Impact of litter size on the hematological and iron status of gilts, sows and newborn piglets: a comparative study of domestic pigs and wild boars.

BACKGROUND: The critically low hepatic iron stores of newborn piglets are considered to be a major cause of neonatal iron deficiency in modern breeds of domestic pig (Sus domestica). The main factor believed to contribute to this phenomenon is large litter size, which has been an objective of selective breeding of pigs for decades. As consequence, iron transferred from the pregnant sow has to be distributed among a greater number of fetuses. RESULTS: Here, we investigated whether litter size influences red blood cell (RBC) indices and iron parameters in Polish Large White (PLW) piglets and gilts. Small and large litters were produced by the transfer of different numbers of embryos, derived from the same superovulated donor females, to recipient gilts. Piglets from large litters obtained following routine artificial insemination were also examined. Our results clearly demonstrated that varying the number of piglets in a litter did not affect the RBC and iron status of 1-day-old piglets, with all showing iron deficiency anemia. In contrast, gilts with small litters displayed higher RBC and iron parameters compared to mothers with large litters. A comparative analysis of the RBC status of wild boars (having less than half as many piglets per litter as domestic pigs) and PLW pigs, demonstrated higher RBC count, hemoglobin level and hematocrit value of both wild boar sows and piglets, even compared to small-litter PLW animals. CONCLUSIONS: These findings provide evidence that RBC and iron status in newborn PLW piglets are not primarily determined by litter size, and indicate the need to study the efficiency of iron transport across the placenta in domestic pig and wild boar females.

Multifaceted physiological and therapeutical impact of curcumin on hormone-related endocrine dysfunctions: A comprehensive review.

Over the past five decades, Curcumin (Cur), derived from turmeric (Curcuma longa), has gained considerable attention for its potential therapeutic applications. Synthesizing insights from clinical trials conducted over the last 25 years, this review delves into diseases where Cur has demonstrated promise, offering a nuanced understanding of its pharmacokinetics, safety, and effectiveness. Focusing on specific examples, the impact of Cur on various human diseases is explored. Endocrine glands and associated signaling pathways are highlighted, elucidating how Cur influences cellular signaling. The article underscores molecular mechanisms such as hormone level alteration, receptor interaction, cytokine and adipokine expression inhibition, antioxidant enzyme activity, and modulation of transcription factors. Cur showcases diverse protective mechanisms against inflammation and oxidative damage by suppressing antiapoptotic genes and impeding tumor promotion. This comprehensive overview emphasizes the potential of Cur as a natural agent for countering aging and degenerative diseases, calling for further dedicated research in this realm.

[Correlation between clinical phenotypes and genotypes among 46 children with SCN1A-related developmental epileptic encephalopathy].

OBJECTIVE: To explore the correlation between clinical phenotypes and genotypes among 46 children with SCN1A-related developmental epileptic encephalopathy (DEE). METHODS: Clinical data of 46 children with DEE and SCN1A variants identified at the Guangzhou Women and Children's Medical Center between January 2018 and June 2022 were collected. The children were grouped based on their age of onset, clinical manifestations, neurodevelopmental status, and results of genetic testing. The correlation between SCN1A genotypes and clinical phenotypes was analyzed. RESULTS: Among the 46 patients, 2 children (4.35%) had developed the symptoms before 3 months of age, 42 (91.30%) were between 3 to 9 months, and 2 cases (4.35%) were after 10 months. Two cases (4.35%) presented with epilepsy of infancy with migrating focal seizures (EIMFS), while 44 (95.7%) had presented with Dravet syndrome (DS), including 28 cases (63.6%) with focal onset (DS-F), 13 cases (29.5%) with myoclonic type (DS-M), 1 case (2.27%) with generalized type (DS-G), and 2 cases (4.55%) with status epilepticus type (DS-SE). Both of the two EIMFS children had severe developmental delay, and among the DS patients, 7 cases had normal development, while the remaining had developmental delay. A total of 44 variants were identified through genetic sequencing, which included 16 missense variants and 28 truncating variants. All EIMFS children had carried the c.677C>T (p.Thr226Met) missense variant. In the DS group, there was a significant difference in the age of onset between the missense variants group and the truncating variants group (P < 0.05). Missense variants were more common in D1 (7/15, 46.7%) and pore regions (8/15, 53.3%), while truncating variants were more common in D1 (12/28, 42.9%). Children with variants outside the pore region were more likely to develop myoclonic seizures. CONCLUSION: The clinical phenotypes of DEE are diverse. There is a difference in the age of onset between individuals with truncating and missense variants in the SCN1A gene. Missense variants outside the pore region are associated with a higher incidence of myoclonic seizures.

A novel model of subretinal edema induced by DL-alpha aminoadipic acid.

In this study we described a new model of subretinal edema induced by single intraocular injection of DL-alpha-aminoadipic acid (DLAAA) that can be employed to study the mechanism of retinal edema and test the efficacy or potential toxicity of treatments. The progression of subretinal edema was evaluated by fundus photography, fluorescein angiography and optical coherence tomography for up to 4 weeks following DLAAA injection. The VEGF, IL-6, TNF-α, Occludin, ZO-1, AQP4, Kir4.1, GFAP and GS levels were examined in DLAAA models by immunostaining, immumohistochemical staining and Western blot. Additionally, bulk RNA-seq was used to detect the mechanism involved in DLAAA-induced retinal Müller cellular injuries. In vivo and vitro assays were further conducted to confirm the sequencing results. Subretinal edema was successfully induced by DLAAA in New Zealand White rabbits (1.29 mg/eye) and C57BL/6 mice (50 or 100 µg/eye). Our results demonstrated that the disruption of blood-retinal-barrier, including vascular hyperpermeability, inflammation, and Müller cell dysfunction of fluid clearance, was involved in subretinal edema formation in the model. Bulk RNA-seq and in vitro studies indicated the activation of p38 MAPK signaling pathway in DLAAA models. This DLAAA-induced subretinal edema model can be used for mechanistic studies or drug screening.

Copper-Catalyzed Transamidation of Unactivated Secondary Amides via C-H and C-N Bond Simultaneous Activations.

Here, we demonstrate that α-C-H and C-N bonds of unactivated secondary amides can be activated simultaneously by the copper catalyst to synthesize α-ketoamides or α-ketoesters in one step, which is a challenging and underdeveloped transformation. Using copper as a catalyst and air as an oxidant, the reaction is compatible with a broad range of acetoamides, amines, and alcohols. The preliminary mechanism studies and density functional theory calculation indicated that the reaction process may undergo first radical α-oxygenation and then transamidation with the help of the resonant six-membered N,O-chelation and molecular oxygen plays a role as an initiator to trigger the transamidation process. The combination of chelation assistance and dioxygen selective oxygenation strategy would substantially extend the modern mild synthetic amide cleavage toolbox, and we envision that this broadly applicable method will be of great interest in the biopharmaceutical industry, synthetic chemistry, and agrochemical industry.

Artificial intelligence techniques for neuropathological diagnostics and research.

Artificial intelligence (AI) research began in theoretical neurophysiology, and the resulting classical paper on the McCulloch-Pitts mathematical neuron was written in a psychiatry department almost 80 years ago. However, the application of AI in digital neuropathology is still in its infancy. Rapid progress is now being made, which prompted this article. Human brain diseases represent distinct system states that fall outside the normal spectrum. Many differ not only in functional but also in structural terms, and the morphology of abnormal nervous tissue forms the traditional basis of neuropathological disease classifications. However, only a few countries have the medical specialty of neuropathology, and, given the sheer number of newly developed histological tools that can be applied to the study of brain diseases, a tremendous shortage of qualified hands and eyes at the microscope is obvious. Similarly, in neuroanatomy, human observers no longer have the capacity to process the vast amounts of connectomics data. Therefore, it is reasonable to assume that advances in AI technology and, especially, whole-slide image (WSI) analysis will greatly aid neuropathological practice. In this paper, we discuss machine learning (ML) techniques that are important for understanding WSI analysis, such as traditional ML and deep learning, introduce a recently developed neuropathological AI termed PathoFusion, and present thoughts on some of the challenges that must be overcome before the full potential of AI in digital neuropathology can be realized.

Levetiracetam may be an unsuitable choice for patients with PRRT2-associated self-limited infantile epilepsy.

INTRODUCTION: Self-limited infantile epilepsy (SeLIE) is a benign epilepsy. Previous studies have shown that monotherapy with most antiseizure medications can effectively relieve seizures in patients with SeLIE, but the efficacy of levetiracetam has not been investigated. OBJECTIVE: This study aimed to investigate the efficacy of levetiracetam in the treatment of SeLIE patients with PRRT2 mutations. METHODS: The clinical data of 39 SeLIE patients (21 males and 18 females, aged 4.79 ± 1.60 months) with pathogenic variants in PRRT2 or 16p11.2 microdeletion were retrospectively analyzed. Based on the use of initial antiseizure medication (ASM), the patients were classified into two groups: Levetiracetam group (LEG) and Other ASMs group (OAG). The difference of efficacy between the two groups was compared. RESULTS: Among the 39 SeLIE patients, 16 were LEG (10 males and 6 females, aged 5.25 ± 2.07 months), with whom two obtained a seizure-free status (12.50%) and 14 ineffective or even deteriorated (87.50%). Among the 14 ineffective or deteriorated cases, 13 were seizure-controlled after replacing levetiracetam with other ASMs including topiramate, oxcarbazepine, lamotrigine, and valproate, and the remaining one finally achieved remission at age 3. Of the 39 patients, 23 were OAG (11 males and 12 females; aged 4.48 ± 1.12 months), of whom 22 achieved seizure remission, except for one patient who was ineffective with topiramate initially and relieved by oxcarbazepine instead. Although there were no significant differences in gender and age of onset between the two groups, the effective rate was significantly different (12.50% in LEG vs. 95.65% in OAG) (P < 0.01). CONCLUSION: The findings showed that patients with SeLIE caused by the PRRT2 mutations did not benefit from the use of levetiracetam, but could benefit from other ASMs.

Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge.

Necroptosis, an actively researched form of programmed cell death closely related to the inflammatory response, is important in a variety of disorders and diseases. However, the relationship between necroptosis and muscle protein degradation in cachexia is rarely reported. This study aimed to elucidate whether necroptosis played a crucial role in muscle protein degradation in a cachexia model of weaned piglets induced by lipopolysaccharide (LPS). In Experiment 1, the piglets were intraperitoneally injected with LPS to construct the cachexia model, and sacrificed at different time points after LPS injection (1, 2, 4, 8, 12, and 24 h). In Experiment 2, necrostatin-1 (Nec-1), a necroptosis blocker, was pretreated in piglets before the injection of LPS to inhibit the occurrence of necroptosis. Blood and longissimus dorsi muscle samples were collected for further analysis. In the piglet model with LPS-induced cachexia, the morphological and ultrastructural damage, and the release of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were dynamically elicited in longissimus dorsi muscle. Further, protein concentration and protein/DNA ratio were dynamically decreased, and protein degradation signaling pathway, containing serine/threonine kinase (Akt), Forkhead box O (FOXO), muscular atrophy F-box (MAFbx), and muscle ring finger protein 1 (MuRF1), was dynamically activated in piglets after LPS challenge. Moreover, mRNA and protein expression of necroptosis signals including receptor-interacting protein kinase (RIP)1, RIP3, and mixed lineage kinase domain-like pseudokinase (MLKL), were time-independently upregulated. Subsequently, when Nec-1 was used to inhibit necroptosis, the morphological damage, the increase in expression of pro-inflammatory cytokines, the reduction in protein content and protein/DNA ratio, and the activation of the protein degradation signaling pathway were alleviated. These results provide the first evidence that necroptosis mediates muscle protein degradation in cachexia by LPS challenge.

[Genetic analysis of a child with developmental disorder and epilepsy due to a homozygous variant of PIGW gene].

OBJECTIVE: To explore the genetic basis for a child featuring global developmental disorder with epilepsy. METHODS: A child who had presented at Guangzhou Women and Children's Medical Center in July 2022 was selected as the study subject. Clinical data was collected. Potential variant was detected by whole exome sequencing (WES). Candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a three-year-old ethnic Zhuang Chinese girl, had presented with global developmental disorder and epilepsy, for which rehabilitation therapy was ineffective. Genetic testing revealed that she has harbored a homozygous c.821T>C (p.Leu274Pro) missense variant of the PIGW gene, for which both of her parents and sister were heterozygous carriers. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as variant of uncertain significance. CONCLUSION: The homozygous c.821T>C (p.Leu274Pro) variant of the PIGW gene probably underlay the onset of disease in this child. Above finding has enriched the mutational spectrum of the PIGW gene.

Tracer-specific reference tissues selection improves detection of 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir PET SUVR changes in Alzheimer's disease.

This study sought to identify a reference tissue-based quantification approach for improving the statistical power in detecting changes in brain glucose metabolism, amyloid, and tau deposition in Alzheimer's disease studies. A total of 794, 906, and 903 scans were included for 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir, respectively. Positron emission tomography (PET) and T1-weighted images of participants were collected from the Alzheimer's disease Neuroimaging Initiative database, followed by partial volume correction. The standardized uptake value ratios (SUVRs) calculated from the cerebellum gray matter, centrum semiovale, and pons were evaluated at both region of interest (ROI) and voxelwise levels. The statistical power of reference tissues in detecting longitudinal SUVR changes was assessed via paired t-test. In cross-sectional analysis, the impact of reference tissue-based SUVR differences between cognitively normal and cognitively impaired groups was evaluated by effect sizes Cohen's d and two sample t-test adjusted by age, sex, and education levels. The average ROI t values of pons were 86.62 and 38.40% higher than that of centrum semiovale and cerebellum gray matter in detecting glucose metabolism decreases, while the centrum semiovale reference tissue-based SUVR provided higher t values for the detection of amyloid and tau deposition increases. The three reference tissues generated comparable d images for 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir and comparable t maps for 18 F-florbetapir and 18 F-flortaucipir, but pons-based t map showed superior performance in 18 F-FDG. In conclusion, the tracer-specific reference tissue improved the detection of 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir PET SUVR changes, which helps the early diagnosis, monitoring of disease progression, and therapeutic response in Alzheimer's disease.

Radiomic analysis for predicting prognosis of colorectal cancer from preoperative 18F-FDG PET/CT.

BACKGROUND: To develop and validate a survival model with clinico-biological features and 18F- FDG PET/CT radiomic features via machine learning, and for predicting the prognosis from the primary tumor of colorectal cancer. METHODS: A total of 196 pathologically confirmed patients with colorectal cancer (stage I to stage IV) were included. Preoperative clinical factors, serum tumor markers, and PET/CT radiomic features were included for the recurrence-free survival analysis. For the modeling and validation, patients were randomly divided into the training (n = 137) and validation (n = 59) set, while the 78 stage III patients [training (n = 55), and validation (n = 23)] was divided for the further experiment. After selecting features by the log-rank test and variable-hunting methods, random survival forest (RSF) models were built on the training set to analyze the prognostic value of selected features. The performance of models was measured by C-index and was tested on the validation set with bootstrapping. Feature importance and the Pearson correlation were also analyzed. RESULTS: Radiomics signature (containing four PET/CT features and four clinical factors) achieved the best result for prognostic prediction of 196 patients (C-index 0.780, 95% CI 0.634-0.877). Moreover, four features (including two clinical features and two radiomics features) were selected for prognostic prediction of the 78 stage III patients (C-index was 0.820, 95% CI 0.676-0.900). K-M curves of both models significantly stratified low-risk and high-risk groups (P < 0.0001). Pearson correlation analysis demonstrated that selected radiomics features were correlated with tumor metabolic factors, such as SUVmean, SUVmax. CONCLUSION: This study presents integrated clinico-biological-radiological models that can accurately predict the prognosis in colorectal cancer using the preoperative 18F-FDG PET/CT radiomics in colorectal cancer. It is of potential value in assisting the management and decision making for precision treatment in colorectal cancer. Trial registration The retrospectively registered study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (No. 1909207-14-1910) and the data were analyzed anonymously.

Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals.

Recent studies in cognitively unimpaired elderly individuals suggest that the APOE ε4 allele exerts a dosage-dependent effect on brain tau deposition. The aim of this study was to investigate sex differences in APOE ε4 gene dosage effects on brain tau deposition in cognitively impaired individuals using quantitative 18F-flortaucipir PET. Preprocessed 18F-flortaucipir tau PET images, T1-weighted structural MRI, demographic information, global cortical amyloid-ß burden measured by 18F-florbetapir PET, CSF total tau and phosphorylated tau measurements were obtained from the Alzheimer's Disease Neuroimaging Initiative database. Two hundred and sixty-eight cognitively impaired individuals with 146 APOE ε4 non-carriers and 122 carriers (85 heterozygotes and 37 homozygotes) were included in the study. An iterative reblurred Van Cittert iteration partial volume correction method was applied to all downloaded PET images. Magnetic resonance images were used for PET spatial normalization. Twelve regional standardized uptake value ratios relative to the cerebellum were computed in standard space. APOE ε4 dosage × sex interaction effect on 18F-flortaucipir standardized uptake value ratios was assessed using generalized linear models and sex-stratified analysis. We observed a significant APOE ε4 dosage × sex interaction effect on tau deposition in the lateral temporal, posterior cingulate, medial temporal, inferior temporal, entorhinal cortex, amygdala, parahippocampal gyrus regions after adjusting for age and education level (P < 0.05). The medial temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions retained a significant APOE ε4 dosage × sex interaction effect on tau deposition after adjusting for global cortical amyloid-ß (P < 0.05). In sex-stratified analysis, there was no significant difference in tau deposition between female homozygotes and heterozygotes (P > 0.05). In contrast, male homozygotes standardized uptake value ratios were significantly greater than heterozygotes or non-carriers throughout all 12 regions of interest (P < 0.05). Female heterozygotes exhibited significantly increased tau deposition compared to male heterozygotes in the orbitofrontal, posterior cingulate, lateral temporal, inferior temporal, entorhinal cortex, amygdala and parahippocampal gyrus (P < 0.05). Results from voxel-wise analysis were similar to the ones obtained from regions of interest analysis. Our findings indicate that an APOE ε4 dosage effect on brain region-specific tau deposition exists in males, but not females. These results have important clinical implications towards developing sex and genotype-guided therapeutics in Alzheimer's disease and uncovers a potential explanation underlying differential APOE ε4-associated Alzheimer's risk in males and females.

Centralized surveillance of hydatidiform mole: 7-year experience from a regional hospital in China.

OBJECTIVE: To assess the strategy and value of centralized surveillance of hydatidiform mole at a regional hospital in China and to investigate the necessity of prophylactic chemotherapy for high-risk complete hydatidiform mole. METHODS: Between February 2013 and February 2020, all women with hydatidiform mole in Dalian Women's and Children's Medical Center (Group) were registered for surveillance and treatment when indicated. Women with complete hydatidiform mole were categorized into low-risk and high-risk groups according to the criteria from Song Hongzhao's trophoblastic neoplasia. Outcomes and treatments were analyzed retrospectively. RESULTS: In total, 703 women with hydatidiform mole were registered for surveillance with a follow-up rate of 97.9% (688/703). 680 women were enrolled and 52 (7.6%) developed post-molar gestational trophoblastic neoplasia, all with low-risk International Federation of Gynecology and Obstetrics (FIGO) scores 0-5. Post-molar gestational trophoblastic neoplasia was diagnosed in 12.3% (51/413) of patients with complete hydatidiform moles and 0.4% (1/263) of patients were diagnosed with partial hydatidiform moles (χ2=32.415, p<0.001). Post-molar gestational trophoblastic neoplasia was diagnosed in 27.7% (28/101) of the high-risk complete hydatidiform mole group and in 7.4% (23/312) of the low-risk complete hydatidiform mole group (χ2=29.196, p<0.001). No difference in the pre-treatment assessments of patients with post-molar gestational trophoblastic neoplasia was found between the low-risk and high-risk complete hydatidiform mole groups (all p>0.05). All 52 patients with post-molar gestational trophoblastic neoplasia were cured, with a complete response rate of 61.2% (30/49) with first-line single-agent chemotherapy. CONCLUSIONS: A centralized hydatidiform mole surveillance program is feasible and effective and may improve the prognosis of patients with post-molar gestational trophoblastic neoplasia. Prophylactic chemotherapy is not recommended for women with high-risk complete hydatidiform mole with adequate surveillance.

Long Noncoding RNA Brain Cytoplasmic RNA 1 Induces Cisplatin-Resistance of Cervical Cancer Cells by Sponging MicroRNA-330-5p and Upregulating High-Mobility Group Box 3.

OBJECTIVES: The aim of the study was to find out the function of long noncoding RNA brain cytoplasmic RNA 1 (BCYRN1) in cisplatin (DDP)-resistance of cervical cancer (CC) cells. Design and Materials, Setting, Methods: BCYRN1 expression in CC and DDP-resistant cells was evaluated, with the association of BCYRN1 and prognosis analyzed. Then, DDP-resistant cells with BCYRN1 knockdown were established and the DDP-resistance of these cells was assessed. BCYRN1 subcellular localization was detected and confirmed. Besides, the binding relations of BCYRN1 and microRNA (miR)-330-5p and between miR-330-5p and high-mobility group box 3 (HMGB3) were examined and verified. Moreover, the role of miR-330-5p and HMGB3 in the mechanism of BCYRN1 modulating DDP-resistance of CC cells was detected. In addition, xenograft transplantation was conducted to confirm the effect of BCYRN1 in CC cell DDP-resistance. RESULTS: BCYRN1 was overexpressed in CC, which resulted in poor prognosis and DDP-resistance. BCYRN1 knockdown in DDP-resistant cells downregulated DDP-resistance. Mechanically, BCYRN1 sponged miR-330-5p to strengthen HMGB3 mRNA level. Besides, miR-330-5p underexpression or HMGB3 overexpression reversed the function of BCYRN1 knockdown in inhibiting DDP-resistance of CC cells. Eventually, BCYRN1 knockdown reduced the DDP-resistance of CC cells in vivo. LIMITATIONS: There are still some deficiencies in the research; for example, whether there are other miRs working as the downstream genes of BCYRN1 in the competing endogenous RNA interaction is not fully clarified, nor the other downstream mechanisms of miR-330-5p. Besides, the experimental findings and their application into practice need extensive validation. CONCLUSIONS: BCYRN1 knockdown could disrupt the DDP-resistance of CC cells through upregulating miR-330-5p to suppress HMGB3 mRNA level.

COVID-MTL: Multitask learning with Shift3D and random-weighted loss for COVID-19 diagnosis and severity assessment.

There is an urgent need for automated methods to assist accurate and effective assessment of COVID-19. Radiology and nucleic acid test (NAT) are complementary COVID-19 diagnosis methods. In this paper, we present an end-to-end multitask learning (MTL) framework (COVID-MTL) that is capable of automated and simultaneous detection (against both radiology and NAT) and severity assessment of COVID-19. COVID-MTL learns different COVID-19 tasks in parallel through our novel random-weighted loss function, which assigns learning weights under Dirichlet distribution to prevent task dominance; our new 3D real-time augmentation algorithm (Shift3D) introduces space variances for 3D CNN components by shifting low-level feature representations of volumetric inputs in three dimensions; thereby, the MTL framework is able to accelerate convergence and improve joint learning performance compared to single-task models. By only using chest CT scans, COVID-MTL was trained on 930 CT scans and tested on separate 399 cases. COVID-MTL achieved AUCs of 0.939 and 0.846, and accuracies of 90.23% and 79.20% for detection of COVID-19 against radiology and NAT, respectively, which outperformed the state-of-the-art models. Meanwhile, COVID-MTL yielded AUC of 0.800 ± 0.020 and 0.813 ± 0.021 (with transfer learning) for classifying control/suspected, mild/regular, and severe/critically-ill cases. To decipher the recognition mechanism, we also identified high-throughput lung features that were significantly related (P < 0.001) to the positivity and severity of COVID-19.

[Clinical characteristics and genetic analysis of a child with infantile Sandhoff disease and eosinophilia].

OBJECTIVE: To explore the genetic basis for a girl featuring epilepsy, developmental delay and regression. METHODS: Clinical data of the patient was collected. Activities of hexosaminidase A (Hex A) and hexosaminidase A&B (Hex A&B) in blood leukocytes were determined by using a fluorometric assay. Peripheral blood samples were collected from the proband and six members from her pedigree. Following extraction of genomic DNA, whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing. RESULTS: Enzymatic studies of the proband have shown reduced plasma Hex A and Hex A&B activities. Genetic testing revealed that she has carried c.1260_1263del and c.1601G>C heterozygous compound variants of the HEXB gene. Her mother, brother and sister were heterozygous carriers of c.1260_1263del, while her father, mother, three brothers and sister did not carry the c.1601G>C variant, suggesting that it has a de novo origin. Increased eosinophils were discovered upon cytological examination of peripheral blood and bone marrow samples. CONCLUSION: The compound heterozygous variants of c.1260_1263del and c.1601G>C of the HEXB gene probably underlay the Sandhoff disease in this child. Eosinophilia may be noted in infantile Sandhoff disease.

Multi-parametric MRI phenotype with trustworthy machine learning for differentiating CNS demyelinating diseases.

BACKGROUND: Misdiagnosis of multiple sclerosis (MS) and neuromyelitis optica (NMO) may delay the treatment, resulting in poor prognosis. However, the precise identification of these two diseases is still challenging in clinical practice. We aimed to evaluate the value of quantitative radiomic features extracted from the brain white matter lesions for differential diagnosis of MS and NMO. METHODS: We recruited 116 CNS demyelinating patients including 78 MS, and 38 NMO. Three neuroradiologists performed visual differential diagnosis based on brain MRI for comparison purpose. A multi-level scheme was designed to harness the selection of discriminative and stable radiomics features extracted from brain while mater lesions in T1-MPRAGE, T2 sequences and clinical factors. Based on the imaging phenotype composed of the selected radiomic and clinical features, Multi-parametric Multivariate Random Forest (MM-RF) model was constructed and verified with both 10-fold cross-validation and independent testing. Result interpretation was provided to build trust in diagnostic decisions. RESULTS: Eighty-six patients were randomly selected to form the training set while the rest 30 patients for independent testing. On the training set, our MM-RF model achieved accuracy 0.849 and AUC 0.826 in 10-fold cross-validation, which were significantly higher than clinical visual analysis (0.709 and 0.683, p < 0.05). In the independent testing, the MM-RF model achieved AUC 0.902, accuracy 0.871, sensitivity 0.873, specificity 0.869, respectively. Furthermore, age, sex and EDSS were found mildly correlated with the radiomic features (p of all < 0.05). CONCLUSIONS: Multi-parametric radiomic features have potential as practical quantitative imaging biomarkers for differentiating MS from NMO.

Automatic identification of myopic maculopathy related imaging features in optic disc region via machine learning methods.

BACKGROUND: Myopic maculopathy (MM) is the most serious and irreversible complication of pathologic myopia, which is a major cause of visual impairment and blindness. Clinic proposed limited number of factors related to MM. To explore additional features strongly related with MM from optic disc region, we employ a machine learning based radiomics analysis method, which could explore and quantify more hidden or imperceptible MM-related features to the naked eyes and contribute to a more comprehensive understanding of MM and therefore may assist to distinguish the high-risk population in an early stage. METHODS: A total of 457 eyes (313 patients) were enrolled and were divided into severe MM group and without severe MM group. Radiomics analysis was applied to depict features significantly correlated with severe MM from optic disc region. Receiver Operating Characteristic were used to evaluate these features' performance of classifying severe MM. RESULTS: Eight new MM-related image features were discovered from the optic disc region, which described the shapes, textural patterns and intensity distributions of optic disc region. Compared with clinically reported MM-related features, these newly discovered features exhibited better abilities on severe MM classification. And the mean values of most features were markedly changed between patients with peripapillary diffuse chorioretinal atrophy (PDCA) and macular diffuse chorioretinal atrophy (MDCA). CONCLUSIONS: Machine learning and radiomics method are useful tools for mining more MM-related features from the optic disc region, by which complex or even hidden MM-related features can be discovered and decoded. In this paper, eight new MM-related image features were found, which would be useful for further quantitative study of MM-progression. As a nontrivial byproduct, marked changes between PDCA and MDCA was discovered by both new image features and clinic features.

Involvement of the cytokine TWEAK in the pathogenesis of psoriasis vulgaris, pustular psoriasis, and erythrodermic psoriasis.

Psoriasis is a common chronic inflammatory dermatitis in which various cytokines play a detrimental role. The cytokine tumor necrosis factor-related weak inducer of apoptosis (TWEAK) is involved in the pathogenesis of multiple inflammatory disorders. However, the potential role of TWEAK in various subtypes of psoriasis has not been studied in depth. To investigate whether the levels of TWEAK are associated with clinical traits and the levels of some known psoriasis-related cytokines, such as interleukin (IL)-17A, IL-22, interferon (IFN)-γ, and IL-36γ, 20 patients with psoriasis vulgaris (PV), 8 patients with pustular psoriasis (PP), 8 patients with erythrodermic psoriasis (EP), and 20 healthy controls (HCs) were recruited into this study. The levels of serum cytokines were detected by commercial enzyme-linked immunosorbent assay kits. The average levels of TWEAK, IL-17A, IL-22, IFN-γ, and IL-36γ were significantly higher in the psoriasis groups than in the HC group. Furthermore, there was a statistically significant correlation between TWEAK and IL-17A/IFN-γ in PV and IL-36γ in EP, but there was no correlation between TWEAK and IL-22 in any subtype of psoriasis. This study suggests that TWEAK may have a role in the pathogenesis of PV, PP, and EP via synergy with IL-17A, IFN-γ, or IL-36γ, but not with IL-22.

EPA and DHA attenuate deoxynivalenol-induced intestinal porcine epithelial cell injury and protect barrier function integrity by inhibiting necroptosis signaling pathway.

Deoxynivalenol (DON) is one of the most common mycotoxins that contaminates food or feed and cause intestinal damage. Long-chain n-3 polyunsaturated fatty acids (PUFA) such as EPA and DHA exert beneficial effects on intestinal integrity in animal models and clinical trials. Necroptosis signaling pathway plays a critical role in intestinal cell injury. This study tested the hypothesis that EPA and DHA could alleviate DON-induced injury to intestinal porcine epithelial cells through modulation of the necroptosis signaling pathway. Intestinal porcine epithelial cell 1 (IPEC-1) cells were cultured with or without EPA or DHA (6.25-25 µg/mL) in the presence or absence of 0.5 µg/mL DON for indicated time points. Cell viability, cell number, lactate dehydrogenase (LDH) activity, cell necrosis, transepithelial electrical resistance (TEER), fluorescein isothiocyanate-labeled dextran 4kDa (FD4) flux, tight junction protein distribution, and protein abundance of necroptosis related signals were determined. EPA and DHA promoted cell growth indicated by higher cell viability and cell number, and inhibited cell injury indicated by lower LDH activity in the media. EPA and DHA also improved intestinal barrier function, indicated by higher TEER and lower permeability of FD4 flux as well as increased proportions of tight junction proteins located in the plasma membrane. Moreover, EPA and DHA decreased cell necrosis demonstrated by live cell imaging and transmission electron microscopy. Finally, EPA and DHA downregulated protein expressions of necroptosis related signals including tumor necrosis factor receptor (TNFR1), receptor interacting protein kinase 1 (RIP1), RIP3, phosphorylated mixed lineage kinase-like protein (MLKL), phosphoglycerate mutase family 5 (PGAM5), dynamin-related protein 1 (Drp1), and high mobility group box-1 protein (HMGB1). EPA and DHA also inhibited protein expression of caspase-3 and caspase-8. These results suggest that EPA and DHA prevent DON-induced intestinal cell injury and enhance barrier function, which is associated with inhibition of the necroptosis signaling pathway.