A retrospective analysis was made on the clinical data and gene mutation characteristics of 2 children admitted to the Children′s Hospital of Zhejiang University School of Medicine for epilepsy without periventricular nodules caused by the ARF1 gene mutation from August 2023 to February 2024, and relevant literature was reviewed.Both patients presented with seizures and psychomotor retardation, and 1 of them was diagnosed with West syndrome.Whole exome sequencing confirmed that the 2 patients carried a missense mutation in the ARF1 gene (c.55C>A, p.R19S).Brain magnetic resonance imaging (MRI) of 2 patients revealed no obvious abnormalities.A summary analysis of 5 cases of ARF1 gene mutations reported in three foreign literatures showed that patients with ARF1 gene mutations usually presented with seizures, developmental delay, hypotonia, mental retardation, and motor stereotypies.MRI showed periventricular nodular heterotopia, corpus callosum dysplasia, subcortical white matter abnormalities, and delayed myelination.This study found for the first time that ARF1-related disorders can occur without significant brain structural malformations, indicating that there are inconsistencies in neuroimaging findings, adding valuable phenotypic information to this gene.The differences in imaging findings may be the result of genetic background or variation in ARF1-interacting proteins, or may be caused by altered regulatory mechanisms of protein activity.

Objective:To evaluate the long-term safety, tolerability and efficacy of Lacosamide add-on therapy in Chinese children with partial-onset seizures.Methods:SP848 was a global multicenter single-arm study involving 60 Chinese children with partial-onset seizures with the age of 4-17 years who were managed by Lacosamide add-on therapy at seven hospitals across China from April 2018 to May 2019.After treatment with at least two kinds of anti-seizure medications simultaneously or sequentially, partial seizures were still poorly controlled and Lacosamide oral solution (syrup) or tablets were added.The minimum initial oral dose was 2 mg/(kg·d), and the maximum allowable dose was 12 mg/(kg·d)or 600 mg/d during the study period.The dose was adjusted according to the tolerance and seizure control level of partial-onset seizures children.Seizure frequency and the median percentage change in partial-onset seizures per 28 days from baseline to the final visit were recorded, including 50% responder rate and 75% responder rate.Results:A total of 60 Chinese children with the mean age of 9.18 (4.00-15.40) years were included in this interim analysis, involving 39 males and 21 females.The mean course of epilepsy was 5.04 (0.50-15.20) years.A total of 43 patients (71.7%) still have been treated.One patient (1.7%) has completed the 6-12 months of follow-up, and 14 patients (23.3%) have completed the follow-up for less than 6 months.The median change in the frequency of partial seizures every 28 days from baseline to the last visit was -2.91, with its median percentage as -25.46%, and the proportions of ≥50%, while ≥75% responder rate were 40.0% and 28.3%, respectively.A total of 52 patients (86.7%) had 265 treatment emergent adverse events (TEAE), 11 patients (18.3%) had 19 serious TEAE, 37 patients (61.7%) had 127 drug-related TEAE, and 11 patients (18.3%) had 16 TEAE leading to the discontinuation of the trial.The most common TEAE were upper respiratory tract infections (20 cases, 33.3%), followed by drowsiness (16 cases, 26.7%), dizziness (15 cases, 25.0%) and vomiting (13 cases, 21.7%). There were no abnormal changes in the electrocardiographic findings during the treatment.Conclusions:For Chinese patients with partial seizures who are older than the age of 4 years and poorly controlled by other drugs, Lacosamide is effective and well tolerated as an add-on therapy drug.The safety characteristics are consistent with those reported in children and adults.No new safety concerns are identified.

The clinical data of a case with late-onset isolated sulfite oxidase deficiency(ISOD)admitted in the Department of Neurology, Children′s Hospital, Zhejiang University School of Medicine in July 2021 were retrospectively analyzed.Fifteen previously published cases of late-onset ISOD were also reviewed.The patient was a girl, who was hospitalized because of " motor regression with mental retardation for 5 days" at 1 year old.The manifestations of the patient were extrapyramidal symptoms, regression of motor development and seizures.The level of urinary sulfites in the patient was increased.Magnetic resonance imaging (MRI) features were bilateral pallidus and substantia nigra.Gene sequencing suggested a pure missense mutation of the sulfite oxidase( SUOX) gene c. 650(exon5)G>A(p.Arg217Gln). In 16 cases of late-onset ISOD, the median age at onset and diagnosis was 10.5 months and 34.0 months, respectively.The common clinical manifestations were hypotonia (13 cases), seizures (10 cases), movement disorders (9 cases), and ectopia lentis (6 cases). The most common brain MRI feature was pallidus changes (11 cases), followed by lesions of substantia nigra (5 cases), and cerebral atrophy (4 cases). Fourteen cases of late-onset ISOD showed a positive urinary sulfite test.The missense mutation of the SUOX gene was found in 9 cases.It suggested that brain MRI involvement of bilateral pallidus, high excretion of urine sulfites and the missense mutation of the SUOX gene were important diagnostic clues for late-onset ISOD.

Transient receptor potential M2 (TRPM2) ion channel is a non-selective cationic channel that can permeate calcium ions, and plays an important role in neuroinflammation, ischemic reperfusion brain injury, neurodegenerative disease, neuropathic pain, epilepsy and other neurological diseases. In ischemic reperfusion brain injury, TRPM2 mediates neuronal death by modulating the different subunits of glutamate N-methyl-D-aspartic acid receptor in response to calcium/zinc signal. In Alzheimer's disease, TRPM2 is activated by reactive oxygen species generated by β-amyloid peptide to form a malignant positive feedback loop that induces neuronal death and is involved in the pathological process of glial cells by promoting inflammatory response and oxidative stress. In epilepsy, the TRPM2-knockout alleviates epilepsy induced neuronal degeneration by inhibiting autophagy and apoptosis related proteins. The roles of TRPM2 channel in the pathogenesis of various central nervous system diseases and its potential drug development and clinical application prospects are summarized in this review.
Amyloid beta-Peptides/metabolism* ; Humans ; Neurodegenerative Diseases ; Neuroglia ; TRPM Cation Channels/genetics* ; Transient Receptor Potential Channels

Since the identification of BCR-ABL fusion gene and the advent of targeted tyrosine kinase inhibitors (TKI), patients with chronic myeloid leukemia (CML) have been "walking" on the path of chronic disease for around twenty years. In recent years, the second - and third -generation TKI have provided further protection for the long-term survival of CML patients. However, TKI discontinuation and the prognostic situation of a small number of patients with TKI resistance or carrying poor prognostic genes are still hot issues in CML-related researches. This article reviews the research progress of CML at the 62nd American Society of Hematology Annual Meeting.

Objective:To observe the effects of miR-21 knockout on proliferation and drug resistance in K562/G01 cells, and to preliminarily explore the mechanism of imatinib sensitivity by knocking out miR-21 in K562/G01 cells.Methods:Using CRISPR/Cas9 to knock out the miR-21 gene in K562/G01 cells, and single-cell-derived clones of miR-21 knockout were obtained by genomic DNA PCR screening, Sanger sequencing, and real-time PCR. We used MTT and cell colony formation assays to assess the cell proliferation, and determined imatinib sensitivity by MTT assay and Annexin-Ⅴ-APC/7-AAD double staining flow cytometry. Using western blot, we examined the potential mechanisms affecting imatinib sensitivity by knocking out miR-21 in K562/G01 cells.Results:Three miR-21 knockout K562/G01 single-cell-derived clones were successfully constructed. The mutation efficiency mediated by CRISPR/Cas9 was 7.12%-8.11%. MiR-21 knockout inhibited the proliferation of K562/G01 cells; the clone formation rates of WT and 1#, 2#, 6# K562/G01 single-cell clones were (57.67±8.25) %, (26.94± 5.36) %, (7.17±2.11) %, (31.50±3.65) %, respectively. MiR-21 knockout increased the sensitivity of K562/G01 cells to imatinib, IC 50 of imatinib in WT, and 1#, 2#, 6# K562/G01 single-cell clones were (21.92±1.36) μmol/ml, (3.98±0.39) μmol/ml, (5.38±1.01) μmol/ml, (9.24±1.36) μmol/ml. After the knockout of miR-21, the activation of PI3K/Akt signaling molecules was inhibited, while the expression of P210 BCR-ABL and p-P210 BCR-ABL was downregulated; however, the expression of PTEN was not affected. Conclusion:The knockout of miR-21 can suppress cell proliferation and improve sensitivity to imatinib in K562/G01 cells, which may be achieved by inhibiting the PI3K/AKT signaling pathway and BCR-ABL expression.

The identification of BCR-ABL fusion gene and the advent of tyrosine kinase inhibitors (TKI) targeting this mutation have promoted the landmark progress of diagnosis and treatment in chronic myeloid leukemia (CML), and have dramatically changed the treatment management and disease prognosis for CML patients. Most of the western countries hold a view that CML is cut and dried, but the situation is not the same in developing countries. Currently, more attention is paid to the discontinuation of TKI. In addition, deep challenges remain in the low- and middle-income countries. This paper reviews the treatment progress of CML and challenges in low-and middle-income countries reported at the 61st American Society of Hematology Annual Meeting.

Objective:To investigate the clinical features and treatment effect of children with central nervous system demyelinating diseases and seropositivity to myelin-oligodendrocyte glycoprotein (MOG) antibody.Methods:The clinical characteristics of 28 had seropositivity to MOG among 115 children with central nervous system demyelinating diseases and who were hospitalized at Department of Neurology, Children′s Hospital of Zhejiang University School of Medicine from March 2017 to February 2019 were retrospectively analyzed.Results:Twenty-eight patients were included in this study, including 10 males and 18 females, with the ratio of male/female of 1.00∶1.80, and the median age of 7 years and 9 months.The clinical manifestations were diverse, including encephalopathy symptoms such as hea-dache, vomiting, and drowsiness (13/28 cases), vision loss (7/28 cases), spinal symptoms (6/28 cases), cerebellar symptoms such as ataxia, slurred speech (4/28 cases), convulsions (2/28 cases), and cranial nerve symptoms (1/28 cases). Among 24 cases who underwent CSF detection, 10 patients (41.7%) had slightly increased white blood cells, 2 patients (8.3%) had elevated protein, 6 patients (25.0%) had positive MOG antibody, and CSF-restricted oligoclonal band was negative in all 24 patients.Twenty-five cases (89.3%) showed brain magnetic resonance imaging (MRI) abnormalities, including cerebral white matter (20/28 cases), cerebellum (10/28 cases), cerebral gray matter (9/28 cases), thalamus/basal ganglia (6/28 cases), brainstem (6/28 cases), optic nerve (5/28 cases), and corpus callosum (4/28 cases). Of the 28 cases, 13 patients had spinal cord involvement, involving cervical spinal cord in 10 cases, thoracic cord in 9 cases and lumbar spinal cord in 5 cases; besides, 8 cases of them had long segmental spinal cord lesions with ≥ 3 segments.Fourteen patients received the visual evoked potentials′ examination, and the subclinical visual impairment was found in 2 of them with unobstructed clinical performance.All patients underwent high-dose Methylprednisolone therapy.The clinical symptoms of 16 patients who were treated with Gamma globulin were relieved in the acute phase.Seven patients had recurrence during the follow-up period, with the recurrence rate of 25.0%.Relapsed patients re-treated with high-dose Methylprednisolone therapy combined with Gamma globulin, clinical symptoms could be alleviated.Conclusion:The main clinical phenotype of children with central nervous system demyelinating diseases and seropositivity to MOG is acute disseminated encephalomyelitis.The spinal cord lesions are mainly involving cervical and thoracic segments.The current treatments of this disease include glucocorticoid and Gamma globulin, which have significant effect, but the disease is easy to relapse.The re-use of glucocorticoid and Gamma globulin after relapse is still effective.

Objective:To investigate the mammography, ultrasound and MRI features of breast ductal carcinoma in situ within papillomas (DCIS-WP) and ductal carcinoma in situ in general (DCIS-IG), and to select the appropriate screening methods for breast cancer.Methods:A retrospective analysis of 134 patients with DCIS-WP and DCIS-IG confirmed by pathology from January 2015 to October 2018 was conducted, including 40 patients with DCIS-WP and 94 patients with DCIS-IG. Mammography, ultrasound and MRI images were analyzed based on BI-RADS criteria, to evaluate the missed diagnosis rate and accuracy rate of three imaging methods, and the consistency of preoperative puncture, intraoperative frozen section and postoperative paraffin section was also observed. Qualitative data were compared using the χ 2 test or Fisher′s exact test. Results:The X-ray missed diagnosis rate of DCIS-WP group and DCIS-IG group was 42.50%（17/40） and 5.32%（5/94）, respectively, while the diagnostic accuracy rate was 22.50%（9/40） and 77.66%（73/94） respectively. The difference between the two groups was statistically significant (χ2=28.268, 35.952, P<0.001). In DCIS-WP group and DCIS-IG group, there were 8 and 2 cases with multiple hypoechoic nodules in the lesions, the difference was statistically significant (χ2=20.819, P<0.001); the missed diagnosis rate was 0 and 24.47%（23/94）, the difference was statistically significant ( P<0.05). On MRI, there were 24 cases and 15 cases of DCIS-WP group and DCIS-IG group with the signs of catheter dilation, 21 cases and 16 cases with multiple papillomas background, 15 cases and 12 cases with sparse internal ring manifestations, 19 cases and 13 cases with different sizes, respectively. The difference between the two groups was statistically significant (χ2=26.378, 17.671, 8.524, 14.530, P<0.05). In DCIS-WP group and DCIS-IG group, 12 cases and 82 cases had the same diagnosis of preoperative puncture, intraoperative frozen pathology and postoperative paraffin pathology respectively, and the difference between the two groups was statistically significant (χ2=44.165, P<0.001). Conclusions:The features of DCIS-WP are different from those of DCIS-IG on mammography and ultrasound. DCIS-WP is likely to be missed on mammography as there is less calcification, while it is easier to be detected by ultrasound. MRI has good diagnostic efficacy for both types of DCIS and is helpful in differentiating them.

Objective:To investigate the clinical efficacy and safety of montelukast combined with mometasone furoate in the treat-ment of children with allergic rhinitis. Methods:Totally 91 children with allergic rhinitis were randomly divided into the observation group (n=46) and the control group (n=45) according to the random number table. The control group was given mometasone fu-roate, while the observation group was treated with montelukast additionally. Both groups were treated for two weeks. The symptom scores including nasal congestion, sneezing, itchy nose and runny nose, serum level changes of IL-4, IL-12 and IgE and adverse drug reactions before and after the treatment in both groups were evaluated and compared. Results:The total effective rate in the observation group (93. 48%) was significantly higher than that in the control group (75. 56%, P<0. 05). Compared with those before the treat-ment, the symptom scores in both groups were decreased after the treatment (P<0. 05), and those in the observation group were lower than those in the control groups (P<0. 05). After the treatment, the serum levels of IL-4 and IgE in both groups were significantly de-creased when compared with those before the treatment, while the IL-12 levels were increased significantly (P<0. 05), and the chan-ges in the observation group were more significantl than those in the control group (P<0. 05). There were no serious adverse drug re-actions during the treatment course in both groups. Conclusion:Montelukast combined with mometasone furoate in the treatment of al-lergic rhinitis shows more notable efficacy with higher security.