Reverse effect of curcumin on CDDP-induced drug-resistance via Keap1/p62-Nrf2 signaling in A549/CDDP cell

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.

Molecular Characterization and Drug-resistance of Mycobacterium tuberculosis Strains in Xuzhou, China

To understand the genetic diversity and drug resistance status of Mycobocterium tuberculosis （M. tuberculosis） circulating in Xuzhou of China, the spacer-oligonucleotide typing （Spoligotyping） and multi-loci VNTRs （variable number tandem repeats） analysis （MLVA） were utilized for the genotyping of the isolates. Drug susceptibility test （DST） was performed by the proportion method on the Lowenstein-Jensen （L-J） medium using isoniazid, rifampicin, ethambutol, and streptomycin. By Spoligotyping, 287 M. tuberculosis isolates were differentiated into 14 clusters. Then with 15-1oci MLVA, these strains could be divided into 32 clusters, 228 genotypes. Of 15 VNTRs, 6 loci had the highly discriminatory powers, 6 loci presented moderate discrimination and 3 loci demonstrated less polymorphism. The DST results showed that 46 strains were resistant to at least one first-line anti-tuberculosis agent. There was a difference in the isoniazid resistance between Beijing and non-Beijing genotype strains. We concluded that the combination of Spoligotyping and 15 VNTR loci as the genotyping in our study was applicable for this region, the drug resistant isolates were identified, and the Beijing family was the most prevalent genotype in the rural counties of Xuzhou.

Three-dimensional collagen-based scaffold model to study the microenvironment and drug-resistance mechanisms of oropharyngeal squamous cell carcinomas

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.

Investigation of immune escape-associated mutations of hepatitis B virus in patients harboring hepatitis B virus drug-resistance mutations

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.

A STUDY OF DECREASING DRUG-RESISTANCE OF HUMAN OVARIAN CANCER CELLS IN VITRO

A chemosensitivity test for ovarian cancer using tritiated thymidine incorporation assay was carried out. A dose-response relationship for cisplatin and potentiation of verapamil in increasing vincristine inhibition to ovarian cancer were investigated. A 5- fold increase of cisplatin density converted the tumors which were initially resistance to standard-dose cisplatin Into drug-sensitive ones. Vera-pamil was found to be able to overcome vincristine-resistance of some tumors in vitro. These results suggest that using high dose cisplatin therapy or increasing local drug concentration by using other administration way, we could expect some ovarian cancers that had failed to standard dose cisplatin therapy to be effective. Combination of vincristine with verapamll may be helpful in treating some vincristineresistant cases.

Comparison of extended spectrum β-lactamasesproducing Escherichia coli with non-ESBLsproducing E.coli:drug-resistance and virulence

The virulent factors of Escherichia coil （E.cofi） play an important role in the process of pathopoiesis. The study aimed to compare drug-resistant genes and virulence genes between extended spectrum β-1actamases （ESBLs）-producing E.coli and non-ESBLs-producing E.cofi to provide a reference for physicians in management of hospital infection. 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, qacEAl-sull and 8 virulence genes （CNF2, hlyA, eaeA, VT1, est, bfpA, elt, and CNF1） were tested by polymerase chain reaction （PCR）. Among the 96 E.coli isolates, the ESBLs-producing E.coli comprised 46 （47.9%） strains and the non-ESBLs-producing E.cofi consisted of 50 （52.1%） strains. The detection rates of multiple drug-resistant strain, qacEAl-sull, CNF2, hlyA, eaeA,VT1, est, bfpA, elt, and CNF1 in 46 ESBLs-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.cofi strains, the positive rates of multiple drug-resistant strain, qacEAl-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.cofi strains and the non-ESBLs-producing E.cofi strains was statistically significant （P〈0.05）. The positive rate of multiple drug-resistant strains is higher in the ESBLs-producing 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.

Pharmacological Effects of Serum Containing Chinese Medicine Bushen Huayu Jiedu Compound Recipe (补肾化瘀解毒复方) in Lung Cancer Drug-resistance Cells

Objective： To explore the pharmacologic effects of Chinese medicine Bushen Huayu Jiedu Compound Recipe （补肾化瘀解毒复方,BSHYJDR） in drug-resistance cells of lung cancer. Methods： Human lung adenocarcinoma A549/DDP cell strain was selected, serum pharmacology and flow cytometer （FCM） method were adopted, $180 tumor-bearing mice and normal mice were given, through gastrogavage, different doses of a decocted concentration of BSHYJDR. Serum from the abdominal aorta was taken to observe the effect of drug-serum on cisplatin （DDP） concentration, free Ca^2＋ concentration and the expression of lung drug-resistance protein LRP-56 in A549/DDP cells. Results： Compared with the drug-resistance group, the intracellular DDP concentration in the group taking a high dose and the normal group of Chinese medicine showed significant difference （P〈0.05）, while no significant difference was found in the low-dose group （P〉0.05）. Compared with the drug-resistance group, the Ca^2＋ concentration in cells and the expression of LRP in lung cancer drug-resistance cells A549/DDP of the high-dose group, the low-dose group and the normal group of Chinese medicine were significantly different （all P〈0.01）, the LRP expression of the normal group was obviously higher than that of the drug-resistance group （P〈0.05）. Cenclusien： It was indicated that serum containing Chinese medicine BSHYJDR in the tumor-bearing mice and the normal mice had certainly different, tumor-bearing mice serum containing could improve drug concentration in lung cancer drug-resistance cells, prevent the inflow and release of Ca^2＋, and inhibit the expression of the drug-resistance gene in the lung cancer drug-resistance cells, which might be the mechanism of BSHYJDR in enhancing the efficacy in reversing and inhibiting tumor.

Establishment and evaluation of an overlap extension polymerase chain reaction technique for rapid and efficient detection of drug-resistance in Mycobacterium tuberculosis

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.

Establishment of extensively drug-resistant Pseudomonas aeruginosa pneumonia model in rat

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.

A Review of the Surgical Procedures for the Treatment of Drug-Resistant Epilepsy and Their Seizure Control Outcomes

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.

Aldo-keto reductases:Role in cancer development and theranostics

Aldo-keto reductases(AKRs)are a superfamily of enzymes that play crucial roles in various cellular processes,including the metabolism of xenobiotics,steroids,and carbohydrates.A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers.AKRs are aberrantly expressed in a wide range of malignant tumors.Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance.AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression.Inhibition of aldose reductase(AR),either alone or in combination with chemotherapeutic drugs,has evolved as a pragmatic therapeutic option for cancer.Several classes of synthetic aldo-keto reductase(AKR)inhibitors have been developed as potential anticancer agents,some of which have shown promise in clinical trials.Many AKR inhibitors from natural sources also exhibit anticancer effects.Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies.These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy.In this review,we discuss the physiological functions of human AKRs,the aberrant expression of AKRs in malignancies,the involvement of AKRs in the acquisition of cancer hallmarks,and the role of AKRs in oncogenic signaling,and drug resistance.Finally,the potential of aldose reductase inhibitors(ARIs)as anticancer drugs is summarized.

Excipient effect on antimicrobial activity of Cinnamon (Cinnamomum zelylanicum album) oil, Thyme (Thymus vulgaris) oil and Ajowan (Trachyspermum ammi) oil

Background:Many herbal essential oils are potential antimicrobials but their pharmaceutical utility is restricted due to a lack of suitable excipients to mollify their dermatotoxicity and irritant property,and outcome of their therapeutic use may vary with different diluents used.Methods:Effect of 16 diluents(dimethyl sulfoxide,liquid paraffin,glycerine,oils of mustard,sunflower,rice bran,palm,groundnut,olive,coconut,sesame,avocado,jojoba,castor,linseed and soybean)was assessed on antimicrobial activity of 2%cinnamon(Cinnamomum zelylanicum album),thyme(Thymus vulgaris)and ajowan(Trachyspermum ammi)oils using agar well diffusion assay.The effect of excipients was evaluated on six Candida albicans,five Escherichia coli,four Acinetobacter lwoffii,two strains each of Staphylococcus aureus,Enterobacter agglomerans,and Enterococcus faecium and one strain each of Acinetobacter calcoaceticus,Escherichia fergusonii,Klebsiella oxytoca,K.pneumoniae ssp.pneumoniae,Leclercia adecarboxylata,Paenibacillus amylolyticus,Proteus mirabilis,P.vulgaris,Pseudomonas aeruginosa,Raoultella terrigena,Staphylococcus capitis ssp.capitis,S.chromogenes,S.epidermidis,S.warneri and Streptococcus pyogenes.Results:Thyme oil(2%)maintained it antimicrobial activity on dilution in dimethyl sulfoxide and glycerine,and ajowan oil(2%)completely lost its antibacterial activity in all diluents except dimethyl sulfoxide.However,cinnamon oil partially lost its antimicrobial activity upon dilution in glycerine,vegetable,and mineral oils in comparison to dimethyl sulfoxide.Olive oil was the best vegetable oil,almost comparable to dimethyl sulfoxide and castor oil was the worst diluent for maintaining antimicrobial activity of cinnamon oil.Conclusion:The study indicated the non-suitability of vegetable oils for pharmaceutical formulations of essential oils except olive oil for dilution of cinnamon oil and glycerol for thyme oil to replace dimethyl sulfoxide as diluent.

“东方巴斯德”——汤飞凡

汤飞凡是我国著名的微生物学家、病毒学家,是名副其实的“中国疫苗之父”,也是世界公认的“衣原体之父”。本文主要从求学工作经历、疫苗等生物制品研究及衣原体研究三个方面介绍汤飞凡的生平事迹和代表性成就,并分析了将科学家汤飞凡的故事融入中学生物学教学的重要价值。

Molecular Characterization of Drug-Resistant Beijing Family Isolates of Mycobacterium Tuberculosis from Tianjin,China

Objective Tuberculosis remains a severe public health issue, and the Beijing family of mycobacterium tuberculosis （M. tuberculosis） is widespread in East Asia, especially in some areas in China, like Beijing and Tianjin. This study aimed at determining the mutation patterns of drug-resistant Beijing strains of M. tuberculosis isolated from Tianjin, China. Methods A total of 822 M. tuberculosis isolates were screened for drug resistance by an absolute concentration method and the genotype was identified by PCR. 169 drug-resistant isolates of the Beijing family were analyzed for the potential mutations in the rpoB, katG, inhA promoter region and in rpsL, rrs and embB genes, which are associated with resistance to rifampin （RFP）, isoniazid （INH）, streptomycin （SM） and ethambutol （EMB） respectively by PCR and DNA sequencing. Results Fifty-eight out of 63 RFP-resistant isolates were found to carry the mutations within the 81-bp RFP resistance determining region （RRDR） of the rpoB gene and the most frequent mutations occurred at codon 531 （44.4%）, 526 （28.6%）, and 516 （7.9%） respectively. 16 mutation pattems affecting 12 different codons around the RRDR of rpoB were found. Of 116 INH-resistant isolates, 56 （48.3%） had the mutation of katG 315 （AGC→ACC） （Ser→Thr）, 3 （2.6%） carried S315N （AGC→AAC） and 27 （16.0%） had the mutation of inhA-15A→T. 84 out of 122 SM-resistant isolates （68.9%） displayed mutations at the codons 43 or 88 with AAG→AGG （Lys→Arg） of the rpsL gene and 22 （18.0%） with the mutations at positions 513A→C, 516C→T or 905 A→G in the rrs gene. Of 34 EMB-resistant isolates, 6 had mutation with M306V （ATG→GTG）, 3 with M306I （ATG→ATT）, 1 with M306I （ATG→ATA）, 1 with D328Y （GAT→TAT）, 1 with V348L （GTC→CTC）, and 1 with G406S （GGC→AGC） in the embB gene. Conelusion These novel findings extended our understanding of resistance-related mutations in the Beijing strains of M. tuberculosis and may provide a scientific basis for development of new strategies for diagnosis and control of tuberculosis in China and other countries where Beijing strains are prevalent.

Clinical analysis of colistin sulfate in the treatment of pneumonia caused by carbapenem-resistant Gram-negative bacteria

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.

Molecular diagnosis and treatment of drug-resistant hepatitis B virus

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.

Distinctive Drug-resistant Mutation Profiles and Interpretations of HIV-1 Proviral DNA Revealed by Deep Sequencing in Reverse Transcriptase

Objective To investigate distinctive features in drug-resistant mutations （DRMs） and interpretations for reverse transcriptase inhibitors （RTIs） between proviral DNA and paired viral RNA in HIV-l-infected patients. Methods Forty-three HIV-l-infected individuals receiving first-line antiretroviral therapy were recruited to participate in a multicenter AIDS Cohort Study in Anhui and Henan Provinces in China in 2004. Drug resistance genotyping was performed by bulk sequencing and deep sequencing on the plasma and whole blood of 77 samples, respectively. Drug-resistance interpretation was compared between viral RNA and paired proviral DNA. Results Compared with bulk sequencing, deep sequencing could detect more DRMs and samples with DRMs in both viral RNA and proviral DNA. The mutations M1841 and M2301 were more prevalent in proviral DNA than in viral RNA （Fisher＇s exact test, P〈0.05）. Considering ＇majority resistant variants＇, 15 samples （19.48%） showed differences in drug resistance interpretation between viral RNA and proviral DNA, and 5 of these samples with different DRMs between proviral DNA and paired viral RNA showed a higher level of drug resistance to the first-line drugs. Considering ＇minority resistant variants＇, 22 samples （28.57%） were associated with a higher level of drug resistance to the tested RTIs for proviral DNA when compared with paired viral RNA. Conclusion Compared with viral RNA, the distinctive information of DRMs and drug resistance interpretations for proviral DNA could be obtained by deep sequencing, which could provide more detailed and precise information for drug resistance monitoring and the rational design of optimal antiretroviral therapy regimens.

Risk Factors for Drug-Resistant Tuberculosis

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.

Clinical effects of detailed nursing management interventions on medication adherence and disease perception in patients with drugresistant tuberculosis

BACKGROUND Tuberculosis(TB)is a chronic respiratory infectious disease that considerably jeopardizes human health,and there is no effective vaccine suitable for its prevention in the entire population.AIM To investigate the promotion of medication adherence and disease cognition in patients with drug-resistant(DR-)TB using detailed nursing management.METHODS In total,114 patients with DR-TB who were diagnosed and treated at our hospital between January 2019 and January 2023 were included in this study.Patients in the control group(n=57)were managed with conventional nursing care,while those in the observation group(n=57)were managed with detailed nursing care.Medication adherence,disease awareness scores,medication safety,and nursing satisfaction were compared between the two groups after the intervention.RESULTS The post-intervention medication compliance rate was 91.23%in the observation group and 75.44%in the control group,with the former being 15.79%higher than the latter(P<0.05).There was no statistically significant difference in the disease awareness scores between the two groups before the intervention;the disease awareness scores of the observation group were significantly higher than those of the control group after the intervention(P<0.05).The incidence of gastrointestinal reactions,joint swelling and pain,hearing loss,electrolyte disorders,and liver and kidney function abnormalities were lower in the observation group than those in the control group.The total nursing satisfaction of the observation group was higher than that of the control group(P<0.05).CONCLUSION Implementation of detailed nursing management for patients with DR-TB can effectively improve medication adherence,enhance awareness of the disease,ensure safety of medication,and improve satisfaction with nursing care.

The role of axon guidance molecules in the pathogenesis of epilepsy

Current treatments for epilepsy can only manage the symptoms of the condition but cannot alter the initial onset or halt the progression of the disease. Consequently, it is crucial to identify drugs that can target novel cellular and molecular mechanisms and mechanisms of action. Increasing evidence suggests that axon guidance molecules play a role in the structural and functional modifications of neural networks and that the dysregulation of these molecules is associated with epilepsy susceptibility. In this review, we discuss the essential role of axon guidance molecules in neuronal activity in patients with epilepsy as well as the impact of these molecules on synaptic plasticity and brain tissue remodeling. Furthermore, we examine the relationship between axon guidance molecules and neuroinflammation, as well as the structural changes in specific brain regions that contribute to the development of epilepsy. Ample evidence indicates that axon guidance molecules, including semaphorins and ephrins, play a fundamental role in guiding axon growth and the establishment of synaptic connections. Deviations in their expression or function can disrupt neuronal connections, ultimately leading to epileptic seizures. The remodeling of neural networks is a significant characteristic of epilepsy, with axon guidance molecules playing a role in the dynamic reorganization of neural circuits. This, in turn, affects synapse formation and elimination. Dysregulation of these molecules can upset the delicate balance between excitation and inhibition within a neural network, thereby increasing the risk of overexcitation and the development of epilepsy. Inflammatory signals can regulate the expression and function of axon guidance molecules, thus influencing axonal growth, axon orientation, and synaptic plasticity. The dysregulation of neuroinflammation can intensify neuronal dysfunction and contribute to the occurrence of epilepsy. This review delves into the mechanisms associated with the pathogenicity of axon guidance molecules in epilepsy, offering a valuable reference for the exploration of therapeutic targets and presenting a fresh perspective on treatment strategies for this condition.