Dimethyl fumarate ameliorates autoimmune hepatitis in mice by blocking NLRP3 inflammasome activation.

Dimethyl fumarate (DMF) is a fumaric acid derivative clinically approved for the treatment of some inflammatory diseases, but the underlying mechanism for its therapeutic effects remains incompletely understood. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation has critical roles in innate immune responses to various infections and sterile inflammations. In this study, we aimed to explore whether DMF affects auto-immune hepatitis (AIH) in mice induced by concanavalin A (Con A) by modulating NLRP3 inflammasome activation. The results showed that DMF suppressed the activation of NLRP3 inflammasome activation in lipopolysaccharide-primed murine bone marrow-derived macrophages upon ATP or nigericin treatment, as evidenced by reduced cleavage of pro-caspase-1, release of mature interleukin-1ß (IL-1ß) and generation of gasdermin D N-terminal fragment (GSDMD-NT). DMF also greatly reduced ASC speck formation upon the stimulation of nigericin or ATP, indicating its inhibitory effect on NLRP3 inflammasome assembly. Consistent with reduced generation of GSDMD-NT, ATP or nigericin-induced pyroptosis was markedly suppressed by DMF. Moreover, DMF treatment alleviated mitochondrial damage induced by ATP or nigericin. Interestingly, all these effects were reversed by the protein kinase A (PKA) pathway inhibitors (H89 and MDL-12330A). Mechanistically, DMF enhanced PKA signaling and thus increased NLRP3 phosphorylation at PKA-specific sites to attenuate its activation. Importantly, DMF decreased serum levels of inflammatory cytokines and ameliorated liver injury in Con A-induced AIH of mice, concomitant with reduced the generation of caspase-1p10 and GSDMD-NT and alleviating mitochondrial aggregation in the liver. Collectively, DMF displayed anti-inflammatory effects by inhibiting NLRP3 inflammasome activation likely through regulating PKA signaling, highlighting its potential application in treating AIH.

Complete genome sequence of Bacillus velezensis WB, an isolate from the watermelon rhizosphere: genomic insights into its antifungal effects.

OBJECTIVES: Here, we report the complete genome of strain WB, isolated from the rhizosphere of a healthy watermelon from a Fusarium wilt diseased field, which possesses antifungal activity against Fusarium oxysporum f. sp. niveum (Fon) and reduces the incidence of Fusarium wilt in watermelon. METHODS: Genome sequences were determined using the Illumina HiSeq and PacBio platforms. Genome assembly was performed by Unicycler software. Gene clusters responsible for secondary metabolite biosynthesis were predicted using antiSMASH. RESULTS: The size of the genome was 3 896 799 base pairs, and there were 3977 coding DNA sequences (CDSs). The G+C content of the circular genome was 46.65%, and there were 27 rRNAs and 86 tRNAs. Strain WB was finally designated Bacillus velezensis based on phylogenomic analyses. In addition, 13 gene clusters were related to the synthesis of antimicrobial secondary metabolites, including surfactin, fengycin, iturin, bacillibactin, bacilysin, bacillaene, and butirosin. CONCLUSION: The complete genome sequence of strain WB reported here will be a valuable reference for studying the biocontrol mechanisms of Fusarium wilt in watermelon.

Emergency irradiation with 3.4 Gy/2f in sellar/suprasellar germinoma patients with rapid visual acuity decline.

BACKGROUND: Rapid visual acuity (VA) decline was a common complaint in patients with sellar/suprasellar germinoma. In our hospital, 3.4 Gy/2f of emergency irradiation was applied to save patient VA and enable subsequent chemoradiotherapy. This study aimed to investigate the efficacy of emergency irradiation with 3.4 Gy/2f in patients with sellar/suprasellar germinoma who had rapid VA decline. METHODS: From January 2014 to December 2017, 33 patients with sellar/suprasellar germinoma who complained of VA decline within 3 months received 3.4 Gy/2f of emergency irradiation in Beijing Tiantan Hospital. The best-corrected VA (BCVA) and mean deviation (MD) were measured. Correlations between visual function change and clinical factors, including age at diagnosis, duration of VA decline, extent of tumor regression, serum level of tumor markers, were analyzed. RESULTS: Among 33 patients with sellar/suprasellar germinoma, the median diameter and volume of sellar/suprasellar lesions were 32 mm (range: 5-55 mm) and 12.9 cm (range 0.6-58.5 cm), respectively. Data on pre- and post-emergency-irradiation BCVA were obtained in 32 patients. For the right eyes, BCVA was improved in 23 patients (71.9%), unchanged in 7 (21.9%), and worsened in 2 (6.2%); and for the left eyes, these numbers were 27 (84.4%), 4 (12.5%), and 1 (3.1%), respectively. In terms of the logarithm of the minimum angle of resolution (logarithm of the minimum angle of resolution = Log (1/BCVA) score, the improvement was significant in both eyes (P < 0.001). In terms of MD, six patients had paired data and the improvement was marginal in the right eyes (P = 0.068) and significant in the left eyes (P = 0.043). However, no clinical factor was found to have correlation with visual function improvement. CONCLUSION: In sellar/suprasellar germinoma patients with VA decline, 3.4 Gy/2f of emergency irradiation was effective in improving visual function.

Soluble antigens from the neurotropic pathogen Angiostrongylus cantonensis directly induce thymus atrophy in a mouse model.

The nematode Angiostrongylus cantonensis (A.C.) is a neurotropic pathogen; stage-III larva invade the human (non-permissive host) central nervous system (CNS) to cause eosinophilic meningitis or meningoencephalitis accompanied by immunosuppression. In an A.C.-infectedmouse (another non-permissive host) model, CNS damage-associated T cell immune deficiency and severe inflammation were proposed to result from activation of the hypothalamic-pituitary-adrenal (HPA) axis. However, glucocorticoids are anti-inflammatory agents. Additionally, while defects in thymic stromal/epithelial cells (TECs) are the major reason for thymic atrophy, TECs do not express the glucocorticoid receptor. Therefore, activation of the HPA axis cannot fully explain the thymic atrophy and inflammation. Using an A.C.-infected mouse model, we found that A.C.-infected mice developed severe thymic atrophy with dramatic impairments in thymocytes and TECs, particularly cortical TECs, which harbor CD4+CD8+ double-positive thymocytes. The impairments resulted from soluble antigens (sAgs) from A.C. in the thymuses of infected mice, as intrathymic injection of these sAgs into live mice and the addition of these sAgs to thymic cell culture resulted in thymic atrophy and cellular apoptosis, respectively. Therefore, in addition to an indirect effect on thymocytes through the HPA axis, our study reveals a novel mechanism by which A.C. infection in non-permissive hosts directly induces defects in both thymocytes and TECs via soluble antigens.

Diagnosis of Strongyloides stercoralis by morphological characteristics combine with molecular biological methods.

Strongyloidiasis is one of the neglected tropical diseases caused by infection with the nematode Strongyloides genus and distributed worldwide. Strongyloidiasis can be fatal in immunosuppressed patients induced hyperinfection or disseminated strongyloidiasis. Unfortunately, until now, due to the unspecific clinical symptom in infected individuals and the low sensitivity diagnosis of strongyloidiasis, many patients were misdiagnosed every year. Furthermore, the larvae of the Strongyloides stercoralis (S. stercoralis) is similar to other nematodes such as hookworm, Trichostrongylus increased the difficulty of diagnosis. In this case, the patient is a 63-year-old male person, who had a nearly 30 years medical history of asthma and emphysema, and 4-5-year medical history of diabetes. The sputum examination found some parasite larvae, then we identify the larvae using clinical observation and morphological characteristics combine with examined cytochrome oxidase subunit 1 (COX1) and 18S rRNA genes by PCR, sequence analysis and finally classified by phylogenetic analysis, the larvae were diagnosed as S. stercoralis. Our results showed that diagnosis with strongyloidiasis by morphological characteristics combine with molecular biological methods can improve the sensitive of diagnosis and provide a final diagnosis for the disease in the clinics.

Surgical treatment of hypothalamic hamartoma causing central precocious puberty: long-term follow-up.

Hypothalamic hamartoma (HH) is a rare condition that often manifests as central precocious puberty (CPP). There is a lack of information available concerning the long-term effectiveness of surgery for the treatment of CPP due to HH. Here the authors describe 3 cases of CPP due to HH, with a follow-up ranging from 9 to 11 years after surgery. Three girls experienced breast growth and menses at 5-18 months of age and 5-36 months of age, respectively. Serum concentrations of luteinizing hormone, follicle-stimulating hormone, and estradiol concentrations ranged from 2.5 to 6.5 mIU/ml, 4.8-5.9 mIU/ml, and 47.9-133.0 pg/ml, respectively. Magnetic resonance imaging confirmed that CPP was caused by HH. Lesions were resected using a right pterional approach. After surgery, endocrine hormone concentrations were normalized, breasts shrunk, and menses ceased in each patient. Moreover, all of them subsequently developed normally and experienced age-appropriate onset of puberty. Each patient's height and weight were normal at the most recent follow-up (9-11 years after surgery), and none had experienced learning difficulties. Central precocious puberty due to HH can be successfully treated with resection. In the 3 cases presented, this approach was associated with both short- and long-term efficacy.

[Transcallosal-interforniceal approach treatment of hypothalamic astrocytoma in children].

OBJECTIVE: To explore the clinical features, diagnosis and efficiency of transcallosal-interforniceal approach treatment of hypothalamic astrocytoma in children. METHODS: A total of 42 pediatric cases of hypothalamic astrocytoma were operated by transcallosal-interforniceal approach. All cases received post-operative radiotherapy and follow-up visits. The clinical and imaging data were analyzed retrospectively. RESULTS: High ICP and hypothalamic lesions were the main clinical manifestations. All patients suffering from hydrocephalus were operated by transcallosal-interforniceal approach. Seventeen cases received subtotal resection and 25 in great part. None died from operation. All cases received post-operative radiotherapy. Twenty-nine cases were followed up for 1 to 7 years. Among which, 25 led a normal life and 4 stayed in a fair condition. CONCLUSIONS: Hypothalamic astrocytoma in children have some characteristic in clinical manifestations and neuroradiological examinations. Transcallosal-interforniceal approach is an effective method of treating hypothalamic astrocytoma in children. Total removal is not imperative. And radiotherapy should be performed.

[Complications after transcallosal transseptal interforniceal resection of hypothalamic hamartoma: analysis of 37 cases].

OBJECTIVE: To summarize the post-operative complications of resection of hypothalamic hamartoma (HH) through transcallosal transseptal interforniceal approach. METHODS: Thirty-seven HH patients, 26 males and 11 females, aged 8.7 underwent resection of the tumor via the transcallosal transseptal interforniceal approach. The symptoms and blood electrolytes were observed. RESULTS: After operation blood electrolyte test showed that 8 cases were normal, 19 cases showed hyponatremia as prime abnormality, and 10 cases had hypernatremia primarily. Among the 19 cases with hyponatremia transient apathy occurred in 2 cases, general epilepsy occurred in one patient, continuous minor epilepsy occurred in another one, 4 patients suffered minor epilepsy, 25 had fever the temperature of 3 of which were beyond 40 degrees C, and 2 had transient diabetes insipidus and 1 had diabetes. CONCLUSION: Resection of HH through the transcallosal transseptal interforniceal approach achieves significant improvement of gelastic seizures with fewer complications. The most common complication is disturbance of serum natrium, which, however, is mild and well managed.

Radical resection of 202 pediatric craniopharyngiomas with special reference to the surgical approaches and hypothalamic protection.

OBJECTIVE: The goal of this study was to disclose the appropriate surgical approaches to radically removing pediatric craniopharyngiomas with optimal hypothalamic protection. METHODS: In 202 patients undergoing primary surgery from April 1997 to December 2002, eight approaches were used to remove craniopharyngiomas in the sellar region and the third ventricle. Among the eight approaches, the transcallosal-interseptal-interforniceal approach was used in 89 cases, the unilateral transfrontal interhemispheric approach in 68 cases, the pterional approach in 20 cases, and the other five approaches in 25 cases. Active preventive and therapeutic measurements of hypothalamic dysfunction were adopted pre- and postoperatively. RESULTS: Of the 202 cases, 184 tumors were totally or nearly totally removed (91.1%); 89 cases were resected with the transcallosal-interseptal-interforniceal approach with a total and subtotal removal rate of 92.1%, and 68 cases were removed with the unilateral transfrontal interhemispheric approach with a total and subtotal removal rate of 95.6%. Two patients died (0.9%). The major postoperative complications included diabetes insipidus in 81.7% of the cases, permanent diabetes insipidus in 11.4%, electrolyte disorder in 74.8%, and seizures in 9.4%. The 5-year survival rate was 68.2%. CONCLUSIONS: Appropriate approaches with direct tumor exposure should be determined in order to remove the craniopharyngioma as much as possible, while at the same time carefully protecting the anteroinferolateral wall of the third ventricle (hypothalamus). Active measurements to manage blood sodium disorder and seizures could help to ensure the safety of the operation.

[Supratentorial cavernous angiomas in children].

OBJECTIVE: To discuss the clinical features, treatment, and prognosis of supratentorial cavernous angiomas in children. METHODS: The clinical data of 25 pediatric patients with supratentorial cavernous angioma, 17 boys and 6 girls, aged 9.6 (1-15), were reviewed retrospectively, and the relationship between the duration of epilepsy before surgery and prognosis was analyzed. RESULTS: The 14 patients with preoperative seizures underwent surgery. All (8/8) of the patients suffering from preoperative seizures with an history of less than one year were seizure free after operation, while only half (3/6) of the patients with an history suffering from preoperative seizures with an history of more than one year were seizure free after operation. Ten of the 11 patients with hemorrhage and hemorrhage-related neurological symptoms as the initial symptoms underwent surgery, and no symptoms of re-bleeding and seizure occurred postoperatively. CONCLUSION: Craniotomy for lesionectomy results in good seizure control and re-bleeding avoidance. Better results with regard to seizure control are associated with shorter duration of symptoms before surgery.

[The clinical features and treatment of intracranial tumors in infants].

OBJECTIVE: To explore the treatment plan of intracranial tumors in infants. METHODS: The clinical features and curative effect of 114 patients of intracranial tumors in infants who were admitted and performed microsurgery were analyzed retrospectively. The total removal of tumor was 72.0%, subtotal removal 17.5%, partial removal 10.5%. The patients of 3 years old or so were advised to perform radiotherapy after operation. Follow-up ranges from 13 months to 7 years. RESULTS: The tumor located at posterior fossa (37.7%), sella region (31.6%), hemisphere (19.3%) including in basal ganglia. The common symptoms included headache, vomiting, ataxia, and decrease of visual acuity. All the patients obtained good recovery except one patient dead after operation. Among 86 follow-up cases, 20 patients deceased and 66 patients survived. But 6 patients developed worse than the children of the same age. CONCLUSION: Good prognosis can not be obtained for embryonal tumors and ependymoma through operation only. Although radiotherapy is useful of inhibiting the growth of tumor, the dosage should be decreased for infants and the complications in long term also should be considered simultaneously. It is a trend towards performing chemotherapy after operation. It is not necessary to perform auxiliary therapy for astrocytoma, oligodendroglioma, and mixed glioma, because the prognosis is good after total removal of the tumor.

[Long-term effect of chemotherapy combined with radiotherapy in treatment of intracranial germinoma: report of 39 cases].

OBJECTIVE: To evaluate the long-term effect of chemotherapy combined with radiotherapy in treatment of intracranial germinomas. METHODS: Chemotherapy combined with radiotherapy was given to 45 patients with intracranial germinomas, 24 in the pineal region, 8 in the pineal and suprasellar regions, 4 in the suprasellar region, and 3 in the pineal region and cerebral ventricle from December 1993 to December 1996. Vincristine (VCR), methotrexate (MTX), bleomycin and cisplatin were administered for 4 days as a course of treatment. Then blood routine examination was taken twice a week and blood biochemical examination was taken once a week. A repeat course of chemotherapy was started 4 weeks after if no abnormality in blood examination was found. Local radiotherapy was taken with low to middle dosage (25 - 35 Gy) 1 - 2 months after the second course of chemotherapy. CT and/or MRI examination are made regularly. 39 patients had been followed up for 5 - 8 years. RESULTS: Out of the 39 cases followed-up, one with the relapsing tumor had undergone operation and radiotherapy 2 years before and was given chemotherapy alone without radiotherapy re-relapsed and died in 4 years. One case relapsed 5 years after chemotherapy and radiotherapy and then was given chemotherapy for two more courses with the result of a shrinking of tumor by 80%. During the follow-up 37 patients (95%) survived without relapse of tumor and resumed their normal work or schooling. CONCLUSION: Chemotherapy combined with local radiotherapy with low to middle dosage is the best choice for treatment of intracranial germinomas.