Tocilizumab for treating mevalonate kinase deficiency and TNF receptor-associated periodic syndrome: a case series and literature review.

BACKGROUND: Mevalonate kinase deficiency (MKD) and TNF receptor-associated periodic syndrome (TRAPS) are categorized as systemic autoinflammatory diseases (SAIDs), which are rare diseases characterized by early onset, severe conditions, and challenging diagnosis and treatment. Although different SAIDs have varying standard treatments, some SAIDs are poorly controlled after routine treatment, seriously affecting the growth and development of children and their quality of life. This study aims to provide more treatment strategies for SAIDs. CASE PRESENTATION: We present two Chinese patients with MKD and TRAPS who were resistant to TNF- (tumor necrosis factor-) α blockade. After using etanercept, baricitinib, and glucocorticoid, patients with MKD and TRAPS still had periodic fever and rash. Due to the unavailability of IL-1 antagonists in the Chinese Mainland, we started administering intravenous tocilizumab (TCZ) at a dosage of 240 mg every three weeks. They had not experienced fever or rash after receiving one or two doses of TCZ. Before treatment with TCZ in the MKD patient, white blood cell (WBC) count, and TNF-α level were normal, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) increased significantly, and IL-6 increased slightly. After treatment with TCZ, ESR and CRP levels returned to normal; however, IL-6 increased occasionally. In the TRAPS patient, ESR, CRP, WBC, IL-6, and TNF-α levels were increased significantly. After TCZ treatment, ESR, CRP, WBC, IL-6, and TNF-α levels returned to normal. The two patients were treated with TCZ for more than six months and achieved clinical and serological remission. Furthermore, they had no adverse reactions after injection of TCZ. CONCLUSION: In the absence of IL-1 antagonists in mainland China, tocilizumab emerges as an alternative drug in SAIDs that are resistant to TNF-α blockade.

Comparative genomic analysis of Lacticaseibacillus paracasei SMN-LBK from koumiss.

Lacticaseibacillus paracasei SMN-LBK, which was isolated in Xinjiang, has been shown to be a probiotic strain and used as the auxiliary starter for dairy fermentation. Comparative genomic analysis was performed to investigate the metabolic preference and ethanol tolerance mechanisms of L. paracasei SMN-LBK. The results of comparative genomics showed that L. paracasei strains had high conservation and genetic diversity. SMN-LBK encoded various genes related to carbohydrate and amino acid metabolism pathways, which endow this strain with good fermentation potential. In addition, 6 CRISPR sequences and 8 cas proteins were found in SMN-LBK, and these could play vital roles in the immune system. Furthermore, a unique cluster of potential secondary metabolism genes related to bacteriocins was detected in the genome of SMN-LBK, and this could be important for the preservation of fermented foods. Multiple genes related to alcohol tolerance were also identified. In conclusion, our study explained the traits that were previously demonstrated for SMN-LBK as phenotypes and provided a theoretical basis for the application of SMN-LBK in the food industry.

Pathophysiology, clinical manifestations and current management of IL-1 mediated monogenic systemic autoinflammatory diseases, a literature review.

BACKGROUND: Systemic autoinflammatory diseases (SAIDs) are hyperinflammatory and immune-dysregulation conditions that present in childhood. This kind of disease is a rare disease with early-onset, severe condition and difficult diagnosis, which seriously affects the growth and development of children. Most children need a genetic diagnosis. However, with the limitation of access to genetic testing and the detection of somatic mutations, the diagnosis of SAIDs remains challenging. IL-1 is one of the important cytokines involved in the pathogenesis of SAIDs. Here we briefly review monogenic SAIDs mediated by aberrant IL-1 production, with the aim to further understand the pathogenesis, clinical manifestations and treatments of IL-1 mediated SAIDs. METHODS: Literature reviews were performed using "PubMed" and "Web of Science" by searching for the terms "autoinflammatory diseases" and "IL-1". RESULTS: Monogenic SAIDs mediated by IL-1 include MKD, FMF, TRAPS, PAAND, PAPA, CAPS, DIRA, Majeed syndrome, NAIAD, NLRC4-MAS, PFIT, APLAID. Monogenic SAIDs have early onset, various clinical manifestations and difficult diagnosis, so early recognition and early treatment can reduce the complications and enhance the quality of life. CONCLUSIONS: There are many kinds of IL-1 mediated SAIDs. Pediatricians should be alert to SAIDs in the face of the patients with repeated fever, repeated rash and poor effect of routine treatment. The patients should be carried out with gene testing and treatment in time.

The Effect of the Ratio of Gamma Aminobutyric Acid-Producing Saccharomyces cerevisiae DL6-20 and Kluyveromyces marxianus B13-5 Addition on Cheese Quality.

Kazakh cheese is a traditional dairy product in Xinjiang, China. The function and potential probiotic characteristics of Saccharomyces cerevisiae DL6-20 and Kluyveromyces marxianus B13-5 in Kazakh cheese and its contribution to cheese fermentation was studied. In this study, the effect of the addition ratio of gamma aminobutyric acid (GABA)-producing S. cerevisiae DL6-20 and K. marxianus B13-5 on cheese quality was investigated. Cheeses were prepared by fermentations with a total of six treatments: comercial culture alone as control (CS), a combination with one yeast, either; K. marxianus B13-5 (CSM); S. cerevisiae DL6-20 (CSS); and three different proportions of this two yeasts (CSM:CSS 1:1, 1:2, 2:1). We measured the GABA content of cheese, as well as basic physical and chemical indicators, microbial content, free amino acid (FAA) content, texture, and flavor compound content. The total FAA content of mixed bacteria fermentation was higher than that of the single bacteria alone. The GABA content CSM:CSS 1:2 GABA content was 0.114 g/100 g, CSM:CSS 2:1 GABA content was 0.12 g/100 g, CSM:CSS1:1 content of GABA produced in the late ripening period of cheese was the highest, reaching 0.189 g/100 g and the number of LAB and yeasts in CSM:CSS 1:1 was higher than that of other cheeses. The mixed-strain fermentation generally produced cheeses with a higher protein content than that of the single-strain fermentation in the late stage of the maturation process, especially the protein content of CSM:CSS 1:1 during the ripening period, when the protein content was highest at day 50. CSM:CSS 1:1 had a low moisture content, making it easy to store. With the exception of water and protein content, there is no significant difference in other physical and chemical indicators. CSM:CSS 1:1 contributed to the formation of cheese texture. In addition, multivariate statistical analysis indicated that mixed-strain fermentation was beneficial to the production of cheese aroma, with the aroma production performance of CSM:CSS 1:2 and CSM:CSS 2:1 found to be better than that of CSM: CSS 1:1.

Differences between Kazak Cheeses Fermented by Single and Mixed Strains Using Untargeted Metabolomics.

Mixed fermentation improves the flavor quality of food. Untargeted metabolomics were used to evaluate the impact of mixed fermentation and single-strain fermentation on the volatile and non-volatile compound profiles of Kazak cheese. Lacticaseibacillus paracasei SMN-LBK and Kluyveromyces marxianus SMN-S7-LBK were used to make mixed-fermentation cheese (M), while L. paracasei SMN-LBK was applied in single-strain-fermentation cheese (S). A higher abundances of acids, alcohols, and esters were produced via mixed fermentation. Furthermore, 397 differentially expressed non-volatile metabolites were identified between S and M during ripening. The flavor compounds in mixed-fermentation cheese mainly resulted from ester production (ethyl butanoate, ethyl acetate, ethyl octanoate, and ethyl hexanoate) and amino acid biosynthesis (Asp, Glu, Gln, and Phe). The metabolites were differentially expressed in nitrogen metabolism, D-glutamine and D-glutamate metabolism, phenylalanine metabolism, D-alanine metabolism, and other metabolic pathways. The amount of flavor compounds was increased in M, indicating that L. paracasei SMN- LBK and K. marxianus SMN-S7-LBK had synergistic effects in the formation of flavor compounds. This study comprehensively demonstrated the difference in metabolites between mixed-fermentation and single-strain-fermentation cheese and provided a basis for the production of Kazak cheese with diverse flavor characteristics.

Effective therapy of tocilizumab on systemic juvenile idiopathic arthritis-associated refractory macrophage activation syndrome.

OBJECTIVES: To evaluate the safety and efficacy of tocilizumab (TCZ) on refractory macrophage activation syndrome (rMAS) associated with systemic juvenile idiopathic arthritis (sJIA-rMAS). METHODS: We retrospectively reviewed the charts of 14 patients diagnosed with sJIA-rMAS, who were treated with TCZ after failing conventional therapies at three hospital centres from January 2016 to December 2020. Demographic, clinical, and laboratory characteristics were recorded at the onset of MAS, before TCZ (pre-TCZ), and 14 days after TCZ (post-TCZ). RESULTS: The clinical manifestation of sJIA-rMAS included fever (100%), skin rashes (35.7%), lymphadenomegaly (42.9%), hepatomegaly (57.1%), splenomegaly (7.1%), gastrointestinal symptoms (28.6%), arthritis (14.3%), myalgia (28.6%), and polyserositis (14.3%). After TCZ treatment, fever (100%, 14/14), gastrointestinal symptoms (100%, 4/4), and myalgia (100%, 4/4) were significantly improved after 1 week (P < 0.05). Skin rashes, lymphadenomegaly, and arthritis also improved in many patients, but these parameters did not reach statistical significance. In post-TCZ group, decreases in levels of C-reactive protein, erythrocyte sedimentation rate, and serum ferritin of sJIA-rMAS were observed compared with pre-TCZ (P < 0.05). No disease relapse or fatality was recorded during the follow-up (25 months, range 3-60 months). CONCLUSIONS: TCZ is safe and effective for the treatment of sJIA-rMAS after failure of conventional therapies.

Impact of NSLAB on Kazakh cheese flavor.

Xinjiang is a multiethnic region of China. Traditionally, most ethnic minorities are known to produce and consume cheese. Nomadic people have been reported to use lactic acid bacteria (LAB) for decades to produce fermented dairy products as part of a balanced diet. Non-starter LAB (NSLAB) contribute to different degrees of ripening, depending on the cheese variety. In the present study, we screened three types of NSLAB with good proteolysis and autolytic abilities from traditional Kazakh cheese: Pediococcus acidilactici R3-5, Staphylococcus epidermidis R4-2, and Lactobacillus rhamnosus R9-6. A control (no NSLAB) was also included, resulting in four distinct types of cheese samples. We used gas chromatography-mass spectrometry and the electronic nose system to identify volatile compounds and analyze the effect of NSLAB on cheese flavor at the ripening stage. The physicochemical indicators changed significantly during the ripening of Kazakh cheese. Compared with the control, the protein content, free fatty acid content, pH, flavor compounds, and odor profiles of the test cheeses were significantly different. The major chemical differences among cheeses were the synthesis of some key volatile components (ethyl caprylate, ethyl caprate, myristyl carbonate, capric acid, caprylic acid, nonanal, and benzyl alcohol). NSLAB can be used as an adjunct starter to make Kazakh cheese and the use of NSLAB affected the cheese flavor quality positively.

Probiotic potential of γ-aminobutyric acid (GABA)-producing yeast and its influence on the quality of cheese.

Kazakh cheese is a traditional dairy product in Xinjiang, China. To study the function and potential probiotic characteristics of yeast in Kazakh cheese and its contribution to cheese fermentation, we screened the γ-aminobutyric acid (GABA)-producing yeasts Pichia kudriavzevii 1-21, Kluyveromyces marxianus B13-5, Saccharomyces cerevisiae DL6-20, and Kluyveromyces lactis DY1-10. We investigated the potential probiotic properties of these strains and their use in cheese fermentation (cheeses designated CSP, CSM, CSS, and CSI, respectively); a control with no added yeast was designated CS. The results showed that the 4 yeast strains all showed high self-polymerization (2- and 24-h autoaggregation capacity of >80 and 90%, respectively), hydrophobicity (40-92% variation, low hydrophobicity in xylene, but within the range of probiotics), and the ability to survive the gastrointestinal tract (survival rate >75% after simulation), indicating the probiotic ability of the strains in vitro. The GABA production capacity of the CSM cheese increased (to 95.6 mg/100 g), but its protein content did not change significantly, and amino acid degradation was obvious. The GABA production capacity of the CSS cheese decreased (to 450 mg/kg); its protein content declined, and its amino acid content increased. Except for water and protein, we found no obvious differences in most physical and chemical indicators. Kluyveromyces marxianus B13-5 helped to form the desired texture. Multivariate statistical analysis showed that fermentation of the cheese with the 4 yeasts improved the production of esters and alcohols. The CSS cheese had good aroma production performance, because S. cerevisiae DL6-20 produced high concentrations of isoamyl alcohol, hexanoic acid ethyl ester, benzyl alcohol, octanoic acid ethyl ester, 3-hydroxy-2-butanone, and hexanoic acid; the content of 2-methyl-propanoic acid was low. Compared with the CSP cheese, the CSI and CSM cheeses had a fruitier aroma and a milder odor, but the CSI and CSM cheeses had high concentrations of ethyl acetate, butanoic acid, ethyl ester, 3-methyl-1-butanol-acetate, ethyl hexanoate, ethyl octanoate, acetic acid 2-phenylethyl ester, and ethyl lactate; concentrations of 3-methyl-butanoic acid, propanoic acid, acetic acid, and butanoic acid were low. The CSP cheese had stronger acid-producing ability. The order of fragrance production performance was CSS > CSI, CSM > CSP > CS. Research into the fermentation mechanisms of GABA-producing yeast in cheese will provide a theoretical basis for the quality control and industrial production of Kazakh cheese.

Kawasaki disease shock syndrome: clinical characteristics and possible use of IL-6, IL-10 and IFN-γ as biomarkers for early recognition.

BACKGROUND: As an acute febrile and inflammatory disease, Kawasaki disease (KD) could develop Kawasaki disease shock syndrome (KDSS) sometimes. However its pathogenesis was still not well known. This study was to learn more about the clinical features and evaluate the role of cytokines in the pathogenesis of KDSS. METHODS: We collected clinical and laboratory data retrospectively for all patients with KDSS(KDSS, n = 27)who were hospitalized at our hospital from Jan 2014 to Oct 2017. For patient with KDSS, we randomly identified 43 patients with KD as control subjects (KD, n = 43). Clinical features, laboratory evaluations were collected. Cytokines IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ in serum were assayed using flow cytometric bead array. RESULTS: The patients with KDSS were older age (43.41 ± 31.42 vs 28.81 ± 21.51 months, P < 0.05), longer duration of fever (10.63 ± 5.12 vs 6.98 ± 2.45 days, P < 0.05), higher WBC count, neutrophils, CRP, ESR, PCT and D-dimer, and lower hemoglobin and albumin, more severe hyponatremia and hypokalemia, more refractory to IVIG therapy, more coronary artery abnormalities (CAAs), aseptic meningitis, and longer duration of hospitalization than patients with KD (all P < 0.05). The levels of serum IL-6 [184.1 (27.7-2577.3) vs 54.1 (4-425) pg/ml], IL-10 [42.6 (5-236.7) vs 9.4 (3-94) pg/ml], TNF-α [2.6 (1.0-23.4) vs 2.1 (1-6) pg/ml] and IFN-γ [18.3 (4.5-94.4) vs 6.7 (2-56) pg/ml] in KDSS patients were significant higher than KD patients (all P < 0.05). ROC curves showed that 66.7 pg/ml of IL-6, 20.85 pg/ml of IL-10 and 8.35 pg/ml of IFN-γ had sensitivity and specificity for identifying KDSS as 85.2 and 62.8%; 66.7 and 83.7%; 74.1 and 74.4% respectively. No fatality was recorded in this series. CONCLUSIONS: KDSS were characteristic as more cytokine production and prone to developing IVIG non-responsiveness and CAAs. KD patients with IL-6 above 66.7 pg/ml, IL-10 above 20.85 pg/ml, and IFN-γ above 8.35 pg/ml suggested higher risk for KDSS.

[Progress on the study of NLRP3 inflammasome in autoinflammatory diseases of children].

Autoinflammatory diseases (AID) in childhood is one of refractory diseases, whose pathogenesis is not completely clear. In recent years, a large number of studies have shown that NLRP3 inflammasome plays an important role in the development of AIDs in children. Inflammasome is a cytosolic multiprotein complex that can activate cysteinyl aspartate-specific protease-1 (caspase-1), to further promote the maturation and secretion of proinflammatory cytokines IL-1ß and IL-18 as well as pyroptosis and regulate innate immune response. IL-1 receptor antagonist (Anakinra) and IL-1ß monoclonal antibody (Canakinumab) have good therapeutic effects in children with AIDs. This article reviews the research progress of NLRP3 inflammasome in the pathogenesis of autoinflammatory diseases.