Inflammasomes in rheumatoid arthritis: a pilot study.

BACKGROUND: The inflammasome plays an important role in rheumatoid arthritis (RA), which has rarely been systematically reported. The aim of this study was to understand whether the levels of inflammasomes were related to the severity of RA disease, which might provide a stronger theoretical basis for RA treatment. METHODS: The mRNA expression levels of some inflammasomes and associated molecules, including IL-1beta and IL-18, in peripheral blood mononuclear cells (PBMCs) from 30 RA patients (n = 30) and 16 healthy control (HC) individuals were determined by quantitative real-time polymerase chain reaction (qRT‒PCR), and the levels of plasma IL-1beta and IL-18 were also measured by enzyme-linked immunosorbent assay (ELISA). Moreover, the clinical characteristics and laboratory results of the patients were collected and analyzed in this study. RESULTS: The relative mRNA expression levels of NLRP3, NLRC4, AIM2, caspase-1, and IL-1beta were significantly higher and those of NLRP1, NLRP2 and NLRC5 were notably lower in the HC group than in the RA group. Moreover, the plasma IL-1beta and IL-18 levels were markedly increased in the RA group. Additionally, the mRNA level of AIM2 was negatively correlated with disease activity score 28 (DAS28) by stepwise linear regression analysis. erythrocyte sedimentation rate (ESR) was positively correlated with DAS28 by multiple linear regression analysis in the RA group. CONCLUSIONS: These findings imply the critical role of NLRP3, NLRC4, AIM2, caspase-1 and plasma IL-1beta and IL-18 in the pathogenesis of RA patients, which provides potential targets for the treatment of RA.

Exosomes as Crucial Players in Pathogenesis of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects multiple systems. Its clinical manifestation varies across patients, from skin mucosa to multiorgan damage to severe central nervous system involvement. The exosome has been shown to play an important role in the pathogenesis of autoimmune diseases, including SLE. We review the recent knowledge of exosomes, including their biology, functions, mechanism, and standardized extraction and purification methods in SLE, to highlight potential therapeutic targets for SLE.

Identification of a novel mutation in the BMPR2 gene in a pulmonary arterial hypertension patient using next-generation sequencing.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a hemodynamic state that is characterized by pulmonary vasoconstriction and vascular remodeling, leading to a continuous increase in mean pulmonary arterial pressure, and eventually right heart failure. Mutations of the bone morphogenetic protein type II receptor (BMPR2) gene are the most common genetic cause of PAH. METHODS: A 52-year-old woman was admitted to Shaoxing People's Hospital after suffering from a cough for 2 months. In our hospital, the proband got a thorough medical examination and was diagnosed with PAH following genetic testing. RESULTS: Genetic test showed that the proband carried a novel heterozygous c.1481C>T (p.Ala494Val) mutation in the BMPR2 gene. The new mutation was initially discovered as a potential pathogenic variant by bioinformatics research, but it needed to be functionally verified. CONCLUSIONS: The novel mutation may be related to the development of the PAH. In addition to general examinations, clinicians must thoroughly examine molecular genetics to provide an accurate diagnosis in the clinic, particularly for rare disorders.

Role of Th22 Cells in the Pathogenesis of Autoimmune Diseases.

Upon antigenic stimulation, naïve CD4+T cells differentiate into different subsets and secrete various cytokines to exert biological effects. Th22 cells, a newly identified CD4+T cell subset,are distinct from the Th1, Th2 and Th17 subsets. Th22 cells secrete certain cytokines such as IL-22, IL-13 and TNF-α, but not others, such as IL-17, IL-4, or interferon-γ (IFN-γ), and they express chemokine receptors CCR4, CCR6 and CCR10. Th22 cells were initially found to play a role in skin inflammatory diseases, but recent studies have demonstrated their involvement in the development of various autoimmune diseases. Here, we review research advances in the origin, characteristics and effector mechanisms of Th22 cells, with an emphasis on the role of Th22 cells and their main effector cytokine IL-22 in the pathogenesis of autoimmune diseases. The findings presented here may facilitate the development of new therapeutic strategies for targeting these diseases.

A Novel Mutation in the Myosin Binding Protein C Gene in a Prader-Willi Syndrome Pedigree.

Prader-Willi syndrome (PWS) is a neurogenetic disorder caused by deficiency expression of paternally imprinted genes of the chromosomal region 15. In this study, we report a novel mutation in the myosin binding protein C (MYBPC3) gene in a Prader-Willi syndrome pedigree. Next-generation sequencing (NGS) and Sanger sequencing were performed to define and confirm the MYBPC3 gene mutation. Bioinformatics analysis was also performed for the mutated MYBPC3 protein using available software tools. The proband was diagnosed as PWS with about 4.727Mb copy number missed in the long arm of chromosome 15 and treated with growth hormone on 0.3 IU/day. Sanger sequencing identified a novel heterozygous mutation in the MYBPC3 gene, c.2002C>G (p.R668G). Bioinformatics analysis suggested the variant disease-causing; the Pro residue at 668 in the MYBPC3 protein was highly conserved. Moreover, interactions among MYBPC3 and other proteins suggested the potential effects on the development of cardiomyopathies. This is the first report of PWS with MYBPC3 gene mutation. Besides general examinations, it is vital for physicians to amply molecular genetics to get an accurate diagnosis in the clinic especially for rare diseases.

Function and Role of Regulatory T Cells in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic and heterogeneous autoimmune disease with symmetrical polyarthritis as its critical clinical manifestation. The basic cause of autoimmune diseases is the loss of tolerance to self or harmless antigens. The loss or functional deficiency of key immune cells, regulatory T (Treg) cells, has been confirmed in human autoimmune diseases. The pathogenesis of RA is complex, and the dysfunction of Tregs is one of the proposed mechanisms underlying the breakdown of self-tolerance leading to the progression of RA. Treg cells are a vital component of peripheral immune tolerance, and the transcription factor Foxp3 plays a major immunosuppressive role. Clinical treatment for RA mainly utilizes drugs to alleviate the progression of disease and relieve disease activity, and the ideal treatment strategy should be to re-induce self-tolerance before obvious tissue injury. Treg cells are one of the ideal options. This review will introduce the classification, mechanism of action, and characteristics of Treg cells in RA, which provides insights into clinical RA treatment.

Inflammasome and Its Therapeutic Targeting in Rheumatoid Arthritis.

Inflammasome is a cytoplasmic multiprotein complex that facilitates the clearance of exogenous microorganisms or the recognition of endogenous danger signals, which is critically involved in innate inflammatory response. Excessive or abnormal activation of inflammasomes has been shown to contribute to the development of various diseases including autoimmune diseases, neurodegenerative changes, and cancers. Rheumatoid arthritis (RA) is a chronic and complex autoimmune disease, in which inflammasome activation plays a pivotal role in immune dysregulation and joint inflammation. This review summarizes recent findings on inflammasome activation and its effector mechanisms in the pathogenesis of RA and potential development of therapeutic targeting of inflammasome for the immunotherapy of RA.

A novel compound heterozygous mutation of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome.

PURPOSE: Gitelman syndrome (GS) is an autosomal recessive renal tubular disorder characterized by salt wasting and hypokalemia resulting from loss-of-function mutations in the solute carrier family 12A3 (SLC12A3) gene encoding the thiazide-sensitive NaCl cotransporter (NCC). Here, we investigated the clinical manifestations and genetic features of a Chinese pedigree with GS. METHODS: Next-generation sequencing and Sanger sequencing analysis were performed to define and confirm the SLC12A3 gene mutations of the patient (proband II:1) and this pedigree. Clinical manifestations and biochemical parameters were collected and analyzed. RESULTS: Genetic analysis of the SLC12A3 gene identified two novel mutations in the proband, heterozygous (c.2842delT) and heterozygous (c.1569_1586del) mutation, respectively. Additionally, heterozygous (c.2842delT) mutation in SLC12A3 gene was found in his father and younger brother. The other heterozygous (c.1569_1586del) mutation in SLC12A3 gene was carried by his mother. CONCLUSIONS: Two novel mutations may be related to the occurrence of the GS in the pedigree. However, additional studies are particularly required to explore the underlying molecular mechanisms.

Mitochondrial A3243G mutation causes mitochondrial encephalomyopathy in a Chinese patient: Case report.

RATIONALE: Mitochondrial mutations are associated with a wide spectrum of clinical abnormalities. More than half of these mutations are distributed in the 22 mitochondrial tRNA genes, including tRNA. In particular, the A3243G mutation in the tRNA gene causes mitochondrial encephalomyopathy. PATIENT CONCERNS: A 12-year-old boy was admitted to Shaoxing People's Hospital because there is a reduction in the volume of speech, dysphonia, unable to write, recognize words, and unable to wear clothes, accompanied by unstable walking after treatment of unexplained fever and somnolence. DIAGNOSES: The proband underwent a thorough examination in our hospital and was diagnosed as mitochondrial encephalomyopathy. The proband carried the pathogenic heteroplasmic mutation A3243G mutation in mitochondrial 12S rRNA gene. Although his parents did not carry the mutation. INTERVENTIONS: Intravenous acyclovir, ceftriaxone, and dexamethasone were used for the patient's antiviral, antimicrobial, and anti-inflammatory therapy, respectively. Intravenous mannitol was gradually tapered for reducing intracranial pressure with furosemide for inducing diuresis. Intravenous arginine could help to treat alkalosis and supple some essential amino acids. Oral oxiracetam capsules, vitamin B1, and coenzyme Q10 were used for providing nutrition and improving energy. His medications were 30 mg vitamin B1, 0.1 g vitamin C, and mecobalamin 750 µg daily after discharge from our hospital. OUTCOMES: The patient was able to walk and talk slowly with improved writing skills and no stroke-like episodes. The neurological examination was negative and muscle tension was identified as grade V. LESSONS: Mitochondrial encephalomyopathy has different phenotypes, in addition to traditional examinations, it is important for clinicians to be familiar with genetic testing methodology as well as applications of these tests in clinic to get an accurate diagnosis.

Mitochondrial COI/tRNASer(UCN) G7444A mutation may be associated with aminoglycoside-induced and non-syndromic hearing impairment.

Mutations in mitochondrial DNA (mtDNA) have been reported to have important roles in aminoglycoside-induced hearing impairment; however, the underlying molecular mechanisms have remained largely elusive. The current study presented a case of a Chinese patient with maternally inherited aminoglycoside-induced hearing impairment. A profound hearing impairment was identified by clinical evaluation; furthermore, analysis of the mitochondrial genome sequence of the patient revealed the presence of an A1555G mutation in the 12S rRNA as well as a G7444A mutation in the COI/tRNASer(UCN) gene. As the G7444A mutation is highly conserved between various species, it may be a modifying factor with regard to the pathological effects of the A1555G mutation.

Distributions and Types of Multidrug-Resistant Acinetobacter baumannii in Different Departments of a General Hospital.

BACKGROUND: Acinetobacter baumannii is the most prevalent strain in hospitals and different clinical departments. OBJECTIVES: The current study aimed to investigate the genetic characteristics and resistance mechanisms of A. baumannii isolated from clinical samples in Shaoxing people's hospital affiliated to Zhejiang University, Shaoxing, China. PATIENTS AND METHODS: Acinetobacter baumannii strains were isolated from blood, phlegm and skin of the patients hospitalized in different departments as respiratory medicine, plastic surgery and intensive care unit (ICU). Multilocus sequence typing (MLST) was used to characterize the isolates. Kirby-Bauer test was used to evaluate antibiotic resistance of the bacteria. The expression of resistance inducing genes was detected by reverse transcription polymerase chain reaction (RT-PCR). The results were analyzed and compared. RESULTS: Two bacterial types, ST208, and ST218, were identified in all 140 samples. The ST208 mainly came from ICU and department of respiratory medicine, while ST218 from department of plastic surgery; 70.21% of ST208 and 84.78% of ST218 were carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-susceptible Acinetobacter baumannii (CSAB), respectively. Multidrug-resistance genes in CRAB isolated from the hospital mainly included, oxa-23, oxa-5, intl 1 and qaceΔ1-sul 1. Besides, the highest and lowest antibiotic resistance was observed in the strains isolated from blood samples and wounds, respectively. CONCLUSIONS: The distribution of AB varies in different clinical departments and samples. In the hospital under study, the main types of AB were ST208 and ST218. The genes which affect the ability of antibiotic-resistance were oxa-23, oxa-51, intl 1 and qaceΔ1-sul 1.

Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk.

Genetic polymorphism of miR-34b/c gene is a candidate factor for attributing predisposition to carcinoma. However, results of mounting studies, concerning association of miR-34b/c gene rs4938723 with risk of cancer, present contradictory results. Therefore, a meta-analysis was performed to systematically assessment the possible association between them. The overall results of meta-analysis indicate a significant association was only observed between rs4938723 and cancer risk in genotype model (P(h)=0.203, OR=1.09, 95% CI=1.01-1.70 for CT vs. TT). After stratifying by ethnicity and cancer type, genotype CT of rs4938723 was significantly association with an increased cancer risk in Asian population (P(h)=0.187, OR=1.10, 95%CI=1.01-1.20), allele C and genotype CT were significantly positive associated with hepatocellular cancer (P(h)=0.113, OR=1.11, 95%CI=1.01-1.23 for C vs. T; P(h)=0.121, OR=1.19, 95%CI=1.03-1.37 for CT vs. TT), but rs4938723 was negative associated with risk of colorectal cancer (P(h)=0.342, OR=0.66, 95%CI=0.47-0.92 for CC vs. TT; P(h)=0.519, OR=0.67, 95%CI=0.49-0.93 for CC vs. CT/TT; P(h)=0.443, OR=0.71, 95%CI=0.51-0.99 for CC/TT vs. CT). These findings suggested that rs4938723 was a susceptible locus only for hepatocellular cancer and colorectal cancer.

[Cost-effectiveness analysis of the current measures for malaria prevention in Yuanjiang valley, Yunnan province].

OBJECTIVE: To evaluate the cost-effectiveness analysis of the measures currently used for malaria prevention in the region of Yuanjiang River Valley. METHODS: The efficacy and cost-effectiveness analysis of chemoprophylaxis, single DDT residual spraying and a combination of both were evaluated through three field intervention trials. RESULTS: (1) From July to November, the rate ratio of malaria incidence among building workers of expressway as the group of chemoprophylaxis using combined piperaquine/sulfadoxine once per month was 0.35 (95% CI: 0.20-0.59); the cost per individual protected (CIP) and the cost per case averted (CCA) were RMB 6.69 yuan and RMB 459 yuan respectively. (2) In the hyper-endemic villages near the river, the rate ratio in the group using chloroquine plus primaquine once every 10 days for 5 months was 0.28 (95% CI: 0.08-0.99); the CIP and CCA were RMB 5.30 yuan and RMB 300 yuan respectively. (3) The standardized morbidity ratio (SMR) was 100%, 98% and 50% respectively for the chemoprophylaxis group with pyrimethamine/sulfadoxine once per month from May to September, the group with single DDT residual spraying in April and the group of combined chemoprophylaxis and DDT spraying. The CIP was RMB 1.49, 2.48 and 3.97 yuan for the three groups respectively. As compared with the previous year, no cases were averted from the chemoprophlaxis group; the CCA was RMB 14,535 yuan and 908 yuan respectively for the DDT spraying group and the group with combined measures. CONCLUSION: There was no significant difference on the chemoprophylaxis cost between the group using piperaquine/sulfadoxine combination once per month and that of chloroquine plus primaquine once per ten days. However, the study proved an efficacy for malaria prevention in the former but not in the latter. In comparison with the groups of single measures, the group with combined measures showed the best efficacy and effectiveness, but highly expensive.