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Perforin is essentially involved in the granule-dependent killing activities of cytotoxic T lymphocytes and NK cells. Monoallelic PRF1 mutation increases the risk of autoimmune diseases, and biallelic PRF1 mutation causes familial hemophagocytic lymphohistiocytosis-2. Here, we report a case of a 12-year-old girl with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), followed by a rapidly progressive onset of hemophagocytic lymphohistiocytosis (HLH) 9 months later, alongside manifestations of demyelinating encephalopathy. Genetic sequencing revealed a heterozygous nonsense mutation in the PRF1 gene (c.984G>A; p.W328*) and a heterozygous missense mutation in the PRF1 gene (c.1349C>T; p.T450M). Eventually, she died because of no suitable allogeneic hematopoietic stem cell available in time. Our observations suggest that CIPD might represent the initial phenotype of biallelic PRF1 mutation and could serve as an early sign of subsequent HLH. A comprehensive understanding of this condition is paramount for timely diagnosis, treatment, and ultimately improved patient outcomes.

ObjectivesX-linked adrenoleukodystrophy (ALD) is a peroxisomal disease caused by mutations in the ABCD1 gene. Childhood cerebral ALD (CCALD) is characterized by inflammatory demyelination, rapidly progressing, often fatal. Hematopoietic stem cell transplant only delays disease progression in patients with early-stage cerebral ALD. Based on emergency humanitarianism, this study aims to investigate the safety and efficacy of sirolimus in the treatment of patients with CCALD.MethodsThis was a prospective, single-center, one-arm clinical trial. We enrolled patients with CCALD, and all enrolled patients received sirolimus treatment for three months. Adverse events were monitored and recorded to evaluate the safety. The efficacy was evaluated using the neurologic function scale (NFS), Loes score, and white matter hyperintensities.ResultsA total of 12 patients were included and all presented with CCALD. Four patients dropped out and a total of eight patients in the advanced stage completed a 3-month follow-up. There were no serious adverse events, and the common adverse events were hypertonia and oral ulcers. After sirolimus treatment, three of the four patients with an initial NFS > 10 showed improvements in their clinical symptoms. Loes scores decreased by 0.5–1 point in two of eight patients and remained unchanged in one patient. Analysis of white matter hyperintensities revealed a significant decrease in signal intensity (n = 7, p = 0.0156).ConclusionsOur study suggested that autophagy inducer sirolimus is safe for CCALD. Sirolimus did not improve clinical symptoms of patients with advanced CCALD significantly. Further study with larger sample size and longer follow-up is needed to confirm the drug efficacy.Clinical Trial registration:https://www.chictr.org.cn/historyversionpuben.aspx, identifier ChiCTR1900021288.

ObjectiveSCN1A, encoding the alpha 1 subunit of the sodium channel, is associated with a range of related epilepsy. This study aims to assess saliva and urine pH in children with SCN1A-related epilepsy.MethodsA prospective controlled observational study with a 1:1 ratio was conducted on seven patients with SCN1A-related epilepsy and seven healthy children of the same family, gender, and age but without a history of seizures. The pH of saliva and urine was measured by pH test paper. Parents of patients with epilepsy recorded seizures to compare the relationship between pH and seizures.ResultsThe fourteen participants were all males, aged 1 to 14 years. Seven patients had different pathogenic SCN1A variants. The pH of saliva and urine was monitored for 21–95 days. The pH of saliva and urine was higher in patients with SCN1A-related epilepsy than in the healthy group. The urine pH in Dravet syndrome patients was high compared with other epilepsy patients. The urine pH in patients with seizures was higher than that in patients without seizures, which occurred during the study.ConclusionsThe pH of saliva and urine was chronically high in patients with SCN1A-related epilepsy, and urine pH was higher in patients with seizures and with Dravet syndrome.

Herbs with a “hot” properties are frequently used to treat cold symptoms in TCM. However, the underlying mechanisms of the herbs with “hot” properties on hypothyroidism have not been investigated. This study aimed to explore four typical “hot” and “cold” property herb on hypothyroidism. Firstly, the difference efficacy between the four typical “hot” property herbs and the four typical “cold” property herbs was assessed by physical signs, thyroid function, and the metabolic profile using multivariate statistical analysis. The influence of the four typical “hot” property herbs on hypothyroidism was validated pathologically. The impact mechanism of the four typical “hot” property herbs on hypothyroidism was investigated through a metabolomics method combined with network analysis. Na+/K+-ATP, ACC1 enzyme, UCP-1, and the PI3K-Akt pathway were used to confirm the metabolite pathways and target-associated metabolites. The results showed that the four typical “hot” property herbs could significantly improve physical signs, thyroid function, and the metabolic profile in hypothyroidism rats, the four typical “cold” property herbs did not show any benefit. Moreover, the four typical “hot” property herbs could improve lipid metabolism, energy metabolism, and thyroid hormone levels by the PI3K-Akt signaling pathway, Ca2+- AMPK signaling pathways, purine metabolism, and tryptophan metabolism. Additionally, the levels of UCP-1, Na+/K + -ATP enzyme, and ACC1 were ameliorated by the four typical “hot” property herbs in hypothyroidism rats. Therefore, a metabolomics strategy combined with network analysis was successfully performed and interpreted the mechanism of the four typical “hot” property herbs on hypothyroidism based on the theory of “cold and hot” properties of TCM well.

Cattle bile Arisaema (CBA) is a traditional medicine used for the treatment of febrile seizures (FS) for thousands of years in China. However, its application is greatly limited due to cost reasons, and pig bile Arisaema (PBA) is the main commercial product instead. Additionally, the underlying mechanism of CBA for the treatment of FS still remains unknown. In this study, we investigated the anti-convulsant effect and potential mechanism of the CBA aqueous extract for the first time through a hot-water bath-induced FS rat model. Our results showed that pre-treatment with CBA dramatically lowered the incidence rate and generation times and prolonged the latency of FS. In addition, CBA effectively ameliorated neuronal damage and regulated neurotransmitter disorder induced by FS in the rat hippocampus. The enzyme-linked immunosorbent assay, western blotting, immunohistochemical, and qRT-PCR results exhibited that CBA suppressed the expression of GFAP, TLR4, NF-κB, HMGB1, NLRP3, TNF-α, IL-1β, and IL-6 and consequently inhibited the neuroinflammation induced by FS. Interestingly, although the CBA and PBA aqueous extracts possessed the same trend on the changes caused by FS, the improvement of FS by CBA is markedly better than that by PBA. These findings indicate that CBA exerts a protective effect on febrile seizures through regulating neurotransmitter disorder and suppressing neuroinflammation.

With an increase in aging populations worldwide, age-related diseases such as Alzheimer’s disease (AD) have become a global concern. At present, a cure for neurodegenerative disease is lacking. There is an urgent need for a biomarker that can facilitate the diagnosis, classification, prognosis, and treatment response of AD. The recent emergence of highly sensitive mass-spectrometry platforms and high-throughput technology can be employed to discover and catalog vast datasets of small metabolites, which respond to changed status in the body. Metabolomics analysis provides hope for a better understanding of AD as well as the subsequent identification and analysis of metabolites. Here, we review the state-of-the-art emerging candidate biomarkers for AD.