Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the discovery of revolutionary anti-TB drugs such as streptomycin, isoniazid, pyrazinamide, ethambutol and rifampicin, along with drug combination treatment, has greatly improved TB control globally. As anti-TB drugs were widely used, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis emerged due to acquired genetic mutations, and this now presents a major problem for effective treatment. Genes associated with drug resistance have been identified, including katG mutations in isoniazid resistance, rpoB mutations in rifampin resistance, pncA mutations in pyrazinamide resistance, and gyrA mutations in quinolone resistance. The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation, drug target alteration, overexpression of drug target, and overexpression of the efflux pump. During the disease process, Mycobacterium tuberculosis may reside in different microenvironments where it is expose to acidic pH, low oxygen, reactive oxygen species and anti-TB drugs, which can facilitate the development of non-replicating persisters and promote bacterial survival. The mechanisms of persister formation may include toxin-antitoxin (TA) modules, DNA protection and repair, protein degradation such as trans-translation, efflux, and altered metabolism. In recent years, the use of new anti-TB drugs, repurposed drugs, and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB. The importance of developing more effective drugs targeting persisters of Mycobacterium tuberculosis is emphasized. In addition, host-directed therapeutics using both conventional drugs and herbal medicines for more effective TB treatment should also be explored. In this article, we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant and persistent tuberculosis to inform future therapeutic development.
Humans ; Pyrazinamide/therapeutic use* ; Isoniazid/therapeutic use* ; Antitubercular Agents/therapeutic use* ; Tuberculosis, Multidrug-Resistant/microbiology* ; Mycobacterium tuberculosis/genetics* ; Tuberculosis/drug therapy* ; Rifampin/therapeutic use* ; Mutation ; Drug Resistance, Multiple, Bacterial/genetics*

ObjectiveTo reveal the targets and molecular mechanisms of the action of Qiangxin Decoction （强心汤） for the treatment of chronic heart failure based on the combination of network pharmacology and molecular docking. MethodsThe active ingredients of Qiangxin Decoction were retrieved from TCMSP database， and the targets of chronic heart failure were screened by searching GeneCards， OMIM， TTD， PharmGkb， and DrugBank databases， and the intersections were taken to obtain the intersecting targets of Qiangxin Decoction for the treatment of chronic heart failure. STRING platform was used to construct the protein-protein interaction network （PPI）， Cytoscape 3.8.0 software was used to calculate the network topology to screen the core targets， and R 4.2.3 was used to construct the “active ingredient-target” network by analyzing the GO enrichment analysis and KEGG pathway enrichment analysis. AutoDock 1.5.7 was used for molecular docking to predict the binding performance of active ingredients and core targets. ResultsSeventy-five intersecting targets were identified for the treatment of chronic heart failure with Qiangxin Decoction， among which the core targets were estrogen receptor 1 （ESR1， degree value=7）， nuclear receptor coactivator 1 （NCOA1， degree value=8）， glucocorticoid receptor （NR3C1， degree value=7）， and nuclear receptor coactivator 2 （NCOA2， degree value=7）. GO enrichment analysis showed that the top 3 items with the smallest P value in molecular function were G protein-coupled amine receptor activity， postsynaptic neurotransmitter receptor activity， and neurotransmitter receptor activity （P＜0.01）； the top 3 items with the smallest P value in biological process were adenylyl cyclase-activated adrenergic receptor signaling pathway， adrenergic receptor signaling pathway， and adenylyl cyclase-regulated G protein-coupled receptor signaling pathway （P＜0.01）； the top 3 items with the smallest P values in cellular composition were components of the postsynaptic membrane， synaptic membrane， and presynaptic membrane （P＜0.01）. KEGG enrichment analysis showed that the top 5 key signaling pathways were neuroactive ligand-receptor interactions， calcium signaling pathway， dopaminergic synapses， cocaine addiction， and cyclic guanosine monophosphate-protein kinase G （cGMP-PKG） signaling pathway. The molecular docking results showed that lignans and isoflavones had lower binding energies and more structural stability with the four core targets （ESR1， NCOA1， NR3C1， NCOA2）. ConclusionThe treatment of chronic heart failure by Qiangxin Decoction was associated with neuroactive ligand-receptor interactions， calcium signaling pathway， dopaminergic synapses， chemoattractant-receptor activation， cGMP-PKG signaling pathway， lipids and atherosclerosis， and cAMP signaling pathway， and lignans and isoflavones may be the core active compounds in its treatment of chronic heart failure.

Objective:To assess the significance of counting the number of caudal vertebral ossification centers (OCN) below fetal terminal conus medullaris in the screening for closed spina bifida and tethered cord syndrome (TCS).Methods:The OCN was counted in 961 normal fetuses(normal group) between 17 and 41 gestational weeks and in 140 fetuses with closed spina bifida or tethered cord syndrome(abnormal group) from Jan.2013 to Dec.2020 in Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Women and Children′s Hospital, School of Medicine, Xiamen University and Maternity and Child Health Care of Guangxi Zhuang Autonomous Region. The OCN was counted in the dorsal mid-sagittal section of fetal caudal spine.The reliability and agreement test were evaluated by intraclass correlation coefficients in another 50 normal fetuses. The OCN was compared between two groups. ROC curve and the cut-off value were constructed and calculated.Results:In normal group, the N increased with the growing of gestational age.In the subgroup of 17-20 weeks, the OCN ranged from 5 to 7 in most fetuses. In the others subgroups, the OCN was equal to or greater than 6 in 99.9% cases and more than 6 in 97.1% cases. In abnormal group, OCN was less than 7 in 93.0% fetuses and less than 6 in 82.8% cases. There were statistical differences between the two groups except for the subgroup of 17-20 gestational weeks( P<0.05). With the cut-off value of 6.5, the specificity and sensitivity were 93.0% and 94.3% respectively for predicting the presence of closed spinal dysraphism or TCS. Conclusions:OCN is a simple way to evaluate the position of conus medullaris and to screen for the skin-covered spine dysraphism or TSC. OCN is more than 6 in most normal fetuses. Further evaluation of spine is required in fetuses with N less than or equal to 6.

Administration, Intravenous ; Ascorbic Acid/therapeutic use* ; COVID-19 ; Humans ; Pneumonia ; SARS-CoV-2

BACKGROUND: Many studies have investigated heavy metal exposure could increase the occurrence of congenital heart defects (CHDs). However, there are limited data regarding the relationship between cobalt exposure and CHD occurrence in offspring. The aim of this study was to analyze the association between cobalt exposure in mothers and the risk of CHDs in offspring. MATERIALS AND METHODS: In order to explore the association between cobalt exposure and occurrence of congenital heart defect (CHD), a case-control study with 490 controls and 399 cases with CHDs in China were developed. The concentrations of cobalt in hair of pregnant woman and fetal placental tissue were measured and processed by a logistic regression analysis to explore the relationship between cobalt exposure and risk of CHDs. RESULTS: The median concentration of hair cobalt in the control and case group was 0.023 ng/mg and 0.033 ng/mg (aOR, 1.837; 95% CI, 1.468-2.299; P < 0.001), respectively. And the median (5-95% range) fetal placental cobalt concentrations were 19.350 ng/g and 42.500 ng/g (aOR, 2.924; 95% CI, 2.211-3.868; P < 0.001) in the control and case groups, respectively. Significant differences in the middle level of cobalt in hair were found in the different CHD subtypes, including septal defects, conotruncal defects, right ventricular outflow tract obstruction, and left ventricular outflow tract obstruction (P < 0.001). Dramatically, different cobalt concentrations in fetal placental tissue were found in all subtypes of cases with CHDs (P < 0.01). CONCLUSIONS The finding suggested that the occurrence of CHDs may be associated with cobalt exposure.
Adolescent ; Adult ; Case-Control Studies ; China ; Cobalt ; adverse effects ; Female ; Hair ; chemistry ; Heart Defects, Congenital ; chemically induced ; Humans ; Maternal Exposure ; adverse effects ; Placenta ; chemistry ; Pregnancy ; Prenatal Exposure Delayed Effects ; chemically induced ; Risk Factors ; Young Adult

Objective:To analyze the effects of angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) on coronavirus disease 2019 (COVID-19) patients with hypertension, and to provide an evidence for selecting antihypertensive drugs in those patients.Methods:Clinical data were retrospectively analyzed in 58 COVID-19 patients with hypertension admitted to Shanghai Public Health Clinical Center from January 20 to February 22, 2020, including epidemiological history, clinical manifestations, laboratory findings, chest CT and outcome. Patients were divided into ACEI/ARB group and non-ACEI/ARB group.Results:Twenty-six patients were in ACEI/ARB group and the other 32 patients in non-ACEI/ARB group, with median age 64.0 (49.5, 72.0) years and 64.0 (57.0, 68.8) years respectively. The median time to onset was 5(3, 8) days in ACEI/ARB group and 4 (3, 7) days in non-ACEI/ARB group, the proportion of patients with severe or critical illness was 19.2% and 15.6% respectively. The main clinical symptoms in two groups were fever (80.8% vs. 84.4%) and cough (23.1% vs. 31.3%). The following parameters were comparable including lymphocyte counts, C-reactive protein, lactate dehydrogenase, D-dimer, bilateral involvement in chest CT (76.9% vs. 71.9%), worsening of COVID-19 (15.4% vs. 9.4%), favorable outcome (92.3% vs. 96.9%) between ACEI/ARB group and non-ACEI/ARB group respectively (all P>0.05). However, compared with non-ACEI/ARB group, serum creatinine [80.49 (68.72, 95.30) μmol/L vs. 71.29 (50.98, 76.98) μmol/L, P=0.007] was higher significantly in ACEI/ARB group. Conclusions:ACEI/ARB drugs have no significant effects on baseline clinical parameters (serum creatine and myoglobin excluded) , outcome, and prognosis of COVID-19 patients with hypertension. Antihypertensive drugs are not suggested to adjust in those patients, but the potential impairment of renal function as elevation of serum creatinine should be paid attention in patients administrating ACEI/ARB drugs.

Objective To compare the different features of contrast enhanced ultrasound(CEUS) and CT angiography (CTA) in abdominal aortic remodeling after thoracic endovascular aortic repair (TEVAR)of DeBakey type Ⅲ aortic dissection(AD),and to investigate the application value of CEUS in the follow-up of DeBakey type Ⅲ AD after TEVAR.Methods CEUS was performed in 28 patients with DeBakey type Ⅲ AD after TEVAR,in which 8 cases type Ⅲ a (simple type) were not involved of abdominal aorta,20 cases Ⅲ b(complex type) were involved in the abdominal aorta,all patients were performed CTA examination of aorta.The functional and morphological changes of abdominal aortic remodeling were observed by two methods in DeBakey type Ⅲ AD after TEVAR.Results There was no new rupture of the abdominal aorta in 8 cases type Ⅲ a AD,but 20 cases of type Ⅲ b AD showed the situation of ruptures,thrombosis,trues and falses lumen after 3 months of follow-up.CEUS was less than CTA in detecting the number of ruptures (P＜0.05),CEUS and CTA results were similar in the measurement of true and false lumen diameter (P＞0.05),but CEUS clearly showed the hemodynamic characteristics of abdominal aortic intimal tear,the size and position of rupture,moving blood flow of rupture,and true or false lumen,which provided more accurate data for the long term abdominal aortic remodeling of DeBakey type Ⅲ AD after TEVAR.Conclusions CEUS and aortic CTA can play a complementary role in DeBakey type Ⅲ AD after TEVAR of long-term follow-up,it is worth promoting.

Purpose To evaluate the abdominal aortic remodeling in both morphology and hemodynamic changes before and after thoracic endovascular aortic repair (TEVAR) for aortic dissection (AD) of DeBakey type Ⅲ by using color Doppler ultrasound and contrast-enhanced ultrasound,in order to provide a novel imaging method for clinical treatment in addition to aortic computed tomography angiography (CTA).Materials and Methods Thirty patients with complicate AD of Debakey type Ⅲ were recruited.The abdominal vessels of patients were examined by color Doppler and contrast-enhanced ultrasound at different times including before TEVAR operation,and 1 day,1 month after operation.The size of true and false lumen,hemodynamic characteristics,thrombosis in false lumen,distal tear sites and blood supply of vital organs were analyzed combined with CTA results.Results The diameter and maximal blood flow velocity of true lumen at abdominal aorta 1 day,1 month after operation were significantly increased compared with those before operation (P＜0.05),but the diameter and maximal velocity of false lumen after operation were significantly decreased compared with those before operation (P＜0.05).The blood supply of affected organs had no significant difference before and after operation (all P＞0.05).The vessel diameter measurements were similar to those of CTA (P＞0.05).Conclusion Color Doppler imaging combined with contrast-enhanced ultrasound is a simple,reproducible method to evaluate the vascular remodeling in hemodynamics and morphology after TEVAR for complicate AD of DeBakey type Ⅲ,which can overcome the shortage of previous assessment only in morphology.

Objective To detect Mycobacterium tuberculosis (MTB)and its resistance against rifampin (RIF ) by applying Xpert MTB/RIF assay in the clinical samples from patients with extrapulmonary tuberculosis,and to discuss the value of this assay in extrapulmonary tuberculosis. Methods Totally 300 clinical samples from the patients who were highly suspected with extrapulmonary tuberculosis and hospitalized in Department of Tuberculosis Section,Shanghai Public Health Clinical Center of Fudan University from May 2014 to May 2015 were collected.Smear and fluorescence staining microscopy,MGIT 960 BACTEC liquid culture,Xpert MTB/RIF assay were applied to detect MTB in these samples.Meanwhile,all the patients received the peripheral blood T-cell spot of tuberculosis test (T-SPOT.TB).The sensitivity and specificity of Xpert MTB/RIF assay for MTB and its resistance against rifampin (RIF)in extrapulmonary tuberculosis samples were evaluated.The measurement data of two independent samples were analyzed by using t test and enumeration data were analyzed by usingχ2 test.Results Totally 282 out of 300 clinical samples from patients with extrapulmonary tuberculosis were included in this study,and 62.7% were male with average age of (32.1 ±24.6 )years and 37.3%were female with average age of (37.8 ±21 .0)years.When MGIT 960 BACTEC liquid culture results were considered as standard diagnosis,the sensitivity,specificity,positive predictive value and negative predictive value of Xpert MTB/RIF assay were 53.8% (95 %CI :37.4%—69.6%),100.0% (95 %CI :86.3%—100.0%),100.0% (95 %CI :80.8%—100.0%)and 63.3% (95 %CI :48.3%—76.2%), respectively.The sensitivity of Xpert MTB/RIF assay in smear-positive/culture-positive samples was 92.3% (95 %CI :62.1 %— 99.6%),while that in smear-negative/culture-positive samples was only 34.6% (95 %CI :17.9%— 55 .6%).Xpert MTB/RIF assay had advantage for detecting MTB in fine needle aspirates,pus,stool and urine,but not in serous effusion and cerebrospinal fluid.However,the sensitivities of MGIT BACTEC 960 liquid culture,fluorescence smear and T-SPOT.TB were 25 .8%, 21 .8% and 70.2%,respectively,and the specificities were 95 .5 %,90.3% and 51 .6%,respectively. The diagnostic value of Xpert MTB/RIF assay was not significantly different from those of MGIT BACTEC 960 liquid culture and fluorescence smear (χ2 =0.61 and 3.45 ,respectively;both P >0.05 ), while it was significantly different from T-SPOT.TB (χ2 =50.58,P <0.05).The sensitivity of T-SPOT. TB was significantly superior to Xpert MTB/RIF assay,but the specificity was relatively low.The sensitivity and specificity of Xpert MTB/RIF assay in RIF resistance detection were 71 .4% (95 %CI :30.3%—94.9%)and 100.0% (95 %CI :86.7%—100.0%),respectively.Conclusions The sensitivity and specificity of Xpert MTB/RIF assay in detecting MTB in fine needle aspirates,pus,stool and urine are relatively high,but not in serous effusion and cerebrospinal fluid.However,the pros of rapid detection and the ability of detecting RIF resistance are useful for the diagnose of extrapulmonary tuberculosis in clinical settings.

Objective To explore the role of MRI(T1ρ)in the early osteoarthritis,curative efficacy monitoring and speculated that the mechanism of curative effect.Methods (1)(early OA model)A total of 28 New Zealand white rabbits were randomly divided into A,B,C three groups.group A(treatment)and B(control)were both for 1 1 rabbits,and 6 rabbits were considered as blank control group(group C).0.5 mL 1.6% papain was injected into the right knee joint cavity both group A and B according to three times (1,4,7 days).The equivalent dilution was injected into the left knee joint cavity simultaneously.3 weeks after the first injection,and T2 WI,3D-FS-SPGR,and T1ρ mapping in sagittal plain were scanned for three groups.Randomly selected two models pathology test in the group A and B,confirm early OA model is established.(2)(treat models)Then give epimedium lavage to group A two month.The equivalent sterile saline lavage to group B.A certain time (T0 = 0,T1 = 1 mon,T2 = 2 mon)after treated do MR scanned for group A and B.Analysis of the image.T1ρvalues and the cartilage thickness in bilateral femoral condyle cartilage were measured by post-processing software.The all femurs were pathological examined.T1ρvalues and the cartilage thickness were statistic analysis. Results (1)Articular cavity injection of papain can successfully establish early osteoarthritis rabbit model which pathology has been confirmed.T1ρvalues of the experimental (group A,B)were significant higher than of the control side(P<0.05).Cartilage thickness values of the experimental (group A,B)and the control side has no statistical significance(P >0.05).(2)T1ρvalues of the Epimedium treat model (right side)were significant lower than of the pre-treatment that of the preintervention (P <0.05 ).T1ρvalues of the NS treatment (left side)and the pre-treatment has no statistical significance(P>0.05).Conclusion (1)T1ρvalues of the early and advanced stage of OA had increased in various degree,and the values related cartilage matrix composition.(2 )Single herb Epimedium has effective to treat early stages osteoarthritis in knee joint.Spec-ulated that the possible mechanism for treatment common channel in the development of OA,which inhibition protease formation and promote proteoglycan secretion.