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1.
Artigo em Inglês | MEDLINE | ID: mdl-32087013

RESUMO

OBJECTIVES: Serum CA72-4 levels are elevated in some gout patients but this has not been comprehensively described. The present study profiled serum CA72-4 expression in gout patients and verified the hypothesis that CA72-4 is a predictor of future flares in a prospective gout cohort. METHODS: To profile CA72-4 expression, a cross-sectional study was conducted in subjects with gouty arthritis, asymptomatic hyperuricaemia, four major arthritis types (OA, RA, SpA, septic arthritis) and healthy controls. A prospective gout cohort study was initiated to test the value of CA72-4 for predicting gout flares. During a 6-month follow-up, gout flares, CA72-4 levels and other gout-related clinical variables were observed at 1, 3 and 6 months. RESULTS: CA72-4 was highly expressed in patients with gouty arthritis [median (interquartile range) 4.55 (1.56, 32.64) U/ml] compared with hyperuricaemia patients [1.47 (0.87, 3.29) U/ml], healthy subjects [1.59 (0.99, 3.39) U/ml] and other arthritis patients [septic arthritis, 1.38 (0.99, 2.66) U/ml; RA, 1.58 (0.95, 3.37) U/ml; SpA, 1.56 (0.98, 2.85) U/ml; OA, 1.54 (0.94, 3.34) U/ml; P < 0.001, respectively]. Gout patients with frequent flares (twice or more in the last year) had higher CA72-4 levels than patients with fewer flares (fewer than twice in the last year). High CA72-4 level (>6.9 U/ml) was the strongest predictor of gout flares (hazard ratio = 3.889). Prophylactic colchicine was effective, especially for patients with high CA72-4 levels (P = 0.014). CONCLUSION: CA72-4 levels were upregulated in gout patients who experienced frequent flares and CA72-4 was a useful biomarker to predict future flares.

2.
Hum Mol Genet ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31985003

RESUMO

High serum urate is a prerequisite for gout and associated with metabolic disease. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control, however there has been little progress in understanding the molecular basis of the associated loci. Here we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify ten new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new candidate loci. By cis- and trans-eQTL colocalization analysis we identified 34 and 20 genes respectively where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway; and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Functional fine-mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL containing putative causal SNPs. This systematic analysis of serum urate GWAS loci identified candidate causal genes at 24 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.

4.
Pediatr Nephrol ; 35(3): 441-446, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31811538

RESUMO

BACKGROUND: The prevalence of hyperuricemia is increasing in adults, while the prevalence among adolescents is seldom reported. METHODS: A cross-sectional survey by multistage, stratified sampling method was carried out in Shandong Province during 2017-2018. A total of 9371 adolescents aged from 13 to 19 years were randomly sampled and analyzed in this survey. RESULTS: The overall mean serum uric acid (sUA) concentration was 6.08 ± 1.57 mg/dL and overall hyperuricemia prevalence was 25.4% and 60.5% (when hyperuricemia was defined as sUA ≥ 7 mg/dL or ≥ 5.5 mg/dL). Prevalence were 42.3% (male) and 8.0% (female) when limit was 7 mg/dL and prevalence were 82.1% (male) and 38.4% (female) when limit was 5.5 mg/dL. Male gender, increased body mass index, increased waist circumstance, increased triglycerides, increased fasting blood glucose, increased systolic blood pressure, decreased estimated glomerular filtration rate, and positive family gout history were associated with the enhanced risk of hyperuricemia according to univariate and/or multivariate logistic regression analysis. Food intake frequency of carbonate beverage, mutton, and other kinds varied between hyperuricemia adolescents and normal sUA ones. CONCLUSIONS: The studied adolescent population showed sUA level and hyperuricemia prevalence which are even higher than those of adults in China. The epidemic of youth hyperuricemia may pose a future threat of gout attacks and other hyperuricemia-related diseases, which alarms the public, health professionals and health policy makers to prepare the future health challenges.

5.
J Natl Cancer Inst ; 112(2): 145-153, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31086947

RESUMO

BACKGROUND: The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase III clinical trial was conducted to evaluate the efficacy, safety, and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine. METHODS: A multicenter, randomized, double-blind trial started on November 22, 2012 in China. In total, 7372 eligible women aged 18-45 years were age-stratified and randomly assigned to receive three doses of the test or control (hepatitis E) vaccine at months 0, 1, and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received three doses of the vaccine. This report presents data from a prespecified interim analysis used for regulatory submission. RESULTS: In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval = 55.6% to 100.0%, 0 of 3306 in the vaccine group vs 10 of 3296 in the control group) and 97.8% (95% confidence interval = 87.1% to 99.9%, 1 of 3240 vs 45 of 3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months. CONCLUSIONS: The E coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18-associated high-grade genital lesions and persistent infection in women.

6.
Hum Vaccin Immunother ; : 1-9, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31770068

RESUMO

An Escherichia. coli-produced HPV-16/18 bivalent vaccine has been proved to be well-tolerated and highly efficacious against diseases associated with vaccine HPV types. As a part of the multi-center, randomized, double-blind phase III clinical trial, this lot-to-lot consistency study aimed to assess the safety and immunogenicity consistency of this novel HPV vaccine, which is also one of the objectives of the phase III trial. A total of 3689 healthy women aged 18-45 years were enrolled and randomly assigned 1:1:1 to three lots of the HPV vaccine groups. The primary outcomes were the IgG antibody level at 1 month after the last dose (month 7). In the immunogenicity per-protocol set (PPS), almost all of the participants seroconverted at month 7 and remained seropositive at month 42. For each paired comparison of the three lot groups, the two-sides of 90% CIs of GMC ratios for both IgG and neutralizing antibodies for HPV-16 and HPV-18 at month 7 were within the equivalence interval [0.5, 2]. Lot consistency was also demonstrated at month 42. The majority of recorded solicited reactions were mild or moderate. The incidences of solicited reactions of Lot 2 and Lot 3 were slightly higher than Lot 1. However, the incidences of solicited reactions of ≥ grade 3 and solicited reactions by symptoms were all similar among the three lot groups. None of the SAEs was considered related to vaccination by the investigator. In conclusion, this study demonstrates lot-to-lot consistency of the 3 consecutive lots of the E. coli-produced HPV-16/18 bivalent vaccine.

7.
J Transl Med ; 17(1): 389, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767029

RESUMO

BACKGROUND: Conflicting evidence exists on the relationship between body mass index (BMI) and serum uric acid (SUA). Therefore, we aimed to evaluate the SUA-BMI relationship in a large-scale epidemiological survey in coastal China. METHODS: This survey was conducted among the general population in the coastal region of China from September 2014 to January 2015. SUA Levels were measured by the automatic Sysmex Chemix-180 biochemical analyzer. RESULTS: A total of 6098 men (BMI: 24.58 ± 3.74 kg/m2) and 7941 women (24.56 ± 3.64 kg/m2) were included in this study. A stronger positive BMI-SUA association was found for men than women (all P-values < 0.05). The piecewise linear spline models indicated a U-shaped relationship of SUA-BMI association for both men and women; and the lowest turning points were at 19.12 kg/m2 for men and 21.3 kg/m2 for women. When BMIs were lower than the nadir point, each 1 kg/m2 increase in BMI related to a 7.74-fold (95% CI - 14.73, - 0.75) reduction for men and 2.70-fold reduction (- 4.47, - 0.94) for women in SUA levels. Once the BMI was higher than the nadir point, each 1 kg/m2 increase in BMI was related to a 5.10-fold (4.44, 5.77) increment for men and 3.93-fold increment (3.42, 4.43) for women in SUA levels. The regression coefficient differences between the two stages were 12.84 (5.66, 20.03) for men and 6.63 (4.65, 8.61) for women. CONCLUSIONS: A U-shaped relationship between BMI and SUA was found for both men and women; the association was stronger for men than women.

8.
Open Forum Infect Dis ; 6(10): ofz380, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31660344

RESUMO

Background: A new Sabin strain inactivated poliovirus vaccine (sIPV) proved to be immunogenic and safe in all IPV primary immunization in the previous study, with the corresponding profiles in sequential immunizations unclear. Methods: Two clinical trials on the "IPV + 2 bivalent oral polio vaccine (2bOPV)" (Trial A) and "2IPV + bOPV" (Trial B) vaccination were conducted. Both clinical trials were randomized, controlled, double-blinded, noninferiority trials, and wild-strain IPV (wIPV) was adopted as the control vaccine. In each clinical trial, 240 healthy infants were enrolled and randomly assigned to receive sequential vaccinations containing sIPV or wIPV. Immunogenicity and safety were assessed using per-protocol and safety populations, respectively. Results: For Trial A, the seroconversion rates in the experimental and control groups were 100% and 99.1%, respectively, against type 1; both 100.0% against type 3. For Trial B, the seroconversion rates in experimental and control groups were 99.2% and 100.0%, respectively, against type 1; both 100% against type 3. No serious adverse events related to vaccines were reported. Conclusions: The new sIPV demonstrated an immunogenicity noninferior to that of the wIPV and a good safety profile in sequential vaccination with bOPV. Clinical trial numbers: NCT:03822754; NCT:03822767.

9.
Arthritis Res Ther ; 21(1): 200, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477161

RESUMO

BACKGROUND: Low doses of febuxostat or benzbromarone are widely used in Asian countries, but lacking studies to compare the efficacy and safety of the two urate-lowering drugs. METHODS: To compare the efficacy and safety of low-dose febuxostat with low-dose benzbromarone in patients with primary gout, a randomized controlled, open-label trial was performed among male patients with primary gout for urate-lowering therapy (ULT) in a dedicated gout clinic in China. Randomization was carried out by a third-party institution according to random number table. Patients were randomly assigned 1:1 to febuxostat group (Feb group) (20 mg daily) or benzbromarone group (Ben group) (25 mg daily) and treated for 12 weeks. General information and biochemical data were collected at baseline and at every visit monthly. Clinical characteristics before and after the ULT were analyzed in the two groups by SPSS and EmpowerStats software. RESULTS: Two hundred forty patients were enrolled and randomized in the two groups, with 214 patients completing 12 weeks' ULT (105 in the Feb group and 109 in the Ben group). After 12 weeks, substantial percentages of patients in both Feb and Ben group achieved the target serum uric acid (sUA) (< 360 µmol/L) and serum urate levels were reduced significantly for both groups (Feb 39.5% and 156.83 µmol/L vs. Ben 35.7% and 163.99 µmol/L). Multivariate analysis suggests baseline sUA level and renal function were associated with the outcome of the rate of achieving target sUA (RAT). Sub-group analysis suggests low doses of febuxostat and benzbromarone rendered better RAT for patients with sUA < 540 µmol/L and creatinine clearance rate (Ccr) ≤ 110 mL min-1 1.73 m-2 at baseline. The drugs were well tolerated, and the incidence of gout flares in Feb group was similar with that in Ben group (22.85% vs. 33.94%). CONCLUSION: Overall, febuxostat 20 mg daily and benzbromarone 25 mg daily reduced sUA, and gout patients with sUA level < 540 µmol/L or Ccr ≤ 110 mL min-1 1.73 m-2 at baseline had better chance to achieve target uric acid levels. The current study suggests sUA level and renal function are key factors to consider when recommending low doses of febuxostat and benzbromarone to gout patients. TRIAL REGISTRATION: Registered with ChiCTR, No. ChiCTR1800019352 (retrospectively registered).

10.
Mol Med Rep ; 20(4): 3292-3300, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432190

RESUMO

Previous studies have demonstrated the effects of hyperuricemia on the damage to target organs, including the kidneys, joints and the heart. However, it is unclear whether hyperuricemia results in damage to the intestines. The aim of the present study was to investigate intestinal barrier dysfunction in a mouse model of hyperuricemia constructed by knocking out the urate oxidase (Uox) gene. The morphology of the intestine was assessed via hematoxylin and eosin, and alcian blue staining. The serum and intestinal tissue levels of uric acid, tumor necrosis factor (TNF)­α and interleukin (IL)­6, in addition to the presence of uremic toxins in the serum, were assessed. The levels of diamine oxidase (DAO), D­lactate (D­LAC) and endotoxins in the serum, which are markers of the intestinal permeability, were measured using ELISA. The expression of the intestinal tight junction proteins zona occludens­1 (ZO­1) and occludin were detected by reverse transcription­quantitative polymerase chain reaction, western blotting and immunohistochemical analysis. The Uox­knockout mice spontaneously developed hyperuricemia. Histopathological analysis indicated notable intestinal defects including sparse villi, mucosal edema and a declining mucus layer in hyperuricemic mice. The expression levels of ZO­1 and occludin in the intestines were downregulated, and the serum levels of DAO, D­LAC and endotoxins were higher in the hyperuricemic mice, compared with control mice. The serum and intestinal tissue levels of IL­6 and TNF­α were significantly increased. Additionally, the expression levels of the serum uremic toxins, serum creatinine, blood urea nitrogen were significantly increased in hyperuricemic mice compared with the control mice, while only a marked increase in indoxyl sulfate (IS) and p­cresol sulfate was reported. Collectively, the results of the present study suggested that intestinal barrier dysfunction and subsequent enhanced intestinal permeability may occur as a result of hyperuricemia in mice. Furthermore, we proposed that the loss of intestinal epithelium barrier function may be associated with uric acid­induced inflammatory responses; however, further investigation is required.


Assuntos
Hiperuricemia , Mucosa Intestinal/metabolismo , Urato Oxidase/deficiência , Ácido Úrico/metabolismo , Animais , Modelos Animais de Doenças , Hiperuricemia/genética , Hiperuricemia/metabolismo , Hiperuricemia/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Ocludina/genética , Ocludina/metabolismo , Permeabilidade , Junções Íntimas/genética , Junções Íntimas/metabolismo , Junções Íntimas/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
11.
Sci Rep ; 9(1): 11638, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406266

RESUMO

Sigmodon hispidus or cotton rat is an excellent animal model for studying human infections of respiratory viruses including respiratory syncytial virus (RSV), which is the leading cause of hospitalization in infants and causes high rates of infection in the elderly and immunocompromised patient populations. Despite several decades of research, no vaccine has been licensed whereas inactivated vaccines have been shown to induce severe adverse reaction in a clinical trial, with other forms of RSV vaccine also found to induce enhanced disease in preclinical animal studies. While arguably the cotton rat is the best small animal model for evaluation of RSV vaccines and antivirals, many important genes of the immune system remain to be isolated. Programmed cell death-1 (PD-1) plays an integral role in regulating many aspects of immunity by inducing suppressive signals. In this study, we report the isolation of mRNA encoding the cotton rat PD-1 (crPD-1) and characterization of the PD-1 protein. crPD-1 bound to its cognate ligand on dendritic cells and effectively suppressed cytokine secretion. Moreover, using the newly acquired gene sequence, we observed a decreased level of crPD-1 levels in cotton rats with enhanced respiratory disease induced by inactivated RSV vaccine, unraveling a new facet of vaccine-induced disease.

12.
Hereditas ; 156: 26, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31367212

RESUMO

Background: One common ATP-binding cassette subfamily G member 2 (ABCG2) gene variant, which is encoded by the single nucleotide polymorphism (SNP) rs2231142, was identified to take an essential part in gouty arthritis. However, the relationship between rs2231142, gout comorbidities and therapeutic effect of allopurinol in Chinese Han male population is still unclear. Wherefore, this study explored into the association between ABCG2 SNP rs2231142 affecting common comorbidities and the therapeutic effect of allopurinol in Chinese Han male gout patients. Results: ABCG2 SNP rs2231142 and the gout comorbidities including nephrolithiasis and CKD were associated (P = 0.014 and P = 0.026). Group CKD stage = 1 were significantly different from those in group CKD stage≥2 regarding genotypes of ABCG2 gene polymorphism, while they were not significantly different from those in group CKD stage≥3. Meanwhile, the genotypes of rs2231142 and allopurinol response were not significantly associated (P = 0.588). Conclusions: ABCG2 rs2231142 may predict the risk of kidney comorbidities for Chinese Han male gout patients, but not allopurinol response.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Predisposição Genética para Doença , Gota/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alopurinol/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , China , Comorbidade , Genótipo , Gota/tratamento farmacológico , Gota/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade
13.
Arch Med Sci ; 15(4): 1047-1055, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31360199

RESUMO

Introduction: To determine the microRNA (miRNA) expression profiles in the plasma of acute gouty arthritis (AGA) patients and investigate the effects of colchicine and etoricoxib treatment on the differential expression of miRNAs. Material and methods: Exiqon miRCURYLNA microRNA Array was used for miRNA expression profiling in AGA. Two of the 21 differentially expressed miRNAs were confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). A randomized, double-blind, parallel-controlled design was used to divide 160 AGA patients into colchicine and etoricoxib groups. Changes in 2 differentially expressed miRNAs, interleukin-1 (IL-1) ß, cyclooxygenase-2 (COX-2) and joint pain scores were detected. Results: Compared with normal subjects and asymptomatic hyperuricemia (HUA) patients, plasma of AGA contained 21 differentially expressed miRNAs. qRT-PCR indicated specific downregulation of miR-223-3p and miR-451a in AGA. There were no statistically significant differences in the baseline characteristics between colchicine and etoricoxib groups. Furthermore, no significant difference in joint pain scores after 5- and 10-day treatment were found between groups (p > 0.05). Comparison of differences between pre- and 5-day post-treatment values confirmed that the upregulation of miR-223-3p and downregulation of IL-1ß induced by colchicine were more significant than etoricoxib (p < 0.05). However, the latter outperformed the former in the upregulation of miR-451a and downregulation of COX-2 (p < 0.05). After 10-day treatment, the magnitude of miR-223-3p upregulation and IL-1ß downregulation in the colchicine group was significantly higher than in the etoricoxib group, while the etoricoxib group had higher expression of miR-451a and lower expression of COX-2 than the colchicine group (p < 0.05). Conclusions: In AGA patients, 21 differentially expressed miRNAs were detected in the plasma. Colchicine could upregulate miR-223-3p and downregulate IL-1ß in the plasma, while etoricoxib may treat AGA by upregulating miR-451a and downregulating COX-2.

14.
Sci China Life Sci ; 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31231780

RESUMO

A new HPV-16/18 bivalent vaccine expressed by the Escherichia coli has been proven to be efficacious in adult women. A randomized, immunogenicity noninferiority study of this candidate vaccine was conducted in December 2015 in China. Girls aged 9-14 years were randomized to receive 2 doses at months 0 and 6 (n=301) or 3 doses at months 0, 1 and 6 (n=304). Girls aged 15-17 years (n=149) and women aged 18-26 years (n=225) received 3 doses. The objectives included noninferiority analysis of the IgG geometric mean concentration (GMC) ratio (95% CI, lower bound>0.5) to HPV-16 and HPV-18 at month 7 in girls compared with women. In the per-protocol set, the GMC ratio of IgG was noninferior for girls aged 9-17 years receiving 3 doses compared with women (1.76 (95% CI, 1.56, 1.99) for HPV-16 and 1.93 (95% CI, 1.69, 2.21) for HPV-18) and noninferior for girls aged 9-14 years receiving 2 doses compared with women (1.45 (95% CI, 1.25, 1.62) for HPV-16 and 1.17 (95% CI, 1.02, 1.33) for HPV-18). Noninferiority was also demonstrated for neutralizing antibodies. The immunogenicity of the HPV vaccine in girls receiving 3 or 2 doses was noninferior compared with that in young adult women.

15.
Anal Chem ; 91(14): 8908-8917, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31251585

RESUMO

Influenza vaccine potency is determined by the quantification of immunologically active hemagglutinin capable of eliciting neutralizing antibodies upon immunization. Currently, the single radial immunodiffusion (SRID) method is the standard in vitro potency assay used for lot release of seasonal inactivated influenza vaccines. Despite the proven usage of SRID, significant limitations such as the time-consuming preparation of reagents and limited dynamic range warrant the need for the development of alternative potency assays. Such alternative approaches need to discriminate and quantify relevant hemagglutinin material, provide strain identity, and be independent of strain-specific and seasonal reagents. Herein, we present a proof of concept method that combines the capture of conformationally well-folded hemagglutinin via a sialic acid binding step with the resolving power of reversed-phase high-performance liquid chromatography for strain identity and determination. Details of the protocol for the selective capture of receptor-binding hemagglutinin, its release from the receptor, and its relative determination are presented. This approach was found to provide flexibility for the reagents to be used and was adaptable to varying strain compositions of influenza vaccines. This proof of concept approach was developed as an antibody-independent methodology.

16.
Vaccine ; 37(30): 4031-4039, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31186190

RESUMO

Chitosan is a polysaccharide capable of augmenting immune responses with a proven safety record in animals and humans. These properties make it a potentially attractive agent for the prevention and treatment of infectious disease. Infection by respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory disease in young children throughout the world. There is no licensed vaccine available against RSV whereas inactivated vaccine is known to cause enhanced respiratory disease instead of protection. Here, we investigated whether chitosan administered one or three days post-infection could protect animals against RSV infection and whether it could alter immune responses or immunopathology induced by inactivated RSV vaccine when administered twice before RSV infection. We found chitosan could modestly protect animals against RSV infection when given post-infection, while, in conjunction with inactivated RSV vaccine when given pre-infection, it could significantly reduce RSV infection in mice. Further mechanistic investigation revealed that chitosan enhanced antigen-specific immune responses through augmenting the induction of regulatory T cells, lung resident T cells and neutralizing antibodies while reversing Th2-skewed immune responses induced by inactivated RSV vaccine but, surprisingly, failing to reverse lung histopathology. Overall, this study sheds more light on the molecular mechanisms underlying inactivated RSV vaccine-induced disease.

17.
Nat Rev Rheumatol ; 15(7): 413-426, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31118497

RESUMO

Hyperuricaemia (increased serum urate concentration) occurs mainly in higher primates, including in humans, because of inactivation of the gene encoding uricase during primate evolution. Individuals with hyperuricaemia might develop gout - a painful inflammatory arthritis caused by monosodium urate crystal deposition in articular structures. Hyperuricaemia is also associated with common chronic diseases, including hypertension, chronic kidney disease, type 2 diabetes and cardiovascular disease. Many mouse models have been developed to investigate the causal mechanisms for hyperuricaemia. These models are highly diverse and can be divided into two broad categories: mice with genetic modifications (genetically induced models) and mice exposed to certain environmental factors (environmentally induced models; for example, pharmaceutical or dietary induction). This Review provides an overview of the mouse models of hyperuricaemia and the relevance of these models to human hyperuricaemia, with an emphasis on those models generated through genetic modifications. The challenges in developing and comparing mouse models of hyperuricaemia and future research directions are also outlined.


Assuntos
Regulação da Expressão Gênica , Proteínas Facilitadoras de Transporte de Glucose/genética , Hiperuricemia/sangue , Ácido Úrico/sangue , Animais , Modelos Animais de Doenças , Proteínas Facilitadoras de Transporte de Glucose/biossíntese , Humanos , Hiperuricemia/genética , Camundongos , Camundongos Knockout
18.
Mol Genet Genomic Med ; 7(7): e00722, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31131560

RESUMO

BACKGROUND: To identify potential causative mutations in SLC2A9 and SLC22A12 that lead to hypouricemia or hyperuricemia (HUA). METHODS: Targeted resequencing of whole exon regions of SLC2A9 and SLC22A12 was performed in three cohorts of 31 hypouricemia, 288 HUA and 280 normal controls. RESULTS: A total of 84 high-quality variants were identified in these three cohorts. Eighteen variants were nonsynonymous or in splicing region, and then included in the following association analysis. For common variants, no significant effects on hypouricemia or HUA were identified. For rare variants, six single nucleotide variations (SNVs) p.T21I and p.G13D in SLC2A9, p.W50fs, p.Q382L, p.V547L and p.E458K in SLC22A12, occurred in totally six hypouricemia subjects and were absent in HUA and normal controls. Allelic and genotypic frequency distributions of the six SNVs differed significantly between the hypouricemia and normal controls even after multiple testing correction, and p.G13D in SLC2A9 and p.V547L in SLC22A12 were newly reported. All these mutations had no significant effects on HUA susceptibility, while the gene-based analyses substantiated the significant results on hypouricemia. CONCLUSION: Our study first presents a comprehensive mutation spectrum of hypouricemia in a large Chinese cohort.

19.
Front Immunol ; 10: 597, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984178

RESUMO

Respiratory syncytial virus (RSV) infection is a severe threat to young children and the elderly. Despite decades of research, no vaccine has been approved. Notably, instead of affording protection, a formalin-inactivated RSV vaccine induced severe respiratory disease including deaths in vaccinated children in a 1960s clinical trial; however, recent studies indicate that other forms of experimental vaccines can also induce pulmonary pathology in pre-clinical studies. These findings suggest that multiple factors/pathways could be involved in the development of enhanced respiratory diseases. Clearly, a better understanding of the mechanisms underlying such adverse reactions is critically important for the development of safe and efficacious vaccines against RSV infection, given the exponential growth of RSV vaccine clinical trials in recent years. By employing an integrated systems biology approach in a pre-clinical cotton rat model, we unraveled a complex network of pulmonary canonical pathways leading to disease development in vaccinated animals upon subsequent RSV infections. Cytokines including IL-1, IL-6 GRO/IL-8, and IL-17 in conjunction with mobilized pulmonary inflammatory cells could play important roles in disease development, which involved a wide range of host responses including exacerbated pulmonary inflammation, oxidative stress, hyperreactivity, and homeostatic imbalance between coagulation and fibrinolysis. Moreover, the observed elevated levels of MyD88 implicate the involvement of this critical signal transduction module as the central node of the inflammatory pathways leading to exacerbated pulmonary pathology. Finally, the immunopathological consequences of inactivated vaccine immunization and subsequent RSV exposure were further substantiated by histological analyses of these key proteins along with inflammatory cytokines, while hypercoagulation was supported by increased pulmonary fibrinogen/fibrin accompanied by reduced levels of plasma D-dimers. Enhanced respiratory disease associated with inactivated RSV vaccine involves a complex network of host responses, resulting in significant pulmonary lesions and clinical manifestations such as tachypnea and airway obstruction. The mechanistic insight into the convergence of different signal pathways and identification of biomarkers could help facilitate the development of safe and effective RSV vaccine and formulation of new targeted interventions.

20.
J Infect Dis ; 220(10): 1551-1557, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30958543

RESUMO

BACKGROUND: The Sabin strain-based inactivated polio vaccine (sIPV) plays a vital role in eradicating poliomyelitis in developing countries. METHODS: The study was designed as a randomized, controlled, double-blinded, noninferiority trial. A total of 1200 healthy infants aged 60-90 days were enrolled and randomly assigned to receive 3 doses of either sIPV (the experimental arm) or IPV (the control arm) at days 0, 30, and 60. Immunogenicity and safety outcomes were assessed using the per-protocol and safety populations, respectively. RESULTS: A total of 553 and 562 participants in the sIPV and IPV groups, respectively, were included in the per-protocol population. Seroconversion rates in the sIPV and IPV groups were 98.0% and 94.1%, respectively, for type 1 poliovirus (P < .01); 94.8% and 84.0%, respectively, for type 2 (P < .01); and 98.9% and 97.7%, respectively, for type 3 (P = .11). A total of 599 and 600 participants in the sIPV and IPV groups, respectively, were included in the safety population. Fever was the most common adverse event, occurring in 61.6% and 49.8% of participants in the experimental and control arms, respectively (P < .01). CONCLUSIONS: The sIPV demonstrated an immunogenicity profile noninferior to that of the conventional IPV and had a good safety profile. CLINICAL TRIALS REGISTRATION: NCT03526978.

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