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1.
Sci Prog ; 104(2): 368504211016953, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34121519

RESUMO

Patients admitted in the intensive care unit (ICU) are always managed with excessive high fraction of inspired oxygen and have hyperoxia for a significant period of time, which has potential harms. The guidelines for the management of patients in ICUs do not provide the target values for partial pressure of oxygen or arterial oxyhemoglobin saturations. The study was a before-after investigation comparing two time periods in which different oxygenation strategies were applied. Data of oxygen control, outcome measures, and mortality of a total of 273 patients (>18 years) admitted at least for 2 days in ICUs and received treatment for the sepsis were retrospectively collected and analyzed. Patients were received usual oxygen supplementation (targeted partial pressure of oxygen: 150 mmHg; a high fraction of inspired oxygen: 0.4; UOS cohort; n = 142) or conservative oxygen supplementation (targeted partial pressure of oxygen: 70-100 mmHg; a high fraction of inspired oxygen as low as possible; COS cohort; n = 131). Mechanical ventilation-free hours were significantly higher for patients of COS cohort than those of UOS cohort (77.99 ± 21.26 h/patient vs 70.01 ± 23.57 h/patient, p = 0.016). ICUs length of stays of patients of COS cohort was fewer than those of UOS cohort (7.05 ± 2.13 days/patient vs 7.69 ± 2.43 days/patients, p = 0.016). The probability of survival of patients was higher among patients of COS cohort than those of UOS cohort (p = 0.049). A higher number of patients from UOS cohort needed vasopressors than those from COS cohort (55 vs 35, p = 0.039). Conservative oxygen supplementation to maintain partial pressure of oxygen was improved outcome measures and decreases mortality as compared to that of usual oxygen supplementation.Level of Evidence: III.Technical Efficacy Stage: 4.

2.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070938

RESUMO

The excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is widely used as a safe and effective liver protectant. However, the mechanism by which MGIG protects against NAFLD remains unknown. Based on the significant correlation between NAFLD and the reprogramming of liver metabolism, we aimed to explore the beneficial effects of MGIG from a metabolic viewpoint in this paper. We treated HepaRG cells with palmitic acid (PA, a saturated fatty acid of C16:0) to induce lipotoxicity and then evaluated the antagonistic effect of MGIG on lipotoxicity by investigating the cell survival rate, DNA proliferation rate, organelle damage, and endoplasmic reticulum stress (ERS). Metabolomics, lipidomics, and isotope tracing were used to investigate changes in the metabolite profile, lipid profile, and lipid flux in HepaRG cells under different intervention conditions. The results showed that MGIG can indeed protect hepatocytes against PA-induced cytotoxicity and ERS. In response to the metabolic abnormality of lipotoxicity, MGIG curtailed the metabolic activation of lipids induced by PA. The content of total lipids and saturated lipids containing C16:0 chains increased significantly after PA stimulation and then decreased significantly or even returned to normal levels after MGIG intervention. Lipidomic data show that glycerides and glycerophospholipids were the two most affected lipids. For excessive lipid accumulation in hepatocytes, MGIG can downregulate the expression of the metabolic enzymes (GPATs and DAGTs) involved in triglyceride biosynthesis. In conclusion, MGIG has a positive regulatory effect on the metabolic disorders that occur in hepatocytes under lipotoxicity, and the main mechanisms of this effect are in lipid metabolism, including reducing the total lipid content, reducing lipid saturation, inhibiting glyceride and glycerophospholipid metabolism, and downregulating the expression of metabolic enzymes in lipid synthesis.

3.
Aging (Albany NY) ; 13(undefined)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34086602

RESUMO

In contrast to the declining trend in most regions worldwide, the incidence of stroke is increasing in China and is leading to an alarming burden for the national healthcare system. In this review, we have generated new insights from this outlier, and we aim to provide new information that will help decrease the global stroke burden, especially in China and other regions sharing similar problems with China. First of all, several unsolved aspects fundamentally accounting for this discrepancy were promising, including the serious situation of hypertension management, underdiagnosis of atrial fibrillation and underuse of anticoagulants, and unhealthy lifestyles (e.g., heavy smoking). In addition, efforts for further alleviating the incidence of stroke were recommended in certain fields, including targeted antiplatelet regimes and protections from cold wave-related stroke. Furthermore, advanced knowledge about cancer-related strokes, recurrent strokes and the status preceding stroke onset that we called stroke-prone status herein, is required to properly mitigate patient stroke risk, and to provide improved outcomes for patients after a stroke has occurred.

4.
Xenobiotica ; : 1-29, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34096834

RESUMO

Zolmitriptan (ZOL), a member of triptans, has been used for the treatment of migraine with definite therapeutic effects. However, several cases of liver injury associated with ZOL have been reported and the underlying mechanisms remain unclear.The present study aimed to investigate the metabolic activation of ZOL in vitro and in vivo. ZOL-derived glutathione (GSH) and N-acetyl cysteine (NAC) conjugates were detected in rat liver microsomal incubations. In addition, the GSH and NAC conjugates were also found in bile and urine of rats given ZOL, respectively.ZOL-derived GSH conjugate M1 was also observed in ZOL-treated rat primary hepatocytes, and the formation of M1 was inhibited by pre-cultured with quinidine (a selective inhibitor of CYP2D6). Combining with recombinant P450 enzymes incubations, we found that CYP2D6 was the predominant enzyme responsible for the metabolic activation of ZOL.ZOL can be metabolized to an α,ß-unsaturated imine intermediate by CYP2D6. Pre-treatment of primary hepatocytes with quinidine was able to reverse ZOL-induced cytotoxicity. The finding facilitates the understanding of the mechanisms involved in ZOL-associated liver adverse reactions.

5.
Chem Commun (Camb) ; 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34105555

RESUMO

We have proposed a simple electrochemical method in this work for the assay of tumor cells through their own steric hindrance effect. Specifically, tumor cells can block the catalysis of terminal deoxynucleotidyl transferase to the aptamer previously immobilized on the electrode surface. By making use of the hindrance effect, cancer cells can be quantitatively analyzed in the range from 1.6 × 102 to 1.6 × 106 cells per mL without complicated design or cumbersome operation, while the detection limit can be about 53 cells per mL. This method can also show satisfactory performance in complex environments, indicating its potential in clinical application.

6.
Environ Sci Technol ; 55(12): 8149-8158, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34038106

RESUMO

Short-chain chlorinated paraffins (SCCPs) have attracted attention because of their toxicological potential in humans and wildlife at environmentally relevant doses. However, limited information is available regarding mechanistic differences across species in terms of the biological pathways that are impacted by SCCP exposure. Here, a concentration-dependent reduced human transcriptome (RHT) approach was conducted to evaluate 15 SCCPs in HepG2 cells and compared with our previous results using a reduced zebrafish transcriptome (RZT) approach in zebrafish embryos (ZFEs). Generally, SCCPs induced a broader suite of biological pathways in ZFEs than HepG2 cells, and all of the 15 SCCPs were more potent in HepG2 cells compared to ZFEs. Despite these general differences, the transcriptional potency of SCCPs in both model systems showed a significant linear relationship (p = 0.0017, r2 = 0.57), and the average ratios of transcriptional potency for each SCCP in RZT to that in RHT were ∼100,000. C10H14Cl8 was the most potent SCCP, while C10H17Cl5 was the least potent in both ZFEs and HepG2 cells. An adverse outcome pathway network-based analysis demonstrated model-specific responses, such as xenobiotic metabolism that may be mediated by different nuclear receptor-mediated pathways between HepG2 cells (e.g., CAR and AhR activation) and ZFEs (e.g., PXR activation). Moreover, induced transcriptional changes in ZFEs associated with pathways and molecular initiating events (e.g., activation of nicotinic acetylcholine receptor) suggest that SCCPs may disrupt neural development processes. The cross-model comparison of concentration-dependent transcriptomics represents a promising approach to assess and prioritize SCCPs.

7.
J Nanobiotechnology ; 19(1): 149, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34020663

RESUMO

BACKGROUND: Photodynamic therapy (PDT) is a clinically implemented modality to combat malignant tumor, while its efficacy is largely limited by several resistance factors from tumor microenvironment (TME), such as hypoxia, anti-oxidant systems, and ATP-dependent tumor adaptive resistances. The aim of this work is to construct a multifunctional nanoplatform to remodel multiple resistant TME for enhanced PDT. RESULTS: Here, a targeting nano-reactor was facilely constructed to reverse the multiple resistances of PDT by incorporating glucose oxidase (GOx) and chlorin e6 (Ce6) into poly (D, L-lactic-co-glycolic acid) (PLGA)/ metal-organic framework (MOF) core-shell nanoassembly, with surface deposition of hyaluronic acid (HA) stabilized MnO2. The nano-reactor could selectively target tumor cells by virtue of surface HA modification, and once internalization, a few reactions were initiated to modulate TME. Glucose was consumed by GOx to inhibit ATP generation, and the produced H2O2 was catalyzed by MnO2 to generate O2 for tumor hypoxia alleviation and photodynamic sensitization, and glutathione (GSH) was also effectively depleted by MnO2 to suppress the tumor antioxidant defense. Consequently, the nano-reactor achieved robust PDT with amplified tumor therapy via intravenous injection. CONCLUSIONS: This nano-reactor offers a multifunctional nanoplatform to sensitize TME-limited tumor treatment means via reversing multiple resistances.

8.
Biochim Biophys Acta Proteins Proteom ; 1869(8): 140669, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33957291

RESUMO

Covalent binding of DNA to proteins produces DNA-protein cross-links (DPCs). DPCs are formed as intermediates of enzymatic processes, generated from the reactions of protein nucleophiles with DNA electrophiles, and produced by endogenous and exogenous cross-linking agents. DPCs are heterogeneous due to the variations of DNA conjugation sites, flanking DNA structures, protein sizes, and cross-link bonds. Unrepaired DPCs are toxic because their bulky sizes physically block DNA replication and transcription, resulting in impaired genomic integrity. Compared to other types of DNA lesions, DPC repair is less understood. Emerging evidence suggests a general repair model that DPCs are proteolyzed by the proteasome and/or DPC proteases, followed by the peptide removal through canonical repair pathways. Herein, we first describe the recently discovered DPCs. We then review the mechanisms of DPC proteolysis with the focus on recently identified DPC proteases. Finally, distinct pathways that bypass or remove the cross-linked peptides following proteolysis are discussed.

9.
Mol Genet Genomic Med ; : e1711, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34057320

RESUMO

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Prenatal screening of FXS allows for early identification and intervention. The present study explored the feasibility of FXS carrier screening during prenatal diagnosis for those who were not offered screening early in pregnancy or prior to conception. METHODS: Pregnant women to be offered amniotic fluid testing were recruited for the free voluntary carrier screening at a single center between August, 2017 and September, 2019. The number of CGG repeats in the 5' un-translated region of the fragile X mental retardation gene 1 (FMR1) was determined. RESULTS: 4286 of 7000 (61.2%) pregnant women volunteered for the screening. Forty (0.93%), five (0.11%), and three (0.07%) carriers for intermediate mutation (45-54 repeats), premutation (55-200 repeats) and full mutation (>200 repeats) of the FMR1 gene were identified respectively. None of the detected premutation alleles were inherited by the fetuses. Of the three full mutation carrier mothers, all had a family history and one transmitted a full mutation allele to her male fetus. CONCLUSION: Implementation of FXS carrier screening during prenatal diagnosis may be considered for the need to increase screening for FXS.

10.
Artigo em Inglês | MEDLINE | ID: mdl-34042422

RESUMO

Cooperative photothermal therapy (PTT) and photodynamic therapy (PDT) represents a promising strategy to conquer tumor with synergistic effect, while their long-term efficacy has been strictly limited by the multiple resistances of tumor. Here, we reported a core-shell nanoplatform for enhanced PTT/PDT combination against metastatic breast cancer. The nanosystem had photosensitizer chlorin e6 (Ce6) and rapamycin (RAP) pure drugs core and the polydopamine (PDA) shell, with surface PEGylation. Notably, we found that RAP was a highly robust sensitizer to boost the efficacy of both PTT and PDT by inhibiting the expression of heat shock protein 70 (HSP 70) and hypoxia inducible factor-1α (HIF-1α), respectively, resulting in cooperatively enhanced antitumor efficiency. Moreover, metastasis, the fatal risk of breast cancer, was also inhibited by virtue of RAP-mediated matrix metalloproteinases-2 (MMP-2) suppression. Upon intravenous injection, the nanosystem could passively accumulate into the tumor and impose potent phototherapies upon dual laser irradiations for complete tumor elimination and metastasis inhibition, giving rise to 100% mice survival over a long observation period. Collectively, this work offers a general solution to address the key limitations of tumor-resistant phototherapies and provides a highly promising nanoplatform for the management of metastatic cancer.

11.
Brain Dev ; 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34020858

RESUMO

BACKGROUND: FGF12 (FHF1) gene encodes voltage-gated sodium channel (Nav)-binding protein fibroblast growth factor homologous factor 1, which could cause seizures by regulating voltage dependence of Nav fast inactivation and neuron excitability. The most common pathogenic variant FGF12 c.341G > A related early-onset epileptic encephalopathies (EOEE) was characterized by intractable seizures and developmental disabilities. RESULTS: Using whole exome sequencing, a de novo hotspot variant c.341G > A (NM_021032.4) of FGF12 was identified in three unrelated EOEE probands. All probands were seizure free after a combination treatment of valproic acid (VPA) and topiramate (TPM). The motor and cognitive skills in two probands were improved due to the early and effective treatment. In order to compare the effectiveness of different treatment strategies for the disease, a review of treatments for FGF12-related epilepsy was made. CONCLUSION: We reported three FGF12 c.341G > A related EOEE patients responded well to a combination antiepileptic therapy of VPA and TPM. The current study is the first to describe the combination therapy of VPA and TPM in FGF12 c.341G > A related EOEE patients. This study may contribute to future medication consultation for intractable epilepsy with FGF12 hotspot variants.

12.
Xenobiotica ; : 1-33, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006188

RESUMO

Deferiprone (DFP) is a metal chelating agent generally used to treat patients with thalassemia, due to iron overload in clinical settings.Studies have revealed that long-term use of DFP can induce hepatotoxicity, however, mechanisms of its toxic action remain unclear. The present studies are aimed to characterize the reactive metabolite of DFP, to define the metabolic pathway, and to determine the P450 enzymes participating in the bioactivation.A demethylation metabolite (M1) was observed in rat liver microsomal incubations. Additionally, a glutathione (GSH) conjugate (M2) and an N-acetylcysteine (NAC) conjugate (M3) were detected in microsomal incubations fortified with DFP and GSH/NAC.Biliary M2 and urinary M3 were respectively found in animals administered DFP.CYP2A6 enzyme dominated the catalysis to bioactivate DFP.

13.
Pancreatology ; 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34001437

RESUMO

BACKGROUND: Surgical resection remains the only potentially curative treatment for pancreatic ductal adenocarcinoma (PDAC). However, a number of patients get disease recurred in a short time post-operation. Few studies have focused on the predictors of different recurrence patterns of PDAC. OBJECTIVE: To try to establish and verify a nomogram to predict recurrence free survival (RFS) in PDAC patients, and to distinguish the risk factors of local recurrence first and distant metastasis first via competing risk model. METHODS: Patients who underwent radical pancreatectomy for PDAC in our center from 2010 to 2018 were reviewed retrospectively. Kaplan-Meier methods and multivariate Cox regression analyses were used to identify the clinicopathological predictors of recurrence post-operation. And then, a nomogram was constructed and validated. Competing risk regression model was used to compare the predictors between local recurrence group and distant metastasis group. RESULTS: A total of 200 patients were included into the final analysis, and 153 patients got disease relapsed post-operation. CA19-9 level, vascular resection, tumor differentiation, lymph node ratio (LNR) and adjuvant chemotherapy were identified as independent risk factors for recurrence free survival (RFS) and incorporated into the nomogram. The C-index of the nomogram was 0.650. Competing risk model indicated that the status of lymph-node metastasis was significantly associated the patterns of first relapse. CONCLUSIONS: Nomogram and competing risk model were constructed to quantify the risk of recurrence following surgery for PDAC. Our findings may be useful for predicting RFS and recurrence pattern in clinical work.

14.
Biosens Bioelectron ; 186: 113309, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33984795

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is continuously worsening globally, herein we have proposed an electrochemical biosensor for the sensitive monitoring of SARS-CoV-2 RNA. The presence of target RNA firstly triggers the catalytic hairpin assembly circuit and then initiates terminal deoxynucleotidyl transferase-mediated DNA polymerization. Consequently, a large number of long single-stranded DNA products can be produced, and these negatively charged DNA products will bind a massive of positively charged electroactive molecular of Ru(NH3)63+ due to the electrostatic adsorption. Therefore, significantly amplified electrochemical signals can be generated for sensitive analysis of SARS-CoV-2 RNA in the range of 0.1-1000 pM with the detection limit as low as 26 fM. Besides the excellent distinguishing ability for SARS-CoV-2 RNA against single-base mismatched RNA, the proposed biosensor can also be successfully applied to complex matrices, as well as clinical patient samples with high stability, which shows great prospects of clinical application.

15.
Zhongguo Zhong Yao Za Zhi ; 46(10): 2578-2587, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34047106

RESUMO

To systematically evaluate the clinical efficacy and safety of Compound Danshen Dripping Pills combined with conventional antihypertensive drugs in the treatment of hypertensive left ventricular hypertrophy. China National Knowledge Infrastructure(CNKI), Wanfang, VIP, PubMed, EMbase, Cochrane Library, Ovid and Web of Science databases were searched by computer to retrieve the randomized controlled trials(RCTs) of Compound Danshen Dripping Pills combined with conventional antihypertensive drugs in the treatment of hypertensive left ventricular hypertrophy from the establishment of databases to July 2020. After two researchers performed data retrieval, data extraction, and risk assessment of bias, they used RevMan 5.3 software for Meta-analysis. A total of 10 RCTs were included, with a total of 979 patients. Meta-analysis results showed that in terms of interventricular septal thickness(MD=-0.70, 95%CI[-1.15,-0.24], P=0.003), left ventricular posterior wall thickness(MD=-0.81, 95%CI[-1.41,-0.21], P=0.008), left ventricular mass index(MD=-8.75, 95%CI[-17.40,-0.10], P=0.05), systolic blood pressure(MD=-8.97, 95%CI[-13.46,-4.48], P<0.000 1), diastolic blood pressure(MD=-5.87, 95%CI[-8.39,-3.34], P<0.000 01) and left ventricular end-diastolic diameter(MD=-1.73, 95%CI[-2.38,-1.08], P<0.000 01), Compound Danshen Dripping Pills combined with conventional antihypertensive drugs was superior to conventional antihypertensive drugs. In terms of left ventricular ejection fraction(MD=0.41, 95%CI[-0.74, 1.55], P=0.49), there was no statistical difference in treatment between the two groups. Because of the small amount of literatures included in the safety aspect, it is impossible to give an accurate conclusion. The GRADE score showed that the level of evidence was low and extremely low. The results show that the Compound Danshen Dripping Pills combined with conventional antihypertensive drugs may effectively improve the clinical efficacy for hypertensive ventricular hypertrophy, and the safety needs to be further explored. Due to the low quality of the included literatures, more high-quality RCTs are needed for verification.


Assuntos
Anti-Hipertensivos , Medicamentos de Ervas Chinesas , Anti-Hipertensivos/efeitos adversos , China , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Volume Sistólico , Resultado do Tratamento , Função Ventricular Esquerda
16.
Cell Death Dis ; 12(5): 409, 2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33866326

RESUMO

The levels of fibroblast growth factor 23 (FGF23) rapidly increases after acute kidney injury (AKI). However, the role of FGF23 in AKI is still unclear. Here, we observe that pretreatment with FGF23 protein into ischemia-reperfusion induced AKI mice ameliorates kidney injury by promoting renal tubular regeneration, proliferation, vascular repair, and attenuating tubular damage. In vitro assays demonstrate that SDF-1 induces upregulation of its receptor CXCR4 in endothelial progenitor cells (EPCs) via a non-canonical NF-κB signaling pathway. FGF23 crosstalks with the SDF-1/CXCR4 signaling and abrogates SDF-1-induced EPC senescence and migration, but not angiogenesis, in a Klotho-independent manner. The downregulated pro-angiogenic IL-6, IL-8, and VEGF-A expressions after SDF-1 infusion are rescued after adding FGF23. Diminished therapeutic ability of SDF-1-treated EPCs is counteracted by FGF23 in a SCID mouse in vivo AKI model. Together, these data highlight a revolutionary and important role that FGF23 plays in the nephroprotection of IR-AKI.

17.
J Neurophysiol ; 125(6): 2054-2067, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33909496

RESUMO

Chronic intermittent hypoxia (CIH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread breathing disorder. CIH-treated rodents exhibit activation of the sympathetic nervous system and hypertension. Heightened carotid body (CB) activity has been implicated in CIH-induced hypertension. CB expresses high abundance of olfactory receptor (Olfr) 78, a G-protein coupled receptor. Olfr 78 null mice exhibit impaired CB sensory nerve response to acute hypoxia. Present study examined whether Olfr78 participates in CB-dependent activation of the sympathetic nervous system and hypertension in CIH-treated mice and in hemeoxygenase (HO)-2 null mice experiencing CIH as a consequence of naturally occurring OSA. CIH-treated wild-type (WT) mice showed hypertension, biomarkers of sympathetic nerve activation, and enhanced CB sensory nerve response to hypoxia and sensory long-term facilitation (sLTF), and these responses were absent in CIH-treated Olfr78 null mice. HO-2 null mice showed higher apnea index (AI) (58 ± 1.2 apneas/h) than WT mice (AI = 8 ± 0.8 apneas/h) and exhibited elevated blood pressure (BP), elevated plasma norepinephrine (NE) levels, and heightened CB sensory nerve response to hypoxia and sLTF. The magnitude of hypertension correlated with AI in HO-2 null mice. In contrast, HO-2/Olfr78 double null mice showed absence of elevated BP and plasma NE levels and augmented CB response to hypoxia and sLTF. These results demonstrate that Olfr78 participates in sympathetic nerve activation and hypertension and heightened CB activity in two murine models of CIH.NEW & NOTEWORTHY Carotid body (CB) sensory nerve activation is essential for sympathetic nerve excitation and hypertension in rodents treated with chronic intermittent hypoxia (CIH) simulating blood O2 profiles during obstructive sleep apnea (OSA). Here, we report that CIH-treated mice and hemeoxygenase (HO)-2-deficient mice, which show OSA phenotype, exhibit sympathetic excitation, hypertension, and CB activation. These effects are absent in Olfr78 null and Olfr78/HO-2 double null mice.

18.
BMJ Open ; 11(4): e047023, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846156

RESUMO

OBJECTIVES: To examine changes in the screening, diagnosis, treatment and management of drug-resistant tuberculosis (DRTB) patients, and investigate the impacts of DRTB-related policies on patients of different demographic and socioeconomic characteristics. DESIGN: A retrospective cohort study using registry data, plus a survey on DRTB-related policies. SETTING: All prefecture-level Centres for Disease Control in Zhejiang Province, China. MAIN OUTCOME MEASURES: Alongside the care cascade, we examined: (1) reported number of presumptive DRTB patients; (2) percentage of presumptive patients with drug susceptibility testing (DST) records; (3) percentage of DRTB/rifampicin-resistant (RR) patients registered; (4) percentage of RR/multidrug-resistant TB (MDRTB) patients that received anti-DRTB treatment; and (5) percentage of RR/MDRTB patients cured/completed treatment among those treated. Multivariate logistic regressions were conducted to explore the impacts of DRTB policies after adjusting for other factors. RESULTS: The number of reported presumptive DRTB patients and the percentage with DST records largely increased during 2015-2018, and the percentage of registered patients who received anti-DRTB treatment also increased from 59.0% to 86.5%. Patients under the policies of equipping GeneXpert plus expanded criteria for DST had a higher likelihood of being registered compared with no GeneXpert (adjusted OR (aOR)=2.57, 95% CI: 1.20 to 5.51), while for treatment initiation the association was only significant when further expanding the registration criteria (aOR=2.38, 95% CI: 1.19 to 4.79). Patients with registered residence inside Zhejiang were more likely to be registered (aOR=1.96, 95% CI: 1.52 to 2.52), treated (aOR=3.83, 95% CI: 2.78 to 5.28) and complete treatment (aOR=1.92, 95% CI: 1.03 to 3.59) compared with those outside. CONCLUSION: The policy changes on DST and registration have effectively improved DRTB case finding and care. Nevertheless, challenges remain in servicing vulnerable groups such as migrants and improving equity in the access to TB care. Future policies should provide comprehensive support for migrants to complete treatment at their current place of residence.


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos/uso terapêutico , China/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Políticas , Estudos Retrospectivos , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
19.
Mol Genet Genomic Med ; 9(5): e1632, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33834621

RESUMO

BACKGROUND: Classical Ehlers-Danlos syndrome (cEDS) is a heterogeneous connective tissue disorder that mainly results from the germline mutation of COL5A1 and COL5A2. The majority of the COL5A2 mutations reported to date represent structural mutations, including missense or in-frame exon-skipping splice mutations. The only reported synonymous mutation was expected to affect on splicing of exon 29 by prediction programs which should be further confirmed. METHODS: Whole exome sequencing was performed to identify the genetic variants of a Chinese boy who was characterized by skin hyperextensibility, abnormal scarring, hypermobile joints and scoliosis. Sanger sequencing was used to validate the variants in his parents. Reverse transcription polymerase chain reaction (RT-PCR) was performed to analyze the functional effects of the variant. RESULTS: A de novo heterozygous synonymous variant (NM_000393.5:c.1977 G>A) of COL5A2 gene was identified in the patient. The results of RT-PCR revealed that the synonymous variant led to skipping of exon 29 in the RNA transcript. CONCLUSIONS: Our study supplies further supporting evidence that the synonymous COL5A2 mutation c.1977 G>A can cause skipping of exon 29 in the RNA transcript, thus resulting in the production of mutant α2(V)-chains and clinical phenotype of cEDS. This result highlights the need to include splicing-altering synonymous mutations into the screening for cEDS.

20.
Viruses ; 13(4)2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921513

RESUMO

Classical swine fever (CSF) is a highly contagious disease of swine caused by classical swine fever virus (CSFV). For decades the disease has been controlled in China by a modified live vaccine (C-strain) of genotype 1. The emergent genotype 2 strains have become predominant in China in the past years that are genetically distant from the vaccine strain. Here, we aimed to evaluate the current infectious status of CSF, and for this purpose 24 isolates of CSFV were identified from different areas of China during 2016-2018. Phylogenetic analysis of NS5B, E2 and full genome revealed that the new isolates were clustered into subgenotype 2.1d and 2.1b, while subgenotype 2.1d was predominant. Moreover, E2 and Erns displayed multiple variations in neutralizing epitope regions. Furthermore, the new isolates exhibited capacity to escape C-strain-derived antibody neutralization compared with the Shimen strain (genotype 1). Potential positive selection sites were identified in antigenic regions of E2 and Erns, which are related with antibody binding affinity. Recombination events were predicted in the new isolates with vaccine strains in the E2 gene region. In conclusion, the new isolates showed molecular variations and antigenic alterations, which provide evidence for the emergence of vaccine-escaping mutants and emphasize the need of updated strategies for CSF control.

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