Phlebitis in Takayasu arteritis: A case-based literature review.

Takayasu arteritis (TAK) is the main type of large vessel arteritis in young adults, which mainly affects the aorta and its main branches, leading to clinical manifestations such as syncope, intermittent limb claudication, hypertension, and abdominal pain. Among them, venous involvement is rarely reported. Here we show a case of TAK presenting as phlebitis. This was a 27-year-old woman, who initially admitted to our hospital with myalgia of the upper and lower extremities and night sweats. She was diagnosed as TAK according to the 1990 American College of Rheumatology TAK criteria. Surprisingly, vascular ultrasonography revealed wall thickening as indicated by macaroni sign of the multiple veins. TAK phlebitis appeared at the active phase, while disappearing rapidly at remission. Phlebitis might have a close relationship with disease activity. By retrospective study in our department, the estimated incidence rate of phlebitis might be 9.1% in TAK. With the literature review, it revealed that phlebitis might be an ignored manifestation in active TAK. However, due to the smaller sample size, it should be noted that a direct cause-effect relationship cannot be established.

Zinc Chelator N,N,N',N'-Tetrakis(2-Pyridylmethyl)Ethylenediamine Reduces the Resistance of Mycobacterium abscessus to Imipenem.

PURPOSE: Imipenem is one of the very few effective options for treating Mycobacterium abscessus (M. abscessus) infections; the development of imipenem resistance is a major health concern. MATERIALS AND METHODS: The susceptibility of 194 clinical M. abscessus isolates to imipenem was determined. The ability of imipenem to synergize with N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a zinc chelator and a metallo-ß-lactamases (MBLs) inhibitor, to inhibit M. abscessus growth was also assessed. RESULTS: M. abscessus exhibited an elevated resistance to imipenem (MIC50 = 16 mg/L, MIC90 = 64 mg/L). A combination of TPEN and imipenem synergized to inhibit the growth of 100% of imipenem-resistant and 79.2% of imipenem-resistance intermediate isolates; no synergy was observed treating imipenem-sensitive isolates. A remarkable decrease in the MIC50 (from 16 to 4 mg/L) and MIC90 (from 64 to 8 mg/L) of imipenem was observed when it was combined with TPEN; the portion of imipenem-resistant isolates also decreased (from 48.4% to 0%). Consistent with these results demonstrating synergy, a time-kill assay showed the addition of TPEN significantly improved the bactericidal activity of imipenem toward M. abscessus. Similarly, EDTA (a potent MBLs inhibitor) promoted the anti-M. abscessus activity of imipenem in a disk assay, corroborating the effect of TPEN and supporting the role of MBLs in imipenem resistance exhibited by some isolates. CONCLUSION: These findings demonstrate that TPEN can reduce the resistance of M. abscessus to imipenem and suggest that the inhibition of MBLs activity is the underlying mechanism.

AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus.

Therapeutic options for Mycobacterium abscessus infections are extremely limited. New or repurposed drugs are needed. The anti-M. abscessus activity of AR-12 (OSU-03012), reported to express broad-spectrum antimicrobial effects, was investigated in vitro and in vivo Antimicrobial susceptibility testing was performed on 194 clinical isolates. Minimum bactericidal concentration and time-kill kinetics assays were conducted to distinguish the bactericidal versus bacteriostatic activity of AR-12. Synergy between AR-12 and five clinically important antibiotics was determined using a checkerboard synergy assay. The activity of AR-12 against intracellular M. abscessus residing within macrophage was also evaluated. Finally, the potency of AR-12 in vivo was determined in a neutropenic mouse model that mimics pulmonary M. abscessus infection. AR-12 exhibited high anti-M. abscessus activity in vitro, with an MIC50 of 4 mg/liter (8.7 µM) and an MIC90 of 8 mg/liter (17.4 µM) for both subsp. abscessus and subsp. massiliense AR-12 and amikacin exhibited comparable bactericidal activity against extracellular M. abscessus in culture. AR-12, however, exhibited significantly greater intracellular antibacterial activity than amikacin and caused a significant reduction in the bacterial load in the lungs of neutropenic mice infected with M. abscessus No antagonism between AR-12 and clarithromycin, amikacin, imipenem, cefoxitin, or tigecycline was evident. In conclusion, AR-12 is active against M. abscessusin vitro and in vivo and does not antagonize the most frequently used anti-M. abscessus drugs. As such, AR-12 is a potential candidate to include in novel strategies to treat M. abscessus infections.

Genetic Evolution of Mycobacterium abscessus Conferring Clarithromycin Resistance during Long-Term Antibiotic Therapy.

Objectives: Clarithromycin is recommended as the core agent for treating M. abscessus infections, which usually calls for at least one year of treatment course, facilitating the development of resistance. This study aimed to identify the underlying mechanism of in vivo development of clarithromycin resistance in M. abscessus clinical isolates. Methods: M. abscessus isolates from patients with lung infections during long-term antibiotic therapy were longitudinally collected and sequenced. PFGE DNA fingerprinting was used to confirm the genetic relationships of the isolates. Whole genome comparative analysis was performed to identify the genetic determinants that confer the clarithromycin resistance. Results: Three pairs of initially clarithromycin-susceptible and subsequently clarithromycin-resistant M. abscessus isolates were obtained. We found that the clarithromycin-resistant isolates emerged relatively rapidly, after 4-16 months of antibiotic therapy. PFGE DNA fingerprinting showed that the clarithromycin-resistant isolates were identical to the initial clarithromycin-susceptible ones. Whole genome sequencing and bioinformatics analysis identified several genetic alternations in clarithromycin-resistant isolates, including genes encoding efflux pump/transporter, integral component of membrane, and the tetR and lysR family transcriptional regulators. Conclusion: We identified genes likely encoding new factors contributing to clarithromycin-resistance phenotype of M. abscessus, which can be useful in prediction of clarithromycin resistance in M. abscessus.

Efflux Pumps Contribute to Intrinsic Clarithromycin Resistance in Clinical, Mycobacterium abscessus Isolates.

PURPOSE: The emergence of clarithromycin resistance is a challenge in treating Mycobacterium abscessus infections. Known mechanisms that contribute to intrinsic clarithromycin resistance focus on rrl gene-related mutations, but resistant clinical isolates often exhibit an inconsistent rrl genotype. PATIENTS AND METHODS: In this study, 194 clinical Mycobacterium abscessus isolates were collected from patients with lung infections and the whole genome of each isolate was sequenced. A comprehensive examination of the molecular mechanisms underlying intrinsic clarithromycin resistance was performed, combining MIC determination, comparative genome sequence analysis and qRT-PCR. RESULTS: Of the 194 isolates, 13 (6.7%) were clarithromycin resistant; only seven of these harbored a rrl 2270/2271 mutation. The remaining six resistant isolates did not exhibit a specific resistance-associated mutation in the clarithromycin target-site genes, rrl, rplC, rplD and rplV, or in the rrl modification gene erm(41). qRT-PCR analysis showed that the increased expression of the efflux pump genes, MAB_2355c, MAB_1409c and MAB_1846, as well as their positive regulatory gene whiB7, consistently correlated with increased clarithromycin resistance. The presence of efflux pump inhibitors significantly decreased the MIC of clarithromycin for nonsusceptible isolates, especially the intrinsic resistant isolates that exhibited no rrl 2270/2271 mutation. CONCLUSION: These findings indicate that efflux pumps play a prominent role in the intrinsic resistance of M. abscessus to clarithromycin, complementing other known resistance mechanisms.

Detection and molecular characterisation of amikacin-resistant Mycobacterium abscessus isolated from patients with pulmonary disease.

OBJECTIVES: The aim of this study was to investigate the molecular mechanisms conferring amikacin (AMK) resistance in Mycobacterium abscessus clinical isolates. METHODS: A total of 194M. abscessus clinical isolates were collected from patients with pulmonary disease during the period 2012-2017. AMK susceptibility was determined by the broth microdilution method. Whole-genome data were used for identification of mutations in resistance-associated genes. Quantitative reverse transcription PCR (qRT-PCR) was performed to measure the gene transcriptional level. RESULTS: AMK showed high in vitro killing activity against M. abscessus, with an MIC50 of 8mg/L and an MIC90 of 16mg/L. Five isolates (2.6%) were resistant to AMK (MIC>1024mg/L), of which four (80.0%) harboured a resistance-associated rrs mutation A1408G. qRT-PCR analysis showed that most of the AMK-resistant isolates (4/5; 80.0%) overexpressed the transcriptional regulator gene whiB7 and the multidrug-efflux transporter gene tap. However, overexpression of the aminoglycoside-modifying enzyme gene eis2 was only observed in one (20.0%) AMK-resistant isolate. CONCLUSION: The AMK resistance rate in M. abscessus clinical isolates in this study was low (2.6%). The A1408G mutation in rrs and overexpression of WhiB7 and Tap were the predominant mechanisms of AMK resistance in M. abscessus.

Molecular Analysis of Linezolid-Resistant Clinical Isolates of Mycobacterium abscessus.

A total of 194 Mycobacterium abscessus isolates were collected from patients, and the whole genomes were sequenced. Eighty-five (43.8%) isolates showed linezolid (LZD) resistance. Only 8.2% of resistant isolates harbored 23S rRNA mutations. Quantitative real-time PCR (qRT-PCR) revealed higher transcriptional levels of efflux pumps lmrS and mmpL9 in LZD-resistant isolates. Genome comparative analysis identified several new LZD resistance-associated genes. This study highlights the role of efflux pumps in LZD-resistant M. abscessus and proposes potential target genes for further studies.

Comparative study of the proliferative ability of skeletal muscle satellite cells under microwave irradiation in fractures with titanium alloy internal fixation in rabbits.

The aim of the present study was to investigate the proliferation of skeletal muscle satellite cells (MSCs) under different amounts of microwave irradiation in fractures with titanium alloy internal fixation. A total of 45 male New Zealand adult white rabbits were used to establish a femoral shaft fracture and titanium alloy internal fixation model. The rabbits were randomly divided into the control group (group A) and the experimental groups (groups B and C). For 15 days, groups B and C were exposed to microwave treatment (25 or 50 W, respectively) for 10 min per day. The quadriceps femoris muscle was used for the isolation and culture of MSCs in vitro. The cultured cells were identified using cellular immunohistochemical staining. Transmission electron microscopy was used to observe mitochondrial ultrastructure damage, MTT assays were used to detect cell viability and cell cycle phases were analyzed by flow cytometry. The results revealed that, following 48 or 72 h of culture, cell viability was significantly greater in group B compared with group A, and was significantly lower in group C compared with group A (P<0.05). Compared with group A, the percentage of the cell population in the G0/G1 phase in group B was significantly decreased (P<0.05) and the proportion in the S and G2/M phases was increased (P<0.05). These results were reversed in group C; the percentage of cells in the S and G2/M phases was significantly lower (P<0.05) and in the G0/G1 phase was significantly higher (P<0.05) than in group A. These results suggested that in the healing of fractures with titanium, the proliferation of MSCs is significantly affected by microwave radiation in a dose-dependent manner.

Clinical features of hypophosphatemic osteomalacia induced by long-term low-dose adefovir dipivoxil.

OBJECTIVE: To investigate the predictors of hypophosphatemic osteomalacia induced by adefovir dipivoxil (ADV) and to monitor for early detection. PATIENTS AND METHODS: Hospitalized patients who were diagnosed with ADV-related hypo-phosphatemic osteomalacia were recruited and retrospectively analyzed in our hospital from January 2012 to December 2016. A telephone interview was conducted at 1, 3, 6, 9, 12, and 24 months after cessation of ADV. RESULTS: In the 8 patients enrolled in the study, the hypophosphatemic osteomalacia symptoms developed at an average of 5.14 (4-7) years since ADV treatment (10 mg/d). The average alkaline phosphatase (ALP) level was 279.50 (137-548) U/L, which was significantly higher than the normal level (45-125 U/L). The serum phosphorus level was an average of 0.59 (0.43-0.69) mmol/L, which was lower than the normal range (2.06-2.60 mmol/L). Serum calcium levels of the enrolled patients remained within normal limits. Reduced estimated glomerular filtration rate (eGFR <29 mL/min/1.73 m2) was seen in 4 cases. The clinical manifestations were mainly progressive systemic bone and joint pain, frequent fractures, trouble in walking, height reduction (4-6 cm), and so on. After cessation of ADV, symptoms like bone pain resolved gradually. Serum phosphorus level restored to normal in 4.5 months after the withdrawal of ADV. However, in 4 patients, renal function failed to return to normal in 24 months. CONCLUSION: More attention should be paid to the duration of ADV treatment. The level of serum phosphorus and ALP, as well as renal function, should be monitored for early detection of potential adverse drug reactions.