Abstract
Background
Mitral regurgitation (MR) is a rather common valvular heart disease. The aim of this systematic review and meta-analysis was to compare the outcomes, and complications of mitral ...valve (MV) replacement with surgical MV repair of non-ischemic MR (NIMR)
Methods
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched until October, 2020. Studies were eligible for inclusion if they included patients with MR and reported early (30-day or in-hospital) or late all-cause mortality. For each study, data on all-cause mortality and incidence of reoperation and operative complications in both groups were used to generate odds ratios (ORs) or hazard ratios (HRs). This study is registered with PROSPERO, CRD42018089608.
Results
The literature search yielded 4834 studies, of which 20 studies, including a total of 21,898 patients with NIMR, were included. The pooled analysis showed that lower age, less female inclusion and incident of hypertension, significantly higher rates of diabetes and atrial fibrillation in the MV replacement group than MV repair group. No significant differences in the rates of pre-operative left ventricle ejection fraction (LVEF) and heart failure were observed between groups. The number of patients in the MV repair group was lower than in the MV replacement group. We found that there were significantly increased risks of mortality associated with replacement of MR. Moreover, the rate of re-operation and post-operative MR in the MV repair group was lower than in the MV replacement group.
Conclusions
In patients with NIMR, MV repair achieves higher survival and leads to fewer complications than surgical MV replacement. In light of these results, we suggest that MV repair surgery should be a priority for NIMR patients.
Objective
The aim at the current study was to investigate the clinical characteristics and risk factors of Raynaud’s phenomenon (RP) in patients with primary Sjögren’s syndrome (pSS).
Methods
...Retrospective analysis of the medical records of 333 new-onset pSS patients was performed. Demographic, clinical, and serological data were compared between individuals with and without RP. Logistic regression analysis was used to identify risk factors.
Results
RP was present in 11.41% of the pSS patients. pSS-RP patients were younger (49.74±14.56 years vs. 54.46±13.20 years,
p
=0.04) and exhibited higher disease activity (11 5.75–15 vs. 7 4–12,
p
=0.03) than those without. The prevalence of lung involvement was significantly higher in pSS patients with RP (60.53% vs. 17.29%;
p
<0.001). A significantly higher proportion of patients with pSS-RP tested positive about antinuclear (ANA), anti-RNP, and anti-centromere antibodies (ACA) compared to those without (
p
=0.003, <0.001, and 0.01, respectively). Multivariate analysis identified lung involvement (odds ratio OR=8.81, 95% confidence interval CI 2.02–38.47;
p
=0.04), anti-RNP positive status (OR=79.41, 95% CI 12.57–501.78;
p
<0.0001), as well as ACA (OR=13.17, 95% CI 2.60–66.72;
p
=0.002) as prognostic factors for pSS-RP.
Conclusion
The presence of RP defined a subset of pSS with a unique phenotype, manifesting as increased lung involvement and a higher frequency of anti-RNP antibodies and ACA, as well as greater disease activity. These results suggest that RP has clinical and prognostic value of pSS patients. Further prospective studies with a larger number of subjects are warranted to confirm our findings and assess the prognostic and treatment implications of RP in pSS patients.
Key Points
•
Raynaud’s phenomenon (RP) was present in 38 (11.41%) of 333 patients with primary Sjögren’s syndrome (pSS), with patients with RP exhibiting a younger age and higher disease activity.
•
The presence of RP indicates a subset of pSS with a unique phenotype, with manifestations including increased lung involvement and a higher frequency of anti-RNP antibodies and anti-centromere antibodies.
•
Patients with pSS and RP need close follow-up and long-term observation (including assessment of microangiopathy), with specific attention paid to the possible development of clinical features of systemic sclerosis.
Renalase, an enzyme that can metabolize catecholamine, was recently reported to attenuate the ischaemia/reperfusion (I/R)-induced cardiac injury. This work was undertaken to investigate the functions ...and regulation mechanisms of renalase in protection against cardiac I/R injury.
An elevated level of renalase was found in C57BL/6 mice challenged with I/R injury. Then, we generated a mouse model with cardiac administration of cholesterol-conjugated renalase siRNA followed by I/R operation. The mice treated with renalase siRNA exhibited increased infarction size and decreased cardiac function compared with the scramble siRNA group. Subsequently, we identified four potential hypoxia-inducible factor-1 alpha (HIF-1α)-binding motifs in the promoter of renalase through bioinformatics approaches. Dual-luciferase reporter assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and western blot were conducted and demonstrated that renalase was a novel target gene of HIF-1α. Furthermore, administration of renalase reduced the infarct area and rescued the deterioration of cardiac function in myocardial HIF-1α knockdown mice subjected to I/R injury. In addition, the levels of norepinephrine in serum as well as nicotinamide adenine dinucleotide (NAD(+)) and ATP in myocardium were determined, which implied that cardiac protection of renalase against I/R may be related, at least in part, to its metabolism of catecholamine and regulation of energy.
These findings have revealed renalase as a novel target gene of HIF-1α in protection against myocardial I/R injury, which provided a basis for therapeutic strategies for enhancing cardiomyocyte survival in patients associated with ischaemic heart diseases.
Wilson's disease (WD) is an inherited disorder characterized by impaired biliary excretion of copper and excessive copper accumulation in multiple organs, primarily leading to hepatic, neurological, ...and psychiatric manifestations. The coexistence of WD and systemic lupus erythematosus (SLE) has rarely been reported, posing challenges in accurately diagnosing these two conditions because of overlapping clinical symptoms.
We presented the case of a 17-year-old girl initially suspected of having SLE due to positive anti-nuclear antibodies and lupus anticoagulants, decreased platelet count, hypocomplementemia, and pleural effusion. However, the patient also exhibited an unusual manifestation of decompensated liver cirrhosis, which is not typical of SLE. Further investigation revealed low serum ceruloplasmin levels, high 24-h urine copper levels, the presence of Kayser-Fleischer rings, and a compound heterozygous mutation in the
gene, confirming the diagnosis of WD.
The co-occurrence of WD and SLE poses a significant diagnostic challenge, often leading to misdiagnosis and delayed diagnosis. Therefore, in patients with well-controlled SLE presenting with unexplained liver fibrosis, neurological involvement, or psychiatric symptoms, it is crucial to consider the possibility of WD. However, further studies are required to elucidate the underlying pathophysiological mechanisms.
Chronic low‐grade inflammation orchestrated by macrophages plays a critical role in metabolic chronic diseases, like obesity and atherosclerosis. However, the underlying mechanism remains to be ...elucidated. Here, the E3 ubiquitin ligase F‐box/WD Repeat‐Containing Protein 2 (FBXW2), the substrate‐binding subunit of E3 ubiquitin ligase SCF (a complex of FBXW2, SKP1, and cullin‐1), as an inflammatory mediator in macrophages, is identified. Myeloid‐specific FBXW2 gene deficiency improves both obesity‐associated with insulin resistance and atherosclerosis in murine models. The beneficial effects by FBXW2 knockout are accompanied by decreased proinflammatory responses and macrophage infiltration in the microenvironment. Mechanistically, it is identified that KH‐type splicing regulatory protein (KSRP) is a new bona fide ubiquitin substrate of SCFFBXW2. Inhibition of KSRP prevents FBXW2‐deficient macrophages from exerting a protective effect on inflammatory reactions, insulin resistance and plaque formation. Furthermore, it is demonstrated that the C‐terminus (P3) of FBXW2 competitively ablates the function of FBXW2 in KSRP degradation and serves as an effective inhibitor of obesity and atherogenesis progression. Thus, the data strongly suggest that SCFFBXW2 is an important mediator in the context of metabolic diseases. The development of FBXW2 (P3)‐mimicking inhibitors and small‐molecular drugs specifically abrogating KSRP ubiquitination‐dependent inflammatory responses are viable approaches for obesity and atherosclerosis treatment.
This work demonstrates the essential role of myeloid E3 ubiquitin ligase F‐box/WD Repeat‐Containing Protein 2 (FBXW2) in obesity‐related insulin resistance and atherosclerosis. Under overnutrition exposure, FBXW2 directly interacts with and ubiquitinates KH‐type splicing regulatory protein (KSRP) in macrophages, thereby overactivating the proinflammatory reaction. A small peptide segment in the C‐terminus (P3) of FBXW2 effectively reverses chronic metabolic diseases progression.
Abstract Background Fibrosis is one of the major pathological features of hypertensive vascular disease. In this study, we aim to explore the possible protective effects of poly(ADP-ribose) ...polymerase (PARP) inhibitor on angiotensin II (AngII)-induced aortic fibrosis. Methods Sprague–Dawley rats were infused subcutaneously with AngII. PARP inhibitor was intraperitoneally injected once a day. Collagen deposition in thoracic aorta was assayed by Masson tricrome staining. The mRNA and protein expression of TGF-β target genes involved in extracellular matrix (ECM) remodeling in aorta was measured. Plasma level and aortic expression of TGF-β1 was assayed. Correlation of systolic blood pressure (SBP) with plasma level of TGF-β1 was analyzed. In cultured rat vascular smooth muscle cells (VSMCs), effects of PARP inhibition on TGF-β1 expression, Smad3 transactivity, and TGF-β/Smad3 target gene expression were investigated. Results Infusion of AngII promoted aortic PARP activation. Treatment with PARP inhibitor alleviated AngII-induced collagen deposition and expression of TGF-β target genes involved in ECM remodeling in aorta of rat. AngII increased plasma level and aortic expression of TGF-β1. A positive correlation between SBP and plasma level of TGF-β1 was revealed. Treatment with PARP inhibitor prevented AngII-induced elevation of SBP. Further experiments uncovered that AngII treatment increased TGF-β dependent gene expression through Smad3 pathway in cultured VSMCs. Inhibition of PARP prevented AngII-induced increases in TGF-β1 expression, Smad3 transactivity and its target gene expression. Conclusions These data indicate that inhibition of PARP prevents aortic fibrosis in AngII-induced hypertension in rats. This beneficial effect is mediated by inhibiting TGF-β/Smad3 pathway.
The transcription factor Sp1 is implicated in the activation of G0/G1 phase genes. Modulation of Sp1 transcription activities may affect G1-S checkpoint, resulting in changes in cell proliferation. ...In this study, our results demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP-1) promoted cell proliferation by inhibiting Sp1 signaling pathway. Cell proliferation and cell cycle assays demonstrated that PARP inhibitors or PARP-1 siRNA treatment significantly inhibited proliferation of hepatoma cells and induced G0/G1 cell cycle arrest in hepatoma cells, while overexpression of PARP-1 or PARP-1 activator treatment promoted cell cycle progression. Simultaneously, inhibition of PARP-1 enhanced the expression of Sp1-mediated checkpoint proteins, such as p21 and p27. In this study, we also showed that Sp1 was poly(ADP-ribosyl)ated by PARP-1 in hepatoma cells. Poly(ADP-ribosyl)ation suppressed Sp1 mediated transcription through preventing Sp1 binding to the Sp1 response element present in the promoters of target genes. Taken together, these data indicated that PARP-1 inhibition attenuated the poly(ADP-ribosyl)ation of Sp1 and significantly increased the expression of Sp1 target genes, resulting in G0/G1 cell cycle arrest and the decreased proliferative ability of the hepatoma cells.
Transforming growth factor type-β (TGF-β)/Smad pathway plays an essential role in vascular fibrosis. Reactive oxygen species (ROS) generation also mediates TGF-β signaling-induced vascular fibrosis, ...suggesting that some sort of interaction exists between Smad and redox pathways. However, the underlying molecular mechanism is largely unknown. This study aims to investigate the influence of poly(ADP-ribose) polymerase 1 (PARP1), a downstream effector of ROS, on TGF-β signaling transduction through Smad3 pathway in rat vascular smooth muscle cells (VSMCs).
TGF-β1 treatment promoted PARP1 activation through induction of ROS generation in rat VSMCs. TGF-β1-induced phosphorylation and nuclear accumulation of Smad3 was prevented by treatment of cells with PARP inhibitor, 3-aminobenzamide (3AB) or N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-(N,N-dimethylamino)acetami (PJ34), or PARP1 siRNA. TGF-β1 treatment promoted poly(ADP-ribosy)lation of Smad3 via activation of PARP1 in the nucleus. Poly(ADP-ribosy)lation enhanced Smad-Smad binding element (SBE) complex formation in nuclear extracts and increased DNA binding activity of Smad3. Pretreatment with 3AB, PJ34, or PARP1 siRNA prevented TGF-β1-induced Smad3 transactivation and expression of Smad3 target genes, including collagen Iα1, collagen IIIα1 and tissue inhibitor of metalloproteinase 1, in rat VSMCs.
PARP1 is indispensable for TGF-β1 induced Smad3 activation in rat VSMCs. Targeting PARP1 may be a promising therapeutic approach against vascular diseases induced by dysregulation of TGF-β/Smad3 pathway.
The coronavirus disease 2019 (COVID-19) pandemic has imposed enormous morbidity and mortality burdens. Patients with rheumatic diseases (RDs) are vulnerable to the COVID-19 infection, given their ...immunocompromised status. Ensuring acceptance of the COVID-19 vaccine is important and has attracted attention by health professionals. In this study, we designed an online cross-sectional survey that used an online questionnaire from 8 May 2021 to 4 October 2021. Attitudes toward the COVID-19 vaccination, personal information, current disease activity status, adverse events (AEs), and knowledge sources of vaccines were collected. Descriptive statistics, nonparametric tests, and ordinal logistic regression were used to analyze the data. A total of 1022 questionnaires were received, among which 70.2% (720/1022) of patients with RDs agreed to vaccination, while only 31.6% of patients were actually vaccinated. Male, employed, high-income patients and those with inactive disease showed a more positive attitude. Concerns of AEs and disease flare were the main factors affecting vaccination willingness. Only 29.6% (304/1022) of patients thought they had received enough information about the COVID-19 vaccine from their doctors. In conclusion, most patients with RDs in China intended to get vaccinated, although the vaccination rate in this particular population was low. Rheumatologists should take more responsibility in COVID-19 vaccination education of patients with RDs.
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