Molecular epidemiology and mechanisms of tigecycline resistance in carbapenem-resistant Klebsiella pneumoniae isolates

BackgroundThe emergence and transmission of tigecycline‐ and carbapenem‐resistant Klebsiella pneumoniae (TCRKP) have become a major concern to public health globally. Here, we investigated the molecular epidemiology and mechanisms of tigecycline resistance in carbapenem‐resistant K pneumoniae (CRKP) isolates.MethodsForty‐five non‐duplicate CRKP isolates were collected from January 2017 to June 2019. We performed antimicrobial susceptibility tests, multilocus sequence typing (MLST), and pulsed‐field gel electrophoresis (PFGE). PCR and DNA sequencing were performed for the detection and mutation analysis of acrR, oqxR, ramR, rpsJ, tet(A), and tet(X) genes, which are related to tigecycline resistance. The expression levels of efflux pump genes acrB and oqxB and their regulator genes rarA, ramA, soxS, and marA were assessed by quantitative real‐time PCR.ResultsThe resistance rate to tigecycline in CRKP isolates was 37.8% (17/45). K pneumoniae ST307 was a predominant clone type (70.6%, 12/17) among the TCRKP isolates. The expression levels of acrB (P < .001) and marA (P = .009) were significantly higher in the tigecycline‐resistant group than in the tigecycline‐intermediate and tigecycline‐susceptible groups. Increased expression of acrB was associated with marA expression (r = 0.59, P = .013).ConclusionsWe found that the activated MarA‐induced overexpression of AcrAB efflux pump plays an important role in the emergence of tigecycline resistance in CRKP isolates.     

Review of Inhalation Health Risks Involving Chloromethylisothiazolinone (CMIT) and Methylisothiazolinone (MIT) Used as Disinfectants in Household Humidifiers

The association between lung injury and exposure to humidifier disinfectant (HD) containing a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) has been controversial in South Korea. This study conducts a literature review in order to evaluate the likelihood of CMIT/MIT reaching the lower part of the respiratory tract and causing lung injury. A literature review focused on the inhalation risk of HD containing a mixture of CMIT and MIT. The major contents included the physicochemical properties of CMIT and MIT contained in HDs and methodological reviews on substance analysis, toxicity tests and clinical cases. HD products marketed in South Korea have been reported to contain approximately 1–2% CMIT and 0.2–0.6% MIT along with magnesium nitrate (20–25%), magnesium chloride (0.2–1.0%), and water (70–75%). The types of CMIT and MIT dispersed into the air and deposited in the respiratory tract are assumed to be either gaseous substances or nanoparticles mixed with magnesium salts. The result of the literature review including clinical cases of lung injury among CMIT/MIT HD product users, demonstrated that these chemicals likely reach the lower respiratory tract and accordingly cause lung injury. A number of humidifier disinfectant-associated lung injury cases with clinical evidence should be prioritized in risk assessment of HD containing CMIT and MIT, even though there might be insufficient evidence in all related areas, including inhalation exposure assessment studies, animal testing, and epidemiological studies.     

Optimal duration of antiviral treatment in patients with gastrointestinal cytomegalovirus disease at a low and high risk of relapse

We evaluated the association between antiviral treatment duration and relapse of gastrointestinal (GI) cytomegalovirus (CMV) disease by analyzing the risk factors for relapse.Patients who were diagnosed with GI CMV disease at a tertiary hospital from January 2008 to April 2019 were retrospectively enrolled. Patients with relapsed disease were those with a recurrence of GI CMV disease at least 4 weeks after the initial antiviral treatment.Of 238 participants, including 145 (51.9%) with upper and 93 (48.1%) with lower GI CMV diseases, 27 (11.3%) had experienced relapses. The difference in antiviral treatment duration between the relapsed and nonrelapsed GI CMV groups was not significant (median days, 21.0 vs 17.0, P = .13). Multivariate analysis revealed that hematologic malignancy (odds ratio, 3.73; P = .026) and ulcerative colitis (odds ratio, 4.61; P = .003) were independent risk factors for relapse. Participants with at least one of these risk factors and those with no independent risk factors were classified under the high- (relapse rate, 25.9%) and low-risk of relapse groups (relapse rate, 6.7%), respectively. Accordingly, we further stratified 180 (75.6%) and 58 (24.4%) participants under the low- and high-risk of relapse groups, respectively. There was no significant difference in relapse rates between the high- and low-risk groups according to antiviral treatment duration.Approximately 10% of the participants experienced relapses after antiviral treatment, with hematologic malignancy and ulcerative colitis featuring as risk factors. Therefore, prolonged antiviral treatment might not be helpful in preventing GI CMV disease relapse.     

Sodium-Glucose Cotransporter-2 Inhibitor-Related Diabetic Ketoacidosis: Accuracy Verification of Operational Definition

BackgroundThe most important aspect of a retrospective cohort study is the operational definition (OP) of the disease. We developed a detailed OP for the detection of sodium-glucose cotransporter-2 inhibitors (SGLT2i) related to diabetic ketoacidosis (DKA). The OP was systemically verified and analyzed.MethodsAll patients prescribed SGLT2i at four university hospitals were enrolled in this experiment. A DKA diagnostic algorithm was created and distributed to each hospital; subsequently, the number of SGLT2i-related DKAs was confirmed. Then, the algorithm functionality was verified through manual chart reviews by an endocrinologist using the same OP.ResultsA total of 8,958 patients were initially prescribed SGLT2i. According to the algorithm, 0.18% (16/8,958) were confirmed to have SGLT2i-related DKA. However, based on manual chart reviews of these 16 cases, there was only one case of SGLT2i-related DKA (positive predictive value = 6.3%). Even after repeatedly narrowing the diagnosis range of the algorithm, the effect of a positive predictive value was insignificant (6.3–10.0%, P > 0.999).ConclusionOwing to the nature of electronic medical record data, we could not create an algorithm that clearly differentiates SGLT2i-related DKA despite repeated attempts. In all retrospective studies, a portion of the samples should be randomly selected to confirm the accuracy of the OP through chart review. In retrospective cohort studies in which chart review is not possible, it will be difficult to guarantee the reliability of the results.     

Tryptophanyl-tRNA Synthetase Sensitizes Hormone Receptor-Positive Breast Cancer to Docetaxel-Based Chemotherapy

PurposeA relatively low response to chemotherapy has been reported for hormone receptor (HR)-positive breast cancer. In this study, we investigated the role of tryptophanyl-transfer RNA synthetase (WARS) in the chemotherapeutic response of HR-positive breast cancer.MethodsPre-chemotherapeutic needle biopsy samples of 45 HR-positive breast cancer patients undergoing the same chemotherapeutic regimen were subjected to immunohistochemistry. To investigate the biological functions of WARS in HR-positive breast cancer, we conducted cell viability assay, flow cytometry analysis, caspase activity assay, Quantitative real-time polymerase chain reaction, and western blotting using WARS gene-modulated HR-positive breast cancer cells (T47D, ZR-75-1, and MCF7).ResultsWARS overexpression in HR-positive breast cancer patients showed a significant correlation with favorable chemotherapy response. Downregulation of WARS increased cell viability following docetaxel treatment in tumor cell lines. On the other hand, WARS overexpression sensitized the therapeutic response to docetaxel. Additionally, downregulation of WARS caused a decrease in the number of apoptotic cell populations by docetaxel. Poly (ADP-ribose) polymerase cleavage and caspase 3/7 activity were increased in docetaxel-treated tumor cells with WARS overexpression.ConclusionOur results suggest that WARS might be a potential predictor for chemotherapy response in patients with HR-positive breast cancer as well as a novel molecular target to improve chemosensitivity.     

The Role of Adiponectin in the Skin

Adiponectin (Ad), a 30 kDa molecule, is an anti-diabetic adipokine; although derived from adipose tissue, it performs numerous activities in various other tissues. It binds to its own receptors, namely adiponectin receptor 1(AdipoR1), adiponectin receptor 2 (AdipoR2), and T-cadherin (CDH13). Ad plays several roles, especially as a regulator. It modulates lipid and glucose metabolism and promotes insulin sensitivity. This demonstrates that Ad has a robust correlation with fat metabolism. Furthermore, although Ad is not in direct contact with other tissues, including the skin, it can be delivered to them by diffusion or secretion via the endocrine system. Recently it has been reported that Ad can impact skin cell biology, underscoring its potential as a therapeutic biomarker of skin diseases. In the present review, we have discussed the association between skin cell biology and Ad. To elaborate further, we described the involvement of Ad in the biology of various types of cells in the skin, such as keratinocytes, fibroblasts, melanocytes, and immune cells. Additionally, we postulated that Ad could be employed as a therapeutic target to maintain skin homeostasis.     

Crystal structure of an RNA.DNA hybrid reveals intermolecular intercalation: dimer formation by base-pair swapping

An intermolecular intercalation of base pairs was found at the CA step in the I222 crystal structure of the RNA.DNA hybrid, r(CAAAGAAAAG).d(CTTTTCTTTG), which contains two-thirds of the polypurine tract sequence of HIV-1 with a substitution of cytosine for the initial adenine. This sequence crystallized in both P212121 and I222 space groups, with an rms difference of only 0.63 A between residues 3 to 18 of the two forms. P212121 and I222 helices are both A-like, but intercalation occurs only in the I222 crystal form. The present structure shows bases stacked in parallel rather than perpendicular as in intercalated DNA (I-DNA). The base intercalation is also different from zipper-like meshing of bases seen in the center of the crystal structure of d(GCGAAAGCT), which does not have Watson-Crick base pairing. The base-step intercalation seen here is reminiscent of domain swapping in proteins; therefore, we call this phenomenon "base-pair swapping." It involves a highly mobile CA step and seems to be sequence-specific and electrostatically stable without disrupting Watson-Crick interactions. It also exhibits a large rise concurrent with unwinding of the helix (low twist). We present a base-pair swapping dimer in nucleic acids.