iannò Maria Federica , Micali Arianna , Mancinelli Elisa , Boeri Mattia , Sozzi Gabriella , Dugo Matteo , Sensi Marialuisa
Published: July 2022

Background

Circulating microRNAs (ct-miRs) are promising cancer biomarkers. This study focuses on platform comparison to assess performance variability, agreement in the assignment of a miR signature classifier (MSC), and concordance for the identification of cancer-associated miRs in plasma samples from non‐small cell lung cancer (NSCLC) patients.

Methods

A plasma cohort of 10 NSCLC patients and 10 healthy donors matched for clinical features and MSC risk level was profiled for miR expression using two sequencing-based and three quantitative reverse transcription PCR (qPCR)-based platforms. Intra- and inter-platform variations were examined by correlation and concordance analysis. The MSC risk levels were compared with those estimated using a reference method. Differentially expressed ct-miRs were identified among NSCLC patients and donors, and the diagnostic value of those dysregulated in patients was assessed by receiver operating characteristic curve analysis. The downregulation of miR-150-5p was verified by qPCR. The Cancer Genome Atlas (TCGA) lung carcinoma dataset was used for validation at the tissue level.

Results

The intra-platform reproducibility was consistent, whereas the highest values of inter-platform correlations were among qPCR-based platforms. MSC classification concordance was >80% for four platforms. The dysregulation and discriminatory power of miR-150-5p and miR-210-3p were documented. Both were significantly dysregulated also on TCGA tissue-originated profiles from lung cell carcinoma in comparison with normal samples.

Conclusion

Overall, our studies provide a large performance analysis between five different platforms for miR quantification, indicate the solidity of MSC classifier, and identify two noninvasive biomarkers for NSCLC.
Tuberous Sclerosis Complex With Multiple Organ Tumors: Case Report and Literature Review
Authors: Zhang Xinhe , Zhong Xinping , Lin Xuyong , Li Xuedan , Tian Haoyu , Chang Bing , Wang Ying , Tong Jing , Wang Ningning , Li Dan , Jin Xiuli , Huang Die , Wang Yanmeng , Cui Huipeng , Guan Lin , Li Yiling
Published: July 2022

Pancreatic neuroendocrine neoplasms (PNEN) are tumors that originate from neuroendocrine cells. Only about 1% patients are related to mutation of tuberous sclerosis complex gene. Here, we reported a rare case with involvement of multiple organs and space-occupying lesions. Initially, the patient was thought to have metastasis of a pancreatic tumor. However, the patient was diagnosed as pancreatic neuroendocrine tumors, liver perivascular epithelioid tumors, splenic hamartoma, and renal angiomyolipoma by pathological examination after surgery. We performed genetic mutation detection to identify that tuberous sclerosis complex 2 gene presented with a heterozygous variant. Tuberous sclerosis often presents with widespread tumors, but it is less common to present with pancreatic neuroendocrine tumors and liver perivascular tumors as highlighted in the case. So we analyzed the relationship between TSC gene mutations and related tumors. And we also reviewed the current molecular mechanisms and treatments for tuberous sclerosis complex.
Indocyanine green fluorescence-guided laparoscopic hepatectomy versus conventional laparoscopic hepatectomy for hepatocellular carcinoma: A single-center propensity score matching study
Authors: Jianxi Wang , Xiongfeng Zou , Zehao Zheng , Zhen Zhao , Tianyi Peng , Ye Lin , Haosheng Jin , Zhixiang Jian , Huiling Wang
Published: July 2022

Background

Indocyanine green fluorescence-guided laparoscopic hepatectomy (ICG-guided LH) is increasingly used for the treatment of hepatocellular carcinoma (HCC). However, whether ICG-guided LH can improve surgical outcomes remains unclear. This study aimed to investigate the short-term outcomes and survival outcomes of ICG-guided LH versus common laparoscopic hepatectomy (CLH) for HCC.

Methods

We conducted a retrospective analysis of 104 ICG-guided LH and 158 CLH patients from 2014 to 2020 at our center. To avoid selection bias, 81 ICG-guided LH and 81 CLH cases were analyzed after 1:1 propensity score matching (PSM). The baseline data and results were compared between the two groups.

Results

The baseline characteristics of both groups were comparable after matching. There was a significant difference in operative time: longer in the ICG-guided LH group than in the CLH group (p=0.004). However, there was no significant difference in operative time in anatomical resection between the two groups (p=0.987). There was a significant difference in operative time in non-anatomical resection: longer in the ICG-guided LH group than in the CLH group (p=0.001). There were no significant differences in positive surgery margin, blood loss, blood transfusion rate, postoperative complication rate, postoperative length of hospital stay, mortality within 30 days, and mortality within 90 days. The ICG-guided LH group appeared to have a trend towards better overall survival (OS), but there was no significant difference in OS (P=0.168) and recurrence-free survival (RFS) (P=0.322) between the two groups.

Conclusions

Although ICG fluorescence-guided LH is a timelier procedure to perform, it is a safe and effective technique with the advantages of intraoperative positioning, low postoperative complication rates, and potential to improve OS.
Cell-Free DNA Sequencing of Intraocular Fluid as Liquid Biopsy in the Diagnosis of Vitreoretinal Lymphoma
Authors: Gu Junxiang , Jiang Tingting , Liu Shixue , Ping Bo , Li Ruiwen , Chen Wenwen , Wang Ling , Huang Xin , Xu Gezhi , Chang Qing
Published: July 2022

Purpose

To seek novel diagnostic approaches, we improved the workflow of cell-free DNA (cfDNA) sequencing and evaluated its feasibility in vitreoretinal lymphoma (VRL) specimens; the profile of mutations was preliminarily analyzed for potential diagnostic value.

Methods

The study was a diagnostic trial. 23 eyes of 23 patients with VRL and 25 eyes of 25 patients with inflammatory eye diseases were enrolled. Approximate 500μl undiluted vitreous humor and 10ml diluted vitreous fluid was obtained through diagnostic vitrectomy and sent for cytopathological examinations. 500μl of the diluted vitreous fluid was spared for cfDNA sequencing. For cfDNA sequencing, DNA fragmentation procedure was added to the workflow to improve the extraction efficiency; mutations detected were analyzed for potential diagnostic model. The sensitivity and specificity of the cytopathology and cfDNA sequencing were compared. The clinical manifestations were preliminarily analyzed for potential correlations with the genotypes.

Results

CfDNA sequencing was accomplished in 23 eyes with VRL and 20 eyes with inflammatory eye diseases. VRL-related mutated genes included MYD88 (18 eyes, 78%), ETV6 (11 eyes, 48%), PIM1 (11 eyes,48%), BTG2 (7 eyes, 30%), IRF4 (7 eyes, 30%), CD79B (6 eyes, 26%), LRP1B (6 eyes, 26%), etc. Logistic regression based on the mutations of MYD88 and ETV6 was of the potential for the diagnosis of VRL (P<0.001, adjusted R2 = 0.789, sensitivity 0.913, specificity 0.950); by comparison, the sensitivity and specificity of the vitreous cytopathology were 0.826 and 1.000, respectively. Further analysis of the mutation profile showed that patients carrying CD79B mutation tended to have higher intraocular interleukin-10 level (P=0.030), that CARD11 mutation was correlated with younger age at ocular onset (P=0.039), and that patients with intracranial involvement carried more multiple-site mutations in the BTG2 gene (P=0.013).

Conclusions

The improved workflow of CfDNA sequencing is of sound feasibility in a limited amount of vitreous humor. The logistic model based on the mutations could help to provide reliable clues for the diagnosis of VRL.
Beyond N staging in colorectal cancer: Current approaches and future perspectives
Authors: Arrichiello Gianluca , Pirozzi Mario , Facchini Bianca Arianna , Facchini Sergio , Paragliola Fernando , Nacca Valeria , Nicastro Antonella , Canciello Maria Anna , Orlando Adele , Caterino Marianna , Ciardiello Davide , Della Corte Carminia Maria , Fasano Morena , Napolitano Stefania , Troiani Teresa , Ciardiello Fortunato , Martini Giulia , Martinelli Erika
Published: July 2022

Traditionally, lymph node metastases (LNM) evaluation is essential to the staging of colon cancer patients according to the TNM (tumor–node–metastasis) system. However, in recent years evidence has accumulated regarding the role of emerging pathological features, which could significantly impact the prognosis of colorectal cancer patients. Lymph Node Ratio (LNR) and Log Odds of Positive Lymph Nodes (LODDS) have been shown to predict patients’ prognosis more accurately than traditional nodal staging and it has been suggested that their implementation in existing classification could help stratify further patients with overlapping TNM stage. Tumor deposits (TD) are currently factored within the N1c category of the TNM classification in the absence of lymph node metastases. However, studies have shown that presence of TDs can affect patients’ survival regardless of LNM. Moreover, evidence suggest that presence of TDs should not be evaluated as dichotomic but rather as a quantitative variable. Extranodal extension (ENE) has been shown to correlate with presence of other adverse prognostic features and to impact survival of colorectal cancer patients. In this review we will describe current staging systems and prognostic/predictive factors in colorectal cancer and elaborate on available evidence supporting the implementation of LNR/LODDS, TDs and ENE evaluation in existing classification to improve prognosis estimation and patient selection for adjuvant treatment.
Case Report: Clinicopathological Analysis of Minute Pulmonary Meningothelial-Like Nodules: Report of 7 Cases
Authors: Wang Ying-xia , Lei Zi , Yang Man , Wang Zhi-yuan , Zhang Xuan , Pan Guo-qing
Published: July 2022

Objective

To investigate the clinical manifestations, radiologic features, pathological features, and immunophenotype of minute pulmonary meningothelial-like nodules (MPMNs).

Method

This is a retrospective observational study. We collected the clinical data of 7 cases of MPMNs, and performed comprehensive characterization using a combination of clinical, morphological, radiologic and immunohistochemical assessments.

Results

Of the 7 cases of MPMNs, 6 were female and 1 was male. The median age was 55 years. All MPMNs were multiple in lung with the size from 0,01 to 0,5cm. Chest CT examination showed ground-glass attenuation or solid nodules. Four cases were concomitant with carcinoma and/or pneumonia, and 3 cases occurred alone. Four of the 7 patients had no obvious symptoms; 3 patients had chest pain or cough or shortness of breath or hemoptysis. Multiple white nodules were found macroscopically, and the diseased cells grew along the alveolar septum, with relatively normal morphology, rich cytoplasm, unclear cell boundary, and uniform nucleus with delicate chromatin and without atypia; and the diseased cells showed nest or whorls distribution. EMA, PR, CD56 and vimentin were positive in all cases by immunohistochemistry.

Conclusions

MPMNs are rare benign lesions in the lung, often multiple, usually less than 0.5cm in diameter, most of which have no obvious clinical symptoms. MPMNs are often found by chest CT, and occur independently or concomitant with other lesions. The positive immunohistochemical staining of EMA, PR, CD56, vimentin supports the diagnosis.
The Improvement Effect of D-Chiro-Inositol and Ecklonia cava K. in the Rat Model of Polycystic Ovarian Syndrome
Authors: Yang Hyun , Lee Sang R. , Jo Seong Lae , Kim Ae-Hyang , Kim Eun-Ryoung , Qu Fan , Hong Eui-Ju , Lee Hye Won
Published: July 2022

Introduction: Polycystic Ovarian Syndrome (PCOS) is known to be an endocrine state that is characterized by oligomenorrhea, hyperandrogenism, and highly cystic follicles in the ovaries. The use of food ingredients and traditional medicine in Asian countries is well known, and previous studies have shown that Ecklonia cava K. [Alariaceae] (EC) is able to alleviate PCOS symptoms. D-Chiro-inositol (DCI) administration in pathologies where steroid biosynthesis is a crucial factor, i.e., PCOS, has provided satisfactory results.

Methods: Therefore, we studied the synergistic effects of the two previously known active compounds. In rats with letrozole-induced PCOS, we focused on alternative therapies using EC and/or DCI extracts to alleviate ovarian failure.

Results: As a nonsteroidal aromatase inhibitor, letrozole inhibits the conversion of testosterone to estrogen and subsequently causes PCOS. We divided 6-week-old female mice into the following six groups and evaluated them: vehicle, PCOS, PCOS + MET (metformin), PCOS + DCI, PCOS + EC, and PCOS + DCI + EC. In our study, PCOS rats treated with EC and DCI had low serum LH and T levels and low serum levels of inflammatory cytokines such as TNFα and IL-6. These treatments also appeared to regulate the production of factors that affect follicle formation and inflammation in the ovaries.

Conclusion: We concluded that EC extract and/or DCI administration influenced aromatase production and reduced LH and T stimulation, and cotreatment with EC and DCI consequently restored ovarian dysfunction or anti-inflammatory responses in rats with PCOS-like symptoms.
Biotransformation, Pharmacokinetics, and Pharmacological Activities of Ginsenoside Rd Against Multiple Diseases
Authors: Li Jing , Huang Qingxia , Yao Yao , Ji Peng , Mingyao E. , Chen Jinjin , Zhang Zepeng , Qi Hongyu , Liu Jiaqi , Chen Zhaoqiang , Zhao Daqing , Zhou Lei , Li Xiangyan
Published: July 2022

Panax ginseng C.A. Mey. has a history of more than 4000 years and is widely used in Asian countries. Modern pharmacological studies have proved that ginsenosides and their compounds have a variety of significant biological activities on specific diseases, including neurodegenerative diseases, certain types of cancer, gastrointestinal disease, and metabolic diseases, in which most of the interest has focused on ginsenoside Rd. The evidentiary basis showed that ginsenoside Rd ameliorates ischemic stroke, nerve injury, cancer, and other diseases involved in apoptosis, inflammation, oxidative stress, mitochondrial damage, and autophagy. In this review, we summarized available reports on the molecular biological mechanisms of ginsenoside Rd in neurological diseases, cancer, metabolic diseases, and other diseases. We also discussed the main biotransformation pathways of ginsenoside Rd obtained by fermentation.
Fluorescent Probes Design Strategies for Imaging Mitochondria and Lysosomes
Authors: Chen Huimin , Yu Zhenjie , Ren Shiwei , Qiu Yuyu
Published: July 2022

Modern cellular biology faces several major obstacles, such as the determination of the concentration of active sites corresponding to chemical substances. In recent years, the popular small-molecule fluorescent probes have completely changed the understanding of cellular biology through their high sensitivity toward specific substances in various organisms. Mitochondria and lysosomes are significant organelles in various organisms, and their interaction is closely related to the development of various diseases. The investigation of their structure and function has gathered tremendous attention from biologists. The advanced nanoscopic technologies have replaced the diffraction-limited conventional imaging techniques and have been developed to explore the unknown aspects of mitochondria and lysosomes with a sub-diffraction resolution. Recent progress in this field has yielded several excellent mitochondria- and lysosome-targeted fluorescent probes, some of which have demonstrated significant biological applications. Herein, we review studies that have been carried out to date and suggest future research directions that will harness the considerable potential of mitochondria- and lysosome-targeted fluorescent probes.
Population Pharmacokinetics and Pharmacodynamics of Isoniazid and its Metabolite Acetylisoniazid in Chinese Population
Authors: Chen Bing , Shi Hao-Qiang , Feng Meihua Rose , Wang Xi-Han , Cao Xiao-Mei , Cai Wei-Min
Published: July 2022

Objective: We aimed to establish a population pharmacokinetic (PPK) model for isoniazid (INH) and its major metabolite Acetylisoniazid (AcINH) in healthy Chinese participants and tuberculosis patients and assess the role of the NAT2 genotype on the transformation of INH to AcINH. We also sought to estimate the INH exposure that would achieve a 90% effective concentration (EC90) efficiency for patients with various NAT2 genotypes.

Method: A total of 45 healthy participants and 157 tuberculosis patients were recruited. For healthy subjects, blood samples were collected 0–14 h after administration of 300 mg or 320 mg of the oral dose of INH; for tuberculosis patients who received at least seven days therapy with INH, blood samples were collected two and/or six hours after administration. The plasma concentration of INH and AcINH was determined by the reverse-phase HPLC method. NAT2 genotypes were determined by allele-specific amplification. The integrated PPK model of INH and AcINH was established through nonlinear mixed-effect modeling (NONMEM). The effect of NAT2 genotype and other covariates on INH and AcINH disposition was evaluated. Monte Carlo simulation was performed for estimating EC90 of INH in patients with various NAT2 genotypes.

Results: The estimated absorption rate constant (Ka), oral clearance (CL/F), and apparent volume of distribution (V2/F) for INH were 3.94 ± 0.44 h−1, 18.2 ± 2.45 L⋅h−1, and 56.8 ± 5.53 L, respectively. The constant of clearance (K30) and the volume of distribution (V3/F) of AcINH were 0.33 ± 0.11 h−1 and 25.7 ± 1.30 L, respectively. The fraction of AcINH formation (FM) was 0.81 ± 0.076. NAT2 genotypes had different effects on the CL/F and FM. In subjects with only one copy of NAT2 *5, *6, and *7 alleles, the CL/F values were approximately 46.3%, 54.9%, and 74.8% of *4/*4 subjects, respectively. The FM values were approximately 48.7%, 63.8%, and 86.9% of *4/*4 subjects, respectively. The probability of target attainment of INH EC90 in patients with various NAT2 genotypes was different.

Conclusion: The integrated parent-metabolite PPK model accurately characterized the disposition of INH and AcINH in the Chinese population sampled, which may be useful in the individualized therapy of INH.
Butyrate Treatment of DSS-Induced Ulcerative Colitis Affects the Hepatic Drug Metabolism in Mice
Authors: Jourova Lenka , Satka Stefan , Frybortova Veronika , Zapletalova Iveta , Anzenbacher Pavel , Anzenbacherova Eva , Hermanova Petra Petr , Drabonova Barbora , Srutkova Dagmar , Kozakova Hana , Hudcovic Tomas
Published: July 2022

The development of inflammatory bowel disease (IBD) is associated with alterations in the gut microbiota. There is currently no universal treatment for this disease, thus emphasizing the importance of developing innovative therapeutic approaches. Gut microbiome-derived metabolite butyrate with its well-known anti-inflammatory effect in the gut is a promising candidate. Due to increased intestinal permeability during IBD, butyrate may also reach the liver and influence liver physiology, including hepatic drug metabolism. To get an insight into this reason, the aim of this study was set to clarify not only the protective effects of the sodium butyrate (SB) administration on colonic inflammation but also the effects of SB on hepatic drug metabolism in experimental colitis induced by dextran sodium sulfate (DSS) in mice. It has been shown here that the butyrate pre-treatment can alleviate gut inflammation and reduce the leakiness of colonic epithelium by restoration of the assembly of tight-junction protein Zonula occludens-1 (ZO-1) in mice with DSS-induced colitis. In this article, butyrate along with inflammation has also been shown to affect the expression and enzyme activity of selected cytochromes P450 (CYPs) in the liver of mice. In this respect, CYP3A enzymes may be very sensitive to gut microbiome-targeted interventions, as significant changes in CYP3A expression and activity in response to DSS-induced colitis and/or butyrate treatment have also been observed. With regard to medications used in IBD and microbiota-targeted therapeutic approaches, it is important to deepen our knowledge of the effect of gut inflammation, and therapeutic interventions were followed concerning the ability of the organism to metabolize drugs. This gut–liver axis, mediated through inflammation as well as microbiome-derived metabolites, may affect the response to IBD therapy.
Semantic Cues Modulate Children’s and Adults’ Processing of Audio-Visual Face Mask Speech
Authors: Schwarz Julia , Li Katrina Kechun , Sim Jasper Hong , Zhang Yixin , Buchanan-Worster Elizabeth , Post Brechtje , Gibson Jenny Louise , McDougall Kirsty
Published: July 2022

During the COVID-19 pandemic, questions have been raised about the impact of face masks on communication in classroom settings. However, it is unclear to what extent visual obstruction of the speaker’s mouth or changes to the acoustic signal lead to speech processing difficulties, and whether these effects can be mitigated by semantic predictability, i.e., the availability of contextual information. The present study investigated the acoustic and visual effects of face masks on speech intelligibility and processing speed under varying semantic predictability. Twenty-six children (aged 8-12) and twenty-six adults performed an internet-based cued shadowing task, in which they had to repeat aloud the last word of sentences presented in audio-visual format. The results showed that children and adults made more mistakes and responded more slowly when listening to face mask speech compared to speech produced without a face mask. Adults were only significantly affected by face mask speech when both the acoustic and the visual signal were degraded. While acoustic mask effects were similar for children, removal of visual speech cues through the face mask affected children to a lesser degree. However, high semantic predictability reduced audio-visual mask effects, leading to full compensation of the acoustically degraded mask speech in the adult group. Even though children did not fully compensate for face mask speech with high semantic predictability, overall, they still profited from semantic cues in all conditions. Therefore, in classroom settings, strategies that increase contextual information such as building on students’ prior knowledge, using keywords, and providing visual aids, are likely to help overcome any adverse face mask effects.