Objective: To assess the effect of curcumin on CDDP-induced drug resistance and explore the underlying molecular mechanism through Nrf2 system and autophagy pathway.Methods: A drug-resistant cell model was established...Objective: To assess the effect of curcumin on CDDP-induced drug resistance and explore the underlying molecular mechanism through Nrf2 system and autophagy pathway.Methods: A drug-resistant cell model was established by exposing A549/CDDP cell to2 μg/mL CDDP. A549/CDDP cell was treated with 20 μg/mL CDDP and 10 μM curcumin. The cell viability and apoptosis level, the signals of Keap1/P62-Nrf2 and autophagy pathway were analyzed.Results: CDDP induction promoted drug-resistant phenotype in A549/CDDP cell and activated autophagy as well as Nrf2 signals in A549/CDDP cell. Meanwhile, curcumin combination attenuated autophagy and Nrf2 activation induced by CDDP, and reversed the drug-resistant phenotype. Notably, curcumin combination augmented Keap1 transcription. Furthermore, Keap1 ablation with short hairpin RNAs hampered the efficacy of curcumin, suggesting Keap1 played a crucial role on reversal effect of curcumin.Conclusions: The present findings demonstrate that CDDP promotes abnormal activation of Nrf2 pathway and autophagy, leading to drug resistance of A549/CDDP cell.Curcumin attenuates this process and combat drug-resistance through its potent activation on Keap1 transcription, which is essential for interplay between oxidative stress induced Nrf2 activation and autophagy/apoptosis switch.展开更多
It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen(HBsAg)are associated with nucleoside/nucleotide analog resistance.AIM To evaluate the assoc...It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen(HBsAg)are associated with nucleoside/nucleotide analog resistance.AIM To evaluate the association between immune escape-associated mutations and nucleoside/nucleotide analog resistance mutations.METHODS In total,19440 patients with chronic hepatitis B virus infection,who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between July 2007 and December 2017,were enrolled.As determined by sequence analysis,6982 patients harbored a virus with resistance mutations and 12458 harbored a virus lacking resistance mutations.Phenotypic analyses were performed to evaluate HBsAg production,replication capacity,and drug-induced viral inhibition of patient-derived drug-resistant mutants with or without the coexistence of sA159V.RESULTS The rate of immune escape-associated mutation was significantly higher in 9 of the 39 analyzed mutation sites in patients with resistance mutations than in patients without resistance mutations.In particular,these mutations were sQ101H/K/R,sS114A/L/T,sT118A/K/M/R/S/V,sP120A/L/Q/S/T,sT/I126A/N/P/S,sM133I/L/T,sC137W/Y,sG145A/R,and sA159G/V.Among these,sA159V was detected in 1.95%(136/6982)of patients with resistance mutations and 1.08%(134/12,458)of patients lacking resistance mutations(P<0.05).The coexistence of sA159V with lamivudine(LAM)and entecavir(ETV)-resistance mutations in the same viral genome was identified during follow-up in some patients with drug resistance.HBsAg production was significantly lower and the replication capacity was significantly higher,without a significant difference in LAM/ETV susceptibility,in sA159V-containing LAM/ETV-resistant mutants than in their sA159V-lacking counterparts.CONCLUSION In summary,we observed a close link between the increase in certain immune escape-associated mutations and the development of resistance mutations.sA159V might increase the fitness of LAM/ETV-resistant mutants under environmental pressure in some cases.展开更多
Objective:Squamous cell carcinoma(SCC)represents the most common histotype of all head and neck malignancies and includes oropharyngeal squamous cell carcinoma(OSCC),a tumor associated with different clinical outcomes...Objective:Squamous cell carcinoma(SCC)represents the most common histotype of all head and neck malignancies and includes oropharyngeal squamous cell carcinoma(OSCC),a tumor associated with different clinical outcomes and linked to human papilloma virus(HPV)status.Translational research has few available in vitro models with which to study the different pathophysiological behavior of OSCCs.The present study proposes a 3-dimensional(3 D)biomimetic collagen-based scaffold to mimic the tumor microenvironment and the crosstalk between the extracellular matrix(ECM)and cancer cells.Methods:We compared the phenotypic and genetic features of HPV-positive and HPV-negative OSCC cell lines cultured on common monolayer supports and on scaffolds.We also explored cancer cell adaptation to the 3 D microenvironment and its impact on the efficacy of drugs tested on cell lines and primary cultures.Results:HPV-positive and HPV-negative cell lines were successfully grown in the 3 D model and displayed different collagen fiber organization.The 3 D cultures induced an increased expression of markers related to epithelial–mesenchymal transition(EMT)and to matrix interactions and showed different migration behavior,as confirmed by zebrafish embryo xenografts.The expression of hypoxia-inducible factor 1α(1α)and glycolysis markers were indicative of the development of a hypoxic microenvironment inside the scaffold area.Furthermore,the 3 D cultures activated drug-resistance signaling pathways in both cell lines and primary cultures.Conclusions:Our results suggest that collagen-based scaffolds could be a suitable model for the reproduction of the pathophysiological features of OSCCs.Moreover,3 D architecture appears capable of inducing drug-resistance processes that can be studied to better our understanding of the different clinical outcomes of HPV-positive and HPV-negative patients with OSCCs.展开更多
BACKGROUND:The virulent factors of Escherichia coli(E.coli) play an important role in the process of pathopoiesis.The study aimed to compare drug-resistant genes and virulence genes between extended spectrum β-lactam...BACKGROUND:The virulent factors of Escherichia coli(E.coli) play an important role in the process of pathopoiesis.The study aimed to compare drug-resistant genes and virulence genes between extended spectrum β-lactamases(ESBLs)-producing E.coli and non-ESBLs-producing E.coli to provide a reference for physicians in management of hospital infection.METHODS:From October 2010 to August 2011,96 drug-resistant strains of E.coli isolated were collected from the specimens in Qingdao Municipal Hospital,Qingdao,China.These bacteria strains were divided into a ESBLs-producing group and a non-ESBLs-producing group.Drug sensitivity tests were performed using the Kirby-Bauer(K-B) method.Disinfectant gene,qacEA1-sull and 8 virulence genes(CNF2,hlyA,eaeA,VT1,est,bfpA,elt,and CNF1) were tested by polymerase chain reaction(PCR).RESULTS:Among the 96 E.coli isolates,the ESBLs-producing E.coli comprised 46(47.9%)strains and the non-ESBLs-producing E.coli consisted of 50(52.1%) strains.The detection rates of multiple drug-resistant strain,qacEA1-sull,CNF2,hlyA,eaeA,VT1,est,bfpA,elt,and CNF1 in 46ESBLs-producing E.coli isolates were 89.1%,76.1%,6.5%,69.6%,69.6%,89.1%,10.9%,26.1%,8.7%,and 19.6%,respectively.In the non-ESBLs-producing E.coli strains,the positive rates of multiple drug-resistant strain,qacEA1-sull,CNF2,hlyA,eaeA,VT1,est,bfpA,elt,and CNF1 were 62.0%,80.0%,16.0%,28.0%,64.0%,38.0%,6.0%,34.0%,10.0%,and 24.0%,respectively.The difference in the detection rates of multiple drug-resistant strain,hlyA and VT1 between the ESBLs-producing E.coli strains and the non-ESBLs-producing E.coli strains was statistically significant(P<0.05).CONCLUSION:The positive rate of multiple drug-resistant strains is higher in the ESBLsproducing strains than in the non-ESBLs-producing strains.The expression of some virulence genes hlyA and VT1 varies between the ESBLs-producing strains and the non-ESBLs-producing strains.Increased awareness of clinicians and enhanced testing by laboratories are required to reduce treatment failures and prevent the spread of multiple drug-resistant strains.展开更多
Background:Rapid and accurate detection of drug resistance inMycobacterium tuberculosis is critical for effective control of tuberculosis(TB).Herein,we established a novel,low cost strategy having high accuracy and sp...Background:Rapid and accurate detection of drug resistance inMycobacterium tuberculosis is critical for effective control of tuberculosis(TB).Herein,we established a novel,low cost strategy having high accuracy and speed for the detection ofM.tuberculosis drug resistance,using gene splicing by overlap extension PCR(SOE PCR).Methods:The SOE PCR assay and Sanger sequencing are designed and constructed to detect mutations of rpoB,embB,katG,andinhA promoter,which have been considered as the major contributors to rifampicin(RFP),isoniazid(INH),and ethambutol(EMB)resistance inM.tuberculosis.One hundred and eightM.tuberculosis isolates came from mycobacterial cultures of TB cases at Chongqing Public Health Medical Center in China from December 2018 to April 2019,of which 56 isolates were tested with the GeneXpert MTB/RIF assay.Performance evaluation of the SOE PCR technique was compared with traditional mycobacterial culture and drug susceptibility testing(DST)or GeneXpert MTB/RIF among these isolates.Kappa identity test was used to analyze the consistency of the different diagnostic methods.Results:We found that the mutations of S531L,S315T and M306V were most prevalent for RFP,INH and EMB resistance,respectively,in the 108 M.tuberculosis isolates.Compared with phenotypic DST,the sensitivity and specificity of the SOE PCR assay for resistance detection were 100.00% and 88.00% for RFP,94.64% and 94.23% for INH,and 68.97% and 79.75% for EMB,respectively.Compared with the GeneXpert MTB/RIF,the SOE PCR method was completely consistent with results of the GeneXpert MTB/RIF,with a concordance of 100% for resistance to RFP.Conclusions:In present study,a novel SOE PCR diagnostic method was successfully developed for the accurate detection ofM.tuberculosis drug resistance.Our results using this method have a high consistency with that of traditional phenotypic DST or GeneXpert MTB/RIF,and SOE PCR testing in clinical isolates can also be conducted rapidly and simultaneously for detection of drug resistance to RFP,EMB,and INH.展开更多
Objective:To establish extensively drug-resistant Pseudomonas aeruginosa(XDR-PA)infection-induced pneumonia model in rats.Methods:Twenty-four male SD rats were randomly divided into blank group,low bacterial group,med...Objective:To establish extensively drug-resistant Pseudomonas aeruginosa(XDR-PA)infection-induced pneumonia model in rats.Methods:Twenty-four male SD rats were randomly divided into blank group,low bacterial group,medium bacterial group,and high bacterial group.The low,medium and high bacterial groups were given intratracheal instillation of 0.1 mL of bacterial suspension(bacterial concentration in turn is 7.5×10^(9),3×10^(10),6×10^(10)CFU/mL),while the blank group were given the same volume of sterile normal saline.After modeling,the general conditions of rats in each group were observed,including mental state,hair,respiration,activity,eating,weight,and the survival curve was drawn.The pathological characteristics of lung tissue and the infiltration of inflammatory cells were observed.Pathogenic identification of each group was carried out by bacterial culture of lung tissue homogenate.Results:The general state of the blank group was normal,and the rats in other groups showed signs of mental depression,bristling,shortness of breath,even oral and nasal bleeding,decreased food intake and activity,and significant weight loss,and different degrees of death within 48 hours,the difference was statistically significant(P<0.05).Pathological results showed that the alveolar structure of rats in the blank group was complete,and the alveolar space was clear without exudation.The lung tissue of the low and medium bacterial groups showed obvious inflammatory cell infiltration,alveolar structure destruction,alveolar septum thickening,interstitial edema,but the pathological damage of the medium group was more severe,with a mortality rate of up to 50%,and the mortality rate of the low bacterial group was 17%.In the high bacterial group,red blood cells,inflammatory cells and a large amount of fibrin-like exudation can be seen in the alveolar space,which has the pathological characteristics of acute respiratory failure,and the mortality rate is as high as 67%.The results of bacterial culture of lung tissue homogenate showed that the blank group had no bacterial colonies,while PA colony growth can be seen in low,medium and high bacterial groups.Conclusion:9 Intratracheal instillation of low bacterial count(0.1 mL of 7.5×10^(9) CFU/mL)XDR-PA bacterial suspension can successfully construct a rat pneumonia model of XDR-PA infection.展开更多
Background: Drug-resistant epilepsy can be defined as the existence of seizures within 6 months, despite adequate therapy regimens with one or more antiepileptic drugs. Epilepsy surgery has been the standard therapy t...Background: Drug-resistant epilepsy can be defined as the existence of seizures within 6 months, despite adequate therapy regimens with one or more antiepileptic drugs. Epilepsy surgery has been the standard therapy to help those patients who suffer from drug-resistant epilepsy. The goal of this surgery is to halt or reduce the intensity of seizures. This literature review aims to provide an overview of existing surgical procedures for the treatment of drug-resistant epilepsy and the degree of seizure control they provide based on available literature. Methods: Data were collected from medical journal databases, aggregators, and individual publications. The most used databases were PubMed, Medline and NCBI. Some of the keywords used to search these databases include: “drug resistant epilepsy”, “seizure control”, and “neurosurgery”. Results: Epileptic surgery is divided into resective and non-resective procedures. Studies have shown that a full resection of the epileptogenic brain area increases the probability of seizure eradication, however, the risks of postoperative impairments grow as the resection area is extended. On the other hand, patients who are unsuitable for seizure focus removal by resective surgery, such as those with multifocal seizures or overlapping epileptogenic zone with a functional cortex, may benefit from non-resective surgical options such as Vagus Nerve Stimulation and Responsive Neurostimulation. Conclusion: This literature review discusses the comprehensive treatment of epilepsy, especially the surgical treatment of drug-resistant epilepsy. The reviewed studies have shown that epilepsy surgery has promising outcomes in achieving seizure freedom/reducing seizure frequency with minimal adverse effects when performed correctly with the appropriate choice of surgical candidates.展开更多
Oral antiviral agents have been developed in the last two decades for the treatment of chronic hepatitis B(CHB).However,antiviral resistance remains an important challenge for long-term CHB therapy.All of the clinical...Oral antiviral agents have been developed in the last two decades for the treatment of chronic hepatitis B(CHB).However,antiviral resistance remains an important challenge for long-term CHB therapy.All of the clinically available oral antiviral agents are nucleoside or nucleotide analogues that target the activity of viral reverse transcriptase(RT),and all are reported to have resistant mutations.Since the hepatitis B virus(HBV)RT,like other viral polymerases,lacks proofreading activity,the emergence of drug-resistance occurs readily under selective pressure from the administration of antiviral agents.The molecular diagnosis of drug-resistant HBV is based on sequence variations,and current diagnostic methods include sequencing,restriction fragment polymorphism analysis,and hybridization.Here,we will discuss the currently available molecular diagnosis tools,in vitro phenotypic assays for validation of drug-resistant HBV,and treatment options for drug-resistant HBV.展开更多
BACKGROUND Multidrug-resistant Gram-negative bacteria,exacerbated by excessive use of antimicrobials and immunosuppressants,are a major health threat.AIM To study the clinical efficacy and safety of colistin sulfate i...BACKGROUND Multidrug-resistant Gram-negative bacteria,exacerbated by excessive use of antimicrobials and immunosuppressants,are a major health threat.AIM To study the clinical efficacy and safety of colistin sulfate in the treatment of carbapenem-resistant Gram-negative bacilli-induced pneumonia,and to provide theoretical reference for clinical diagnosis and treatment.METHODS This retrospective analysis involved 54 patients with Gram-negative bacilli pneumonia admitted to intensive care unit of The General Hospital of the Northern Theater Command of the People's Liberation Army of China from August 2020 to June 2022.After bacteriological culture,the patients'airway secretions were collected to confirm the presence of Gram-negative bacilli.The patients were divided into the experimental and control groups according to the medication used.The research group consisted of 28 patients who received polymyxin sulfate combined with other drugs through intravenous,nebulization,or intravenous combined with nebulization,with a daily dosage of 1.5–3.0 million units.The control group consisted of 26 patients who received standard dosages of other antibiotics(including sulbactam sodium for injection,cefoperazone sodium sulbactam for injection,tigecycline,meropenem,or vaborbactam).RESULTS Of the 28 patients included in the research group,26 patients showed improvement,treatment was ineffective for two patients,and one patient died,with the treatment efficacy rate of 92.82%.Of the 26 patients in the control group,18 patients improved,treatment was ineffective for eight patients,and two patients died,with the treatment efficacy rate of 54.9%;significant difference was observed between the two groups(P<0.05).The levels of white blood cell(WBC),procalcitonin(PCT),and C-reactive protein(CRP)in both groups were significantly lower after treatment than before treatment(P<0.05),and the levels of WBC,PCT,and CRP in the research group were significantly lower than those in the control group(P<0.05).Compared with before treatment,there were no significant changes in aspartate aminotransferase,creatinine,and glomerular filtration rate in both groups,while total bilirubin and alanine aminotransferase decreased after treatment(P<0.05)with no difference between the groups.In patients with good clinical outcomes,the sequential organ failure assessment(SOFA)score was low when treated with inhaled polymyxin sulfate,and specific antibiotic treatment did not improve the outcome.Sepsis and septic shock as well as a low SOFA score were independent factors associated with good clinical outcomes.CONCLUSION Polymyxin sulfate has a significant effect on the treatment of patients with multiple drug-resistant Gram-negative bacilli pneumonia and other infections in the lungs and is safe and reliable.Moreover,the administration route of low-dose intravenous injection combined with nebulization shows better therapeutic effects and lower adverse reactions,providing new ideas for clinical administration.展开更多
Objective: Drug resistance is considered one of the main threats for tuberculosis control. Our aim was to identify risk factors for drug resistance in tuberculosis patients in the Northern Portugal. Study Design and M...Objective: Drug resistance is considered one of the main threats for tuberculosis control. Our aim was to identify risk factors for drug resistance in tuberculosis patients in the Northern Portugal. Study Design and Methods: Retrospective case-control study. The medical records and drug susceptibility test data from TB patients diagnosed between 31 March 2009 and 1 April 2010 were examined. We enrolled 119 patients with any drug resistance to first line anti-TB drugs and 238 with drug-susceptible TB, matched by age group. Variables analyzed included: gender, country of origin, employment situation, site of disease, previous treatment, presence of diabetes mellitus, HIV infection, alcohol abuse, intravenous drug use, abuse of other drugs and smoking habits. Multivariate conditional logistic regression was used to identify independent predictors for drug-resistant TB. Results: Diabetes mellitus [adjusted odds ratio (OR): 3.54;95% CI: 1.45 - 8.66], intravenous drug use (OR: 4.77;95% CI: 1.24 - 18.32) and previous TB treatment (OR: 2.48;95% CI: 1.12 - 5.49) were found to be risk factors for drug-resistant disease development. Conclusions: Diabetes mellitus, prior tuberculosis treatment, and intravenous drug use were risk factors for drug-resistant disease. The association between diabetes and drug-resistant TB should be further explored. Identifying clinical predictors of drug resistance can allow prompt identification of patients at risk for drug-resistant TB.展开更多
Introduction: The emergency of Mycobacterium tuberculosis resistant to the first line drug reduced access possibility to second line drugs for appropriate treatment and required for urgent action especially in le Demo...Introduction: The emergency of Mycobacterium tuberculosis resistant to the first line drug reduced access possibility to second line drugs for appropriate treatment and required for urgent action especially in le Democratic Republic of Congo (DRC), which counts among the highest tuberculosis (TB) burden countries in Africa. Objective: To present prevalence and describe multidrug-resistant tuberculosis cases in North-Kivu Province identified by using Genexpert technology. Methods: We conducted an observational prospective study on multidrug-resistant tuberculosis (MDR-TB) cases in North-Kivu Province, DRC from 2017 to 2018. All cases of MDR-TB identified by Genexpert MTB/ RIB were included in this series. Result: Of 15,544 tuberculosis cases registered during the study period, 19 cases of MDR-TB were identified. 57.9% was male, 89.5% was retreatment cases and 5.3% was coinfection HIV/TB cases. Conclusion: This new molecular technology diagnostic facilitates multidrug-resistance tuberculosis detection and improves the reporting of data lack.展开更多
The infection and drug resistance rates of Helicobacter pylori(H.pylori)are high and must be prevented and treated by better strategies.Based on recent research advances in this field as well as the results from our t...The infection and drug resistance rates of Helicobacter pylori(H.pylori)are high and must be prevented and treated by better strategies.Based on recent research advances in this field as well as the results from our team and those on traditional Chinese medicine,we review the causes of drug resistance,and prevention and treatment strategies for drug-resistant H.pylori infection,with an aim to make suggestions for the development of new drugs,such as establishment of new target identification and screening systems,modification of existing drug structures,use of new technologies,application of natural products,and using a commercial compound library.This article may provide reference for eradication of drug-resistant H.pylori.展开更多
BACKGROUND Pyogenic ventriculitis caused by extensively drug-resistant Acinetobacter baumannii(A.baumannii)is one of the most severe complications associated with craniotomy.However,limited therapeutic options exist f...BACKGROUND Pyogenic ventriculitis caused by extensively drug-resistant Acinetobacter baumannii(A.baumannii)is one of the most severe complications associated with craniotomy.However,limited therapeutic options exist for the treatment of A.baumannii ventriculitis due to the poor penetration rate of most antibiotics through the blood-brain barrier.CASE SUMMARY A 68-year-old male patient with severe traumatic brain injury developed pyogenic ventriculitis on postoperative day 24 caused by extensively drug-resistant A.baumannii susceptible to tigecycline only.Successful treatment was accomplished through multi-route administration of tigecycline,including intravenous combined with continuous ventricular irrigation plus intraventricular administration.The pus was cleared on the 3rd day post-irrigation,and cerebrospinal fluid cultures were negative after 12 d.CONCLUSION Our findings suggest that multi-route administration of tigecycline can be a therapeutic option against pyogenic ventriculitis caused by extensively drugresistant A.baumannii.展开更多
BACKGROUND Bedaquiline is among the prioritized drugs recommended by the World Health Organization for the treatment of extensively drug-resistant tuberculosis(XDRTB).Many patients have not achieved better clinical im...BACKGROUND Bedaquiline is among the prioritized drugs recommended by the World Health Organization for the treatment of extensively drug-resistant tuberculosis(XDRTB).Many patients have not achieved better clinical improvement after bedaquiline is stopped at 24 wk.However,there is no recommendation or guideline on bedaquiline administration beyond 24 wk,which is an important consideration when balancing the benefit of prognosis for XDR-TB against the uncertain safety concerning the newer antibiotics.CASE SUMMARY This paper reported 2 patients with XDR-TB(a female of 58 years of age and a female of 18 years of age)who received bedaquiline for 36 wk,as local experience to be shared.The 2 cases had negative cultures after 24 wk of treatment,but lung imaging was still positive.After discussion among experts,the consensus was made to bedaquiline prolongation by another 12 wk.The 36-wk prolonged use of bedaquiline in both cases achieved a favorable response without increasing the risk of cardiac events or new safety signals.CONCLUSION Longer regimen,including 36-wk bedaquiline treatment,might be an option for patients with XDR-TB.More studies are needed to explore the effectiveness and safety of prolonged use of bedaquiline for 36 wk vs standard 24 wk in the treatment of multidrug-resistant/XDR-TB or to investigate further the biomarkers and criteria indicative for extension of bedaquline to facilitate clinical use of thisnovel drug.展开更多
Background:Pentylenetetrazole kindling has long been used for the screening of investigational antiseizure drugs.The presence of lamotrigine,at a very low dose,does not hamper kindling in mice;rather it modifies this ...Background:Pentylenetetrazole kindling has long been used for the screening of investigational antiseizure drugs.The presence of lamotrigine,at a very low dose,does not hamper kindling in mice;rather it modifies this epileptogenesis process into drug-resistant epilepsy.The lamotrigine-pentylenetetrazole kindled mice show resistance to lamotrigine,phenytoin,and carbamazepine.It may also be possible that other licensed antiseizure drugs,like the mentioned drugs,remain ineffective in this model;therefore,this was the subject of this study.Methods:Swiss albino mice were kindled with pentylenetetrazole for 35 days in the presence of either methylcellulose vehicle or lamotrigine(subtherapeutic dose,ie,5 mg/kg).Vehicle vs lamotrigine-kindled mice were compared in terms of(a)resistance/response toward nine antiseizure drugs applied as monotherapies and two drug combinations;(b)lamotrigine bioavailability in blood and brain;(c)blood-brain barrier integrity;and(d)amino acids and monoamines in the cerebral cortex and hippocampus.Results:Lamotrigine vs vehicle-kindled mice are similar(or not significantly different P>.05 from each other)in terms of(a)response toward drug combinations;(b)lamotrigine bioavailability;and(c)blood-brain barrier integrity except for,significantly(P<.05)reduced taurine and increased glutamate in the cerebral cortex and hippocampus.Aside from these,lamotrigine-kindled mice show significant(P<.05)resistant to lamotrigine(15 mg/kg),levetiracetam(40 mg/kg);carbamazepine(40 mg/kg),zonisamide(100 mg/kg),gabapentin(224 mg/kg),pregabalin(30 mg/kg),phenytoin(35 mg/kg),and topiramate(300 mg/kg).Conclusion:Lamotrigine-pentylenetetrazole kindling takes longer to develop(~5 weeks)in comparison to lamotrigine-amygdale(~4 weeks)and lamotriginecorneal(~2 weeks)kindling models.However,drug screening through this model may yield superior drugs with novel antiseizure mechanisms.展开更多
BACKGROUND Perampanel(PER),a third-generation antiepileptic drug,is a selective and noncompetitiveα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist,and has been approved for the treatment of ad...BACKGROUND Perampanel(PER),a third-generation antiepileptic drug,is a selective and noncompetitiveα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist,and has been approved for the treatment of adults and adolescents with focal epilepsy.However,there are only a few studies about the efficacy and tolerability of PER in young children with multidrug-resistant epilepsy.In this case,we aimed to share our clinical experience in this group.CASE SUMMARY A 4-year-old boy without perinatal asphyxia and familial history of epilepsy began to have ictal seizures from age 14 mo,with jerky movement of four limbs and head nodding.Abnormal multifocal discharge and background activity were recorded through electroencephalography,and no pathogenic mutation was found in the whole exome sequencing for the patient and his parents.He had received valproate,levetiracetam,topiramate,oxcarbazepine,clonazepam and lacosamide sequentially at different times,but he still had frequent seizures even after vagus nerve stimulation(VNS)implantation.He was diagnosed with idiopathic multidrug-resistant epilepsy.However,his seizure frequency was significantly reduced after PER administration in a dose-dependent manner,and better cognitive behavior was observed.In addition,the adverse reactions of anger and aggression also appeared.CONCLUSION PER is effective as add-on therapy for young children with multidrug-resistant epilepsy who have previously undergone VNS implantation.展开更多
There are various bacteria living in this world. The most common one is Staphylococcus aureus. Almost everyone has heard of it. It is easy to find their habitats, such as hospitals, homes, parks, schools etc. Some of ...There are various bacteria living in this world. The most common one is Staphylococcus aureus. Almost everyone has heard of it. It is easy to find their habitats, such as hospitals, homes, parks, schools etc. Some of them are difficult to be eliminated because of drug-resistant mutations. Hence, lots of researchers devoted their efforts to eliminate them. This review illustrates the characteristics of the Staphylococcus aureus and the main threat of their drug-resistant strains, especially methicillin-resistant S. aureus. What’s more, the article also highlights the plight in the drug development.展开更多
Objectives: Bedaquiline (BDQ) is the first new anti-tuberculosis (TB) drug introduced to the market after 45 years. Recent studies have shown the potential benefits of adding bedaquiline to regimens for drug-resistant...Objectives: Bedaquiline (BDQ) is the first new anti-tuberculosis (TB) drug introduced to the market after 45 years. Recent studies have shown the potential benefits of adding bedaquiline to regimens for drug-resistant TB (DR-TB). In search of more effective regimens for DR-TB, bedaquiline was introduced in the TB program in the Philippines under operational research to assess its effectiveness, safety, and tolerability when given with background regimens among patients with multi-or extensively DR-TB (MDR/XDR-TB). Design: A prospective cohort study of patients with MDR/XDR-TB was given with a bedaquiline-containing regimen from June 2016 to May 2017. Demographic data, presence of comorbidities, and microbiologic profile on entry were recorded. Bedaquiline was administered at the recommended dose of 400 mg once daily for 14 days, then 200 mg three times a week for 22 weeks together with World Health Organization (WHO)-compliant background regimen. The time to culture conversion, interim outcomes at the 6th month of treatment, end-of-treatment outcomes, and post-treatment follow-up outcomes after one year was determined. The frequency and severity of adverse events (SAE) were recorded as part of pharmacovigilance. Results: Seventy-five patients were given with bedaquiline-containing regimen during the study period. Forty-two (56.0%) had second-line injectable resistance, 23 (30.7%) had fluoroquinolone-resistance, 6 (8.0%) had MDR-TB, and 4 (5.3%) had XDR-TB. In the 6th month of post-enrolment, 79% were culture-negative. The treatment success rate was 65.3% (37 were cured and 12 completed treatment), 7 (9.3%) died, 17 (22.7%) lost to follow-up, and 2 (2.7%) were withdrawn from treatment. Adverse events included vomiting (80%), dizziness (69%), nausea (52%), cough (44%), and headache (36%). The post-treatment follow-up of 49 patients in the 12th month showed 92% were culture-negative while 8% of TBC were not done. Conclusion: Bedaquiline-containing regimens for patients with MDR/XDR-TB were highly effective with an acceptable safety profile and favorable treatment outcomes, but the proportion of patients who lost to follow-up remains substantial.展开更多
Drug resistance is one of the major challenges facing the success of chemotherapy against human hepatocarcinoma (HCC) as well as other types of cancer. Studies with cell lines can serve as initial screening for agents...Drug resistance is one of the major challenges facing the success of chemotherapy against human hepatocarcinoma (HCC) as well as other types of cancer. Studies with cell lines can serve as initial screening for agents that could modulate drug resistance. Development of a good experimental model of drug-resistant cells is a prerequisite for the success of such cellular studies;but could be laborious and generally time-consuming. Additionally, the high mortality rate associated with advanced HCC calls for a probe into the mechanism of resistance by developing experimental model that mimics clinical method of its treatment. Consequently, we have reported a simplified method of selection of drug-resistant hepatocarcinoma cells from human hepatocellular carcinoma (HEPG2) cell line using pharmacologic agents, cisplatin (CDDP) and 5-fluorouracil (5-FU). HEPG2 cell line was incubated for 24 hours with different concentrations of CDDP (0 - 20 μM) or 5-FU (0 - 100 μM). Cell viability was assayed by CCK-8 (Cell Counting Kit) analysis, and the inhibitory concentrations (IC50) for CDDP and 5-FU were established by dose-dependent cytotoxicity curves. The IC50(s) were confirmed by flow cytometric analysis of cell death due to CDDP or 5-FU. Clinical method of treatment was imitated by treating the parental HEPG2 cell line in pulse, at the optimal concentration of either CDDP or 5-FU for 4 to 6 hours. Induction was repeated 6 times, whilst allowing the cells to attain at least 70% confluence between intervals of induction. The resultant drug-resistant sublines, (HEPG2CR) and (HEPG2FR) were found to be stable after over 3 months of drug withdrawal and maintenance in drug-free medium. This was done with the views of establishing a simple, efficient and direct protocol for the development of good cellular models for the study of drug resistance in liver cancer, with possible application in other cancer types.展开更多
Background: Photodynamic therapy (PDT) is a less invasive cancer treatment using photochemical reactions induced by light irradiation to a photosensitizer (PS). Highly selective PDT with fast accumulation of the PS in...Background: Photodynamic therapy (PDT) is a less invasive cancer treatment using photochemical reactions induced by light irradiation to a photosensitizer (PS). Highly selective PDT with fast accumulation of the PS in target site might be a promising treatment option for drug-resistant prostate cancer facing high incidence rate of elderly men who have no effective treatment options and require a minimally invasive treatment. Hemagglutinating virus of Japan envelope (HVJ-E) allows selective and fast drug delivery to the drug-resistant prostate cancer cells via rapid cell membrane fusion. PS named porphyrus envelope (PE) has been developed by insertion of lipidated protoporphyrin IX (PpIX lipid) into HVJ-E. In this study, we investigated the optimal conditions for PE preparation and laser irradiation for highly selective PDT using PE with a short drug-light interval. Materials and Methods: Human hormon refractory prostate cancer cell line PC-3 and human normal prostate epithelial cell line PNT2 were cultured. PpIX lipid uptake and cytotoxicity of PDT in the cells incubated with PE for 10 min were evaluated by measuring fluorescence intensity and by using a cell counting reagent 24 h after PDT, respectively. Results: PpIX lipid uptake and cytotoxicity of PDT were increased with PpIX lipid concentration. Cytotoxicity of PDT using PE was more than 9 times as strong as that with PpIX lipid and PpIX induced by 5-aminolevulinic acid. Much stronger cytotoxicity was induced in PC-3 cells than PNT2 cells with the ratio of cell death rate for cancer to normal cells up to 4.64 ± 0.09. Conclusions: Fast PS delivery with HVJ-E allows highly selective PDT with a short drug-light interval. Therefore, PDT using PE has a potential to shorten treatment period and reduce side effects of PDT.展开更多
基金supported by the National Natural Science Foundation of China(81272485,81503236,81641141)the Natural Science Foundation of Anhui Province,China(1608085QH212)+1 种基金the Key Scientific Research Foundation of the Higher Education Institutions of Anhui Province(KJ2015A155)Key Projects of Anhui Province University Outstanding Youth Talent Supporting Program(gxyqZD2016178,gxyqZD2016179)
文摘Objective: To assess the effect of curcumin on CDDP-induced drug resistance and explore the underlying molecular mechanism through Nrf2 system and autophagy pathway.Methods: A drug-resistant cell model was established by exposing A549/CDDP cell to2 μg/mL CDDP. A549/CDDP cell was treated with 20 μg/mL CDDP and 10 μM curcumin. The cell viability and apoptosis level, the signals of Keap1/P62-Nrf2 and autophagy pathway were analyzed.Results: CDDP induction promoted drug-resistant phenotype in A549/CDDP cell and activated autophagy as well as Nrf2 signals in A549/CDDP cell. Meanwhile, curcumin combination attenuated autophagy and Nrf2 activation induced by CDDP, and reversed the drug-resistant phenotype. Notably, curcumin combination augmented Keap1 transcription. Furthermore, Keap1 ablation with short hairpin RNAs hampered the efficacy of curcumin, suggesting Keap1 played a crucial role on reversal effect of curcumin.Conclusions: The present findings demonstrate that CDDP promotes abnormal activation of Nrf2 pathway and autophagy, leading to drug resistance of A549/CDDP cell.Curcumin attenuates this process and combat drug-resistance through its potent activation on Keap1 transcription, which is essential for interplay between oxidative stress induced Nrf2 activation and autophagy/apoptosis switch.
基金the National Natural Science Foundation of China,No.81572010,No.81671399,No.81721002 and No.81971329the Capital Health Research and Development of Special Fund Program,No.2016-2-5032and the Beijing Natural Science Foundation No.7172206.
文摘It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen(HBsAg)are associated with nucleoside/nucleotide analog resistance.AIM To evaluate the association between immune escape-associated mutations and nucleoside/nucleotide analog resistance mutations.METHODS In total,19440 patients with chronic hepatitis B virus infection,who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between July 2007 and December 2017,were enrolled.As determined by sequence analysis,6982 patients harbored a virus with resistance mutations and 12458 harbored a virus lacking resistance mutations.Phenotypic analyses were performed to evaluate HBsAg production,replication capacity,and drug-induced viral inhibition of patient-derived drug-resistant mutants with or without the coexistence of sA159V.RESULTS The rate of immune escape-associated mutation was significantly higher in 9 of the 39 analyzed mutation sites in patients with resistance mutations than in patients without resistance mutations.In particular,these mutations were sQ101H/K/R,sS114A/L/T,sT118A/K/M/R/S/V,sP120A/L/Q/S/T,sT/I126A/N/P/S,sM133I/L/T,sC137W/Y,sG145A/R,and sA159G/V.Among these,sA159V was detected in 1.95%(136/6982)of patients with resistance mutations and 1.08%(134/12,458)of patients lacking resistance mutations(P<0.05).The coexistence of sA159V with lamivudine(LAM)and entecavir(ETV)-resistance mutations in the same viral genome was identified during follow-up in some patients with drug resistance.HBsAg production was significantly lower and the replication capacity was significantly higher,without a significant difference in LAM/ETV susceptibility,in sA159V-containing LAM/ETV-resistant mutants than in their sA159V-lacking counterparts.CONCLUSION In summary,we observed a close link between the increase in certain immune escape-associated mutations and the development of resistance mutations.sA159V might increase the fitness of LAM/ETV-resistant mutants under environmental pressure in some cases.
文摘Objective:Squamous cell carcinoma(SCC)represents the most common histotype of all head and neck malignancies and includes oropharyngeal squamous cell carcinoma(OSCC),a tumor associated with different clinical outcomes and linked to human papilloma virus(HPV)status.Translational research has few available in vitro models with which to study the different pathophysiological behavior of OSCCs.The present study proposes a 3-dimensional(3 D)biomimetic collagen-based scaffold to mimic the tumor microenvironment and the crosstalk between the extracellular matrix(ECM)and cancer cells.Methods:We compared the phenotypic and genetic features of HPV-positive and HPV-negative OSCC cell lines cultured on common monolayer supports and on scaffolds.We also explored cancer cell adaptation to the 3 D microenvironment and its impact on the efficacy of drugs tested on cell lines and primary cultures.Results:HPV-positive and HPV-negative cell lines were successfully grown in the 3 D model and displayed different collagen fiber organization.The 3 D cultures induced an increased expression of markers related to epithelial–mesenchymal transition(EMT)and to matrix interactions and showed different migration behavior,as confirmed by zebrafish embryo xenografts.The expression of hypoxia-inducible factor 1α(1α)and glycolysis markers were indicative of the development of a hypoxic microenvironment inside the scaffold area.Furthermore,the 3 D cultures activated drug-resistance signaling pathways in both cell lines and primary cultures.Conclusions:Our results suggest that collagen-based scaffolds could be a suitable model for the reproduction of the pathophysiological features of OSCCs.Moreover,3 D architecture appears capable of inducing drug-resistance processes that can be studied to better our understanding of the different clinical outcomes of HPV-positive and HPV-negative patients with OSCCs.
文摘BACKGROUND:The virulent factors of Escherichia coli(E.coli) play an important role in the process of pathopoiesis.The study aimed to compare drug-resistant genes and virulence genes between extended spectrum β-lactamases(ESBLs)-producing E.coli and non-ESBLs-producing E.coli to provide a reference for physicians in management of hospital infection.METHODS:From October 2010 to August 2011,96 drug-resistant strains of E.coli isolated were collected from the specimens in Qingdao Municipal Hospital,Qingdao,China.These bacteria strains were divided into a ESBLs-producing group and a non-ESBLs-producing group.Drug sensitivity tests were performed using the Kirby-Bauer(K-B) method.Disinfectant gene,qacEA1-sull and 8 virulence genes(CNF2,hlyA,eaeA,VT1,est,bfpA,elt,and CNF1) were tested by polymerase chain reaction(PCR).RESULTS:Among the 96 E.coli isolates,the ESBLs-producing E.coli comprised 46(47.9%)strains and the non-ESBLs-producing E.coli consisted of 50(52.1%) strains.The detection rates of multiple drug-resistant strain,qacEA1-sull,CNF2,hlyA,eaeA,VT1,est,bfpA,elt,and CNF1 in 46ESBLs-producing E.coli isolates were 89.1%,76.1%,6.5%,69.6%,69.6%,89.1%,10.9%,26.1%,8.7%,and 19.6%,respectively.In the non-ESBLs-producing E.coli strains,the positive rates of multiple drug-resistant strain,qacEA1-sull,CNF2,hlyA,eaeA,VT1,est,bfpA,elt,and CNF1 were 62.0%,80.0%,16.0%,28.0%,64.0%,38.0%,6.0%,34.0%,10.0%,and 24.0%,respectively.The difference in the detection rates of multiple drug-resistant strain,hlyA and VT1 between the ESBLs-producing E.coli strains and the non-ESBLs-producing E.coli strains was statistically significant(P<0.05).CONCLUSION:The positive rate of multiple drug-resistant strains is higher in the ESBLsproducing strains than in the non-ESBLs-producing strains.The expression of some virulence genes hlyA and VT1 varies between the ESBLs-producing strains and the non-ESBLs-producing strains.Increased awareness of clinicians and enhanced testing by laboratories are required to reduce treatment failures and prevent the spread of multiple drug-resistant strains.
基金supported by the Joint Medical Research Project of Chongqing Science&Technology Bureau and Chongqing Health Commission(2018MSXM013)。
文摘Background:Rapid and accurate detection of drug resistance inMycobacterium tuberculosis is critical for effective control of tuberculosis(TB).Herein,we established a novel,low cost strategy having high accuracy and speed for the detection ofM.tuberculosis drug resistance,using gene splicing by overlap extension PCR(SOE PCR).Methods:The SOE PCR assay and Sanger sequencing are designed and constructed to detect mutations of rpoB,embB,katG,andinhA promoter,which have been considered as the major contributors to rifampicin(RFP),isoniazid(INH),and ethambutol(EMB)resistance inM.tuberculosis.One hundred and eightM.tuberculosis isolates came from mycobacterial cultures of TB cases at Chongqing Public Health Medical Center in China from December 2018 to April 2019,of which 56 isolates were tested with the GeneXpert MTB/RIF assay.Performance evaluation of the SOE PCR technique was compared with traditional mycobacterial culture and drug susceptibility testing(DST)or GeneXpert MTB/RIF among these isolates.Kappa identity test was used to analyze the consistency of the different diagnostic methods.Results:We found that the mutations of S531L,S315T and M306V were most prevalent for RFP,INH and EMB resistance,respectively,in the 108 M.tuberculosis isolates.Compared with phenotypic DST,the sensitivity and specificity of the SOE PCR assay for resistance detection were 100.00% and 88.00% for RFP,94.64% and 94.23% for INH,and 68.97% and 79.75% for EMB,respectively.Compared with the GeneXpert MTB/RIF,the SOE PCR method was completely consistent with results of the GeneXpert MTB/RIF,with a concordance of 100% for resistance to RFP.Conclusions:In present study,a novel SOE PCR diagnostic method was successfully developed for the accurate detection ofM.tuberculosis drug resistance.Our results using this method have a high consistency with that of traditional phenotypic DST or GeneXpert MTB/RIF,and SOE PCR testing in clinical isolates can also be conducted rapidly and simultaneously for detection of drug resistance to RFP,EMB,and INH.
基金Science and Technology Projects in Key Fields of Traditional Chinese Medicine in Tianjin(No.2021010)Discipline Development Fund of First Teaching Hospital of Tianjin University of Traditional Chinese Medicine(No.XKJJ201734)。
文摘Objective:To establish extensively drug-resistant Pseudomonas aeruginosa(XDR-PA)infection-induced pneumonia model in rats.Methods:Twenty-four male SD rats were randomly divided into blank group,low bacterial group,medium bacterial group,and high bacterial group.The low,medium and high bacterial groups were given intratracheal instillation of 0.1 mL of bacterial suspension(bacterial concentration in turn is 7.5×10^(9),3×10^(10),6×10^(10)CFU/mL),while the blank group were given the same volume of sterile normal saline.After modeling,the general conditions of rats in each group were observed,including mental state,hair,respiration,activity,eating,weight,and the survival curve was drawn.The pathological characteristics of lung tissue and the infiltration of inflammatory cells were observed.Pathogenic identification of each group was carried out by bacterial culture of lung tissue homogenate.Results:The general state of the blank group was normal,and the rats in other groups showed signs of mental depression,bristling,shortness of breath,even oral and nasal bleeding,decreased food intake and activity,and significant weight loss,and different degrees of death within 48 hours,the difference was statistically significant(P<0.05).Pathological results showed that the alveolar structure of rats in the blank group was complete,and the alveolar space was clear without exudation.The lung tissue of the low and medium bacterial groups showed obvious inflammatory cell infiltration,alveolar structure destruction,alveolar septum thickening,interstitial edema,but the pathological damage of the medium group was more severe,with a mortality rate of up to 50%,and the mortality rate of the low bacterial group was 17%.In the high bacterial group,red blood cells,inflammatory cells and a large amount of fibrin-like exudation can be seen in the alveolar space,which has the pathological characteristics of acute respiratory failure,and the mortality rate is as high as 67%.The results of bacterial culture of lung tissue homogenate showed that the blank group had no bacterial colonies,while PA colony growth can be seen in low,medium and high bacterial groups.Conclusion:9 Intratracheal instillation of low bacterial count(0.1 mL of 7.5×10^(9) CFU/mL)XDR-PA bacterial suspension can successfully construct a rat pneumonia model of XDR-PA infection.
文摘Background: Drug-resistant epilepsy can be defined as the existence of seizures within 6 months, despite adequate therapy regimens with one or more antiepileptic drugs. Epilepsy surgery has been the standard therapy to help those patients who suffer from drug-resistant epilepsy. The goal of this surgery is to halt or reduce the intensity of seizures. This literature review aims to provide an overview of existing surgical procedures for the treatment of drug-resistant epilepsy and the degree of seizure control they provide based on available literature. Methods: Data were collected from medical journal databases, aggregators, and individual publications. The most used databases were PubMed, Medline and NCBI. Some of the keywords used to search these databases include: “drug resistant epilepsy”, “seizure control”, and “neurosurgery”. Results: Epileptic surgery is divided into resective and non-resective procedures. Studies have shown that a full resection of the epileptogenic brain area increases the probability of seizure eradication, however, the risks of postoperative impairments grow as the resection area is extended. On the other hand, patients who are unsuitable for seizure focus removal by resective surgery, such as those with multifocal seizures or overlapping epileptogenic zone with a functional cortex, may benefit from non-resective surgical options such as Vagus Nerve Stimulation and Responsive Neurostimulation. Conclusion: This literature review discusses the comprehensive treatment of epilepsy, especially the surgical treatment of drug-resistant epilepsy. The reviewed studies have shown that epilepsy surgery has promising outcomes in achieving seizure freedom/reducing seizure frequency with minimal adverse effects when performed correctly with the appropriate choice of surgical candidates.
文摘Oral antiviral agents have been developed in the last two decades for the treatment of chronic hepatitis B(CHB).However,antiviral resistance remains an important challenge for long-term CHB therapy.All of the clinically available oral antiviral agents are nucleoside or nucleotide analogues that target the activity of viral reverse transcriptase(RT),and all are reported to have resistant mutations.Since the hepatitis B virus(HBV)RT,like other viral polymerases,lacks proofreading activity,the emergence of drug-resistance occurs readily under selective pressure from the administration of antiviral agents.The molecular diagnosis of drug-resistant HBV is based on sequence variations,and current diagnostic methods include sequencing,restriction fragment polymorphism analysis,and hybridization.Here,we will discuss the currently available molecular diagnosis tools,in vitro phenotypic assays for validation of drug-resistant HBV,and treatment options for drug-resistant HBV.
文摘BACKGROUND Multidrug-resistant Gram-negative bacteria,exacerbated by excessive use of antimicrobials and immunosuppressants,are a major health threat.AIM To study the clinical efficacy and safety of colistin sulfate in the treatment of carbapenem-resistant Gram-negative bacilli-induced pneumonia,and to provide theoretical reference for clinical diagnosis and treatment.METHODS This retrospective analysis involved 54 patients with Gram-negative bacilli pneumonia admitted to intensive care unit of The General Hospital of the Northern Theater Command of the People's Liberation Army of China from August 2020 to June 2022.After bacteriological culture,the patients'airway secretions were collected to confirm the presence of Gram-negative bacilli.The patients were divided into the experimental and control groups according to the medication used.The research group consisted of 28 patients who received polymyxin sulfate combined with other drugs through intravenous,nebulization,or intravenous combined with nebulization,with a daily dosage of 1.5–3.0 million units.The control group consisted of 26 patients who received standard dosages of other antibiotics(including sulbactam sodium for injection,cefoperazone sodium sulbactam for injection,tigecycline,meropenem,or vaborbactam).RESULTS Of the 28 patients included in the research group,26 patients showed improvement,treatment was ineffective for two patients,and one patient died,with the treatment efficacy rate of 92.82%.Of the 26 patients in the control group,18 patients improved,treatment was ineffective for eight patients,and two patients died,with the treatment efficacy rate of 54.9%;significant difference was observed between the two groups(P<0.05).The levels of white blood cell(WBC),procalcitonin(PCT),and C-reactive protein(CRP)in both groups were significantly lower after treatment than before treatment(P<0.05),and the levels of WBC,PCT,and CRP in the research group were significantly lower than those in the control group(P<0.05).Compared with before treatment,there were no significant changes in aspartate aminotransferase,creatinine,and glomerular filtration rate in both groups,while total bilirubin and alanine aminotransferase decreased after treatment(P<0.05)with no difference between the groups.In patients with good clinical outcomes,the sequential organ failure assessment(SOFA)score was low when treated with inhaled polymyxin sulfate,and specific antibiotic treatment did not improve the outcome.Sepsis and septic shock as well as a low SOFA score were independent factors associated with good clinical outcomes.CONCLUSION Polymyxin sulfate has a significant effect on the treatment of patients with multiple drug-resistant Gram-negative bacilli pneumonia and other infections in the lungs and is safe and reliable.Moreover,the administration route of low-dose intravenous injection combined with nebulization shows better therapeutic effects and lower adverse reactions,providing new ideas for clinical administration.
文摘Objective: Drug resistance is considered one of the main threats for tuberculosis control. Our aim was to identify risk factors for drug resistance in tuberculosis patients in the Northern Portugal. Study Design and Methods: Retrospective case-control study. The medical records and drug susceptibility test data from TB patients diagnosed between 31 March 2009 and 1 April 2010 were examined. We enrolled 119 patients with any drug resistance to first line anti-TB drugs and 238 with drug-susceptible TB, matched by age group. Variables analyzed included: gender, country of origin, employment situation, site of disease, previous treatment, presence of diabetes mellitus, HIV infection, alcohol abuse, intravenous drug use, abuse of other drugs and smoking habits. Multivariate conditional logistic regression was used to identify independent predictors for drug-resistant TB. Results: Diabetes mellitus [adjusted odds ratio (OR): 3.54;95% CI: 1.45 - 8.66], intravenous drug use (OR: 4.77;95% CI: 1.24 - 18.32) and previous TB treatment (OR: 2.48;95% CI: 1.12 - 5.49) were found to be risk factors for drug-resistant disease development. Conclusions: Diabetes mellitus, prior tuberculosis treatment, and intravenous drug use were risk factors for drug-resistant disease. The association between diabetes and drug-resistant TB should be further explored. Identifying clinical predictors of drug resistance can allow prompt identification of patients at risk for drug-resistant TB.
文摘Introduction: The emergency of Mycobacterium tuberculosis resistant to the first line drug reduced access possibility to second line drugs for appropriate treatment and required for urgent action especially in le Democratic Republic of Congo (DRC), which counts among the highest tuberculosis (TB) burden countries in Africa. Objective: To present prevalence and describe multidrug-resistant tuberculosis cases in North-Kivu Province identified by using Genexpert technology. Methods: We conducted an observational prospective study on multidrug-resistant tuberculosis (MDR-TB) cases in North-Kivu Province, DRC from 2017 to 2018. All cases of MDR-TB identified by Genexpert MTB/ RIB were included in this series. Result: Of 15,544 tuberculosis cases registered during the study period, 19 cases of MDR-TB were identified. 57.9% was male, 89.5% was retreatment cases and 5.3% was coinfection HIV/TB cases. Conclusion: This new molecular technology diagnostic facilitates multidrug-resistance tuberculosis detection and improves the reporting of data lack.
基金Supported by National Natural Science Foundation of China,No.81760739 and No.31460023.
文摘The infection and drug resistance rates of Helicobacter pylori(H.pylori)are high and must be prevented and treated by better strategies.Based on recent research advances in this field as well as the results from our team and those on traditional Chinese medicine,we review the causes of drug resistance,and prevention and treatment strategies for drug-resistant H.pylori infection,with an aim to make suggestions for the development of new drugs,such as establishment of new target identification and screening systems,modification of existing drug structures,use of new technologies,application of natural products,and using a commercial compound library.This article may provide reference for eradication of drug-resistant H.pylori.
文摘BACKGROUND Pyogenic ventriculitis caused by extensively drug-resistant Acinetobacter baumannii(A.baumannii)is one of the most severe complications associated with craniotomy.However,limited therapeutic options exist for the treatment of A.baumannii ventriculitis due to the poor penetration rate of most antibiotics through the blood-brain barrier.CASE SUMMARY A 68-year-old male patient with severe traumatic brain injury developed pyogenic ventriculitis on postoperative day 24 caused by extensively drug-resistant A.baumannii susceptible to tigecycline only.Successful treatment was accomplished through multi-route administration of tigecycline,including intravenous combined with continuous ventricular irrigation plus intraventricular administration.The pus was cleared on the 3rd day post-irrigation,and cerebrospinal fluid cultures were negative after 12 d.CONCLUSION Our findings suggest that multi-route administration of tigecycline can be a therapeutic option against pyogenic ventriculitis caused by extensively drugresistant A.baumannii.
文摘BACKGROUND Bedaquiline is among the prioritized drugs recommended by the World Health Organization for the treatment of extensively drug-resistant tuberculosis(XDRTB).Many patients have not achieved better clinical improvement after bedaquiline is stopped at 24 wk.However,there is no recommendation or guideline on bedaquiline administration beyond 24 wk,which is an important consideration when balancing the benefit of prognosis for XDR-TB against the uncertain safety concerning the newer antibiotics.CASE SUMMARY This paper reported 2 patients with XDR-TB(a female of 58 years of age and a female of 18 years of age)who received bedaquiline for 36 wk,as local experience to be shared.The 2 cases had negative cultures after 24 wk of treatment,but lung imaging was still positive.After discussion among experts,the consensus was made to bedaquiline prolongation by another 12 wk.The 36-wk prolonged use of bedaquiline in both cases achieved a favorable response without increasing the risk of cardiac events or new safety signals.CONCLUSION Longer regimen,including 36-wk bedaquiline treatment,might be an option for patients with XDR-TB.More studies are needed to explore the effectiveness and safety of prolonged use of bedaquiline for 36 wk vs standard 24 wk in the treatment of multidrug-resistant/XDR-TB or to investigate further the biomarkers and criteria indicative for extension of bedaquline to facilitate clinical use of thisnovel drug.
文摘Background:Pentylenetetrazole kindling has long been used for the screening of investigational antiseizure drugs.The presence of lamotrigine,at a very low dose,does not hamper kindling in mice;rather it modifies this epileptogenesis process into drug-resistant epilepsy.The lamotrigine-pentylenetetrazole kindled mice show resistance to lamotrigine,phenytoin,and carbamazepine.It may also be possible that other licensed antiseizure drugs,like the mentioned drugs,remain ineffective in this model;therefore,this was the subject of this study.Methods:Swiss albino mice were kindled with pentylenetetrazole for 35 days in the presence of either methylcellulose vehicle or lamotrigine(subtherapeutic dose,ie,5 mg/kg).Vehicle vs lamotrigine-kindled mice were compared in terms of(a)resistance/response toward nine antiseizure drugs applied as monotherapies and two drug combinations;(b)lamotrigine bioavailability in blood and brain;(c)blood-brain barrier integrity;and(d)amino acids and monoamines in the cerebral cortex and hippocampus.Results:Lamotrigine vs vehicle-kindled mice are similar(or not significantly different P>.05 from each other)in terms of(a)response toward drug combinations;(b)lamotrigine bioavailability;and(c)blood-brain barrier integrity except for,significantly(P<.05)reduced taurine and increased glutamate in the cerebral cortex and hippocampus.Aside from these,lamotrigine-kindled mice show significant(P<.05)resistant to lamotrigine(15 mg/kg),levetiracetam(40 mg/kg);carbamazepine(40 mg/kg),zonisamide(100 mg/kg),gabapentin(224 mg/kg),pregabalin(30 mg/kg),phenytoin(35 mg/kg),and topiramate(300 mg/kg).Conclusion:Lamotrigine-pentylenetetrazole kindling takes longer to develop(~5 weeks)in comparison to lamotrigine-amygdale(~4 weeks)and lamotriginecorneal(~2 weeks)kindling models.However,drug screening through this model may yield superior drugs with novel antiseizure mechanisms.
文摘BACKGROUND Perampanel(PER),a third-generation antiepileptic drug,is a selective and noncompetitiveα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist,and has been approved for the treatment of adults and adolescents with focal epilepsy.However,there are only a few studies about the efficacy and tolerability of PER in young children with multidrug-resistant epilepsy.In this case,we aimed to share our clinical experience in this group.CASE SUMMARY A 4-year-old boy without perinatal asphyxia and familial history of epilepsy began to have ictal seizures from age 14 mo,with jerky movement of four limbs and head nodding.Abnormal multifocal discharge and background activity were recorded through electroencephalography,and no pathogenic mutation was found in the whole exome sequencing for the patient and his parents.He had received valproate,levetiracetam,topiramate,oxcarbazepine,clonazepam and lacosamide sequentially at different times,but he still had frequent seizures even after vagus nerve stimulation(VNS)implantation.He was diagnosed with idiopathic multidrug-resistant epilepsy.However,his seizure frequency was significantly reduced after PER administration in a dose-dependent manner,and better cognitive behavior was observed.In addition,the adverse reactions of anger and aggression also appeared.CONCLUSION PER is effective as add-on therapy for young children with multidrug-resistant epilepsy who have previously undergone VNS implantation.
文摘There are various bacteria living in this world. The most common one is Staphylococcus aureus. Almost everyone has heard of it. It is easy to find their habitats, such as hospitals, homes, parks, schools etc. Some of them are difficult to be eliminated because of drug-resistant mutations. Hence, lots of researchers devoted their efforts to eliminate them. This review illustrates the characteristics of the Staphylococcus aureus and the main threat of their drug-resistant strains, especially methicillin-resistant S. aureus. What’s more, the article also highlights the plight in the drug development.
文摘Objectives: Bedaquiline (BDQ) is the first new anti-tuberculosis (TB) drug introduced to the market after 45 years. Recent studies have shown the potential benefits of adding bedaquiline to regimens for drug-resistant TB (DR-TB). In search of more effective regimens for DR-TB, bedaquiline was introduced in the TB program in the Philippines under operational research to assess its effectiveness, safety, and tolerability when given with background regimens among patients with multi-or extensively DR-TB (MDR/XDR-TB). Design: A prospective cohort study of patients with MDR/XDR-TB was given with a bedaquiline-containing regimen from June 2016 to May 2017. Demographic data, presence of comorbidities, and microbiologic profile on entry were recorded. Bedaquiline was administered at the recommended dose of 400 mg once daily for 14 days, then 200 mg three times a week for 22 weeks together with World Health Organization (WHO)-compliant background regimen. The time to culture conversion, interim outcomes at the 6th month of treatment, end-of-treatment outcomes, and post-treatment follow-up outcomes after one year was determined. The frequency and severity of adverse events (SAE) were recorded as part of pharmacovigilance. Results: Seventy-five patients were given with bedaquiline-containing regimen during the study period. Forty-two (56.0%) had second-line injectable resistance, 23 (30.7%) had fluoroquinolone-resistance, 6 (8.0%) had MDR-TB, and 4 (5.3%) had XDR-TB. In the 6th month of post-enrolment, 79% were culture-negative. The treatment success rate was 65.3% (37 were cured and 12 completed treatment), 7 (9.3%) died, 17 (22.7%) lost to follow-up, and 2 (2.7%) were withdrawn from treatment. Adverse events included vomiting (80%), dizziness (69%), nausea (52%), cough (44%), and headache (36%). The post-treatment follow-up of 49 patients in the 12th month showed 92% were culture-negative while 8% of TBC were not done. Conclusion: Bedaquiline-containing regimens for patients with MDR/XDR-TB were highly effective with an acceptable safety profile and favorable treatment outcomes, but the proportion of patients who lost to follow-up remains substantial.
文摘Drug resistance is one of the major challenges facing the success of chemotherapy against human hepatocarcinoma (HCC) as well as other types of cancer. Studies with cell lines can serve as initial screening for agents that could modulate drug resistance. Development of a good experimental model of drug-resistant cells is a prerequisite for the success of such cellular studies;but could be laborious and generally time-consuming. Additionally, the high mortality rate associated with advanced HCC calls for a probe into the mechanism of resistance by developing experimental model that mimics clinical method of its treatment. Consequently, we have reported a simplified method of selection of drug-resistant hepatocarcinoma cells from human hepatocellular carcinoma (HEPG2) cell line using pharmacologic agents, cisplatin (CDDP) and 5-fluorouracil (5-FU). HEPG2 cell line was incubated for 24 hours with different concentrations of CDDP (0 - 20 μM) or 5-FU (0 - 100 μM). Cell viability was assayed by CCK-8 (Cell Counting Kit) analysis, and the inhibitory concentrations (IC50) for CDDP and 5-FU were established by dose-dependent cytotoxicity curves. The IC50(s) were confirmed by flow cytometric analysis of cell death due to CDDP or 5-FU. Clinical method of treatment was imitated by treating the parental HEPG2 cell line in pulse, at the optimal concentration of either CDDP or 5-FU for 4 to 6 hours. Induction was repeated 6 times, whilst allowing the cells to attain at least 70% confluence between intervals of induction. The resultant drug-resistant sublines, (HEPG2CR) and (HEPG2FR) were found to be stable after over 3 months of drug withdrawal and maintenance in drug-free medium. This was done with the views of establishing a simple, efficient and direct protocol for the development of good cellular models for the study of drug resistance in liver cancer, with possible application in other cancer types.
文摘Background: Photodynamic therapy (PDT) is a less invasive cancer treatment using photochemical reactions induced by light irradiation to a photosensitizer (PS). Highly selective PDT with fast accumulation of the PS in target site might be a promising treatment option for drug-resistant prostate cancer facing high incidence rate of elderly men who have no effective treatment options and require a minimally invasive treatment. Hemagglutinating virus of Japan envelope (HVJ-E) allows selective and fast drug delivery to the drug-resistant prostate cancer cells via rapid cell membrane fusion. PS named porphyrus envelope (PE) has been developed by insertion of lipidated protoporphyrin IX (PpIX lipid) into HVJ-E. In this study, we investigated the optimal conditions for PE preparation and laser irradiation for highly selective PDT using PE with a short drug-light interval. Materials and Methods: Human hormon refractory prostate cancer cell line PC-3 and human normal prostate epithelial cell line PNT2 were cultured. PpIX lipid uptake and cytotoxicity of PDT in the cells incubated with PE for 10 min were evaluated by measuring fluorescence intensity and by using a cell counting reagent 24 h after PDT, respectively. Results: PpIX lipid uptake and cytotoxicity of PDT were increased with PpIX lipid concentration. Cytotoxicity of PDT using PE was more than 9 times as strong as that with PpIX lipid and PpIX induced by 5-aminolevulinic acid. Much stronger cytotoxicity was induced in PC-3 cells than PNT2 cells with the ratio of cell death rate for cancer to normal cells up to 4.64 ± 0.09. Conclusions: Fast PS delivery with HVJ-E allows highly selective PDT with a short drug-light interval. Therefore, PDT using PE has a potential to shorten treatment period and reduce side effects of PDT.
