Acquisition of antimicrobial-resistant variants in repeated infections caused by Pseudomonas aeruginosa revealed by whole genome sequencing

Pseudomonas aeruginosa, responsible for serious nosocomial-acquired infections, possesses intrinsic antibiotic resistance mechanisms and commonly exhibits multidrug resistance. Here, we report the evolving resistance profiles of strains isolated from the sputum of a patient being treated for repeated P. aeruginosa infections following cancer resection. Whole genome sequencing of six isolates obtained over a 2-month period revealed two key single nucleotide polymorphisms in the mexR and gyrB genes that affected efflux pump expression and antimicrobial resistance.     

Microscopic polyangiitis associated with marked systemic bleeding tendency caused by disseminated intravascular coagulation

A 57-year-old woman was admitted to our hospital because of severe dyspnea due to pulmonary hemorrhage and rapidly progressive renal failure. The patient was positive for perinuclear pattern anti-neutrophil cytoplasmic antibody (p-ANCA) and was manifested with gastrointestinal bleeding and brain hemorrhage. Thus, she was diagnosed as having microscopic polyangiitis (MPA). Laboratory examination demonstrated severe thrombocytopenia, increased prothrombin time and a high concentration of fibrin degradation products. In addition, the elevated plasma levels of D-dimer, thrombin-antithrombin complex and plasmin-plasmin inhibitor complex led us to make a diagnosis of disseminated intravascular coagulation (DIC). Complication of DIC was considered to have caused further deterioration in bleeding tendency due to MPA in the present case. The patient was treated with plasma exchange, hemodialysis, administration of corticosteroid including pulse therapy and cyclophosphamide. Continuous infusion of gabexate mesilate proved effective for improvement of systemic bleeding tendency. However, she finally died of severe infectious diseases. In conclusion, it is suggested that ANCA-associated vasculitis could be accompanied by DIC and gabexate mesilate may be a useful therapeutic agent for these disorders.     

Involvement of specific macrophage-lineage cells surrounding arterioles in barrier and scavenger function in brain cortex.

The transport of solutes between blood and brain is regulated by a specific barrier. Capillary endothelial cells of brain are known to mediate barrier function and facilitate transport. Here we report that specific cells surrounding arterioles, known as Mato's fluorescent granular perithelial (FGP) cells or perivascular microglial cells, contribute to the barrier function. Immunohistochemical and in situ hybridization studies indicate that, in normal brain cortex, type I and type II macrophage scavenger receptors are expressed only in FGP/perivascular microglial cells, and surface markers of macrophage lineage are also detected on them. These cells mediate the uptake of macromolecules, including modified low density lipoprotein, horseradish peroxidase, and ferritin injected either into the blood or into the cerebral ventricles. Accumulation of scavenged materials with aging or after the administration of a high-fat diet results in the formation of honeycomb-like foam cells and the narrowing of the lumen of arterioles in the brain cortex. These results indicate involvement of FGP/perivascular microglial cells in the barrier and scavenger functions in the central nervous system.     

Osteoblasts induce Ca2+ oscillation-independent NFATc1 activation during osteoclastogenesis

Intercellular cross-talk between osteoblasts and osteoclasts is important for controlling bone remolding and maintenance. However, the precise molecular mechanism by which osteoblasts regulate osteoclastogenesis is still largely unknown. Here, we show that osteoblasts can induce Ca(2+) oscillation-independent osteoclastogenesis. We found that bone marrow-derived monocyte/macrophage precursor cells (BMMs) lacking inositol 1,4,5-trisphosphate receptor type2 (IP(3)R2) did not exhibit Ca(2+) oscillation or differentiation into multinuclear osteoclasts in response to recombinant receptor activator of NF-kappaB ligand/macrophage colony-stimulating factor stimulation. IP(3)R2 knockout BMMs, however, underwent osteoclastogenesis when they were cocultured with osteoblasts or in vivo in the absence of Ca(2+) oscillation. Furthermore, we found that Ca(2+) oscillation-independent osteoclastogenesis was insensitive to FK506, a calcineurin inhibitor. Taken together, we conclude that both Ca(2+) oscillation/calcineurin-dependent and -independent signaling pathways contribute to NFATc1 activation, leading to efficient osteoclastogenesis in vivo.     

Two cases of pulmonary infection by Mycobacterium abscessus in which drug susceptibility testing results conflicted with clinical courses]

We encountered two cases of pulmonary infection by Mycobacterium abscessus (M. abscessus). [Case 1] A 66-year-old man who had been treated for non-tuberculous mycobacterium in the past was admitted because of productive cough. His chest X-ray film showed cavitation and direct microscopy of sputum revealed positive acid-fast bacilli (AFB). He was given rifampicin (RFP), ethambutol (EB), and clarythromycin (CAM), and then his symptoms and radiographic findings improved. [Case 2] A 74-year-old man with multiple myeloma as an underlying disease was admitted because of a cavitation found on chest radiography and a positive result for AFB in his sputum. Standard antituberculous drug therapy with isoniazid (INH), RFP, EB, and pyradinamide (PZA) was initiated and then the chest radiographic findings improved. As M. abscessus was isolated two weeks after the induction of therapy, the therapeutic regimen was changed to another combination therapy consisting of EB, clarithromycin (CAM) and ciprofloxacin (CPFX), and then his symptoms and radiographic findings were further improved. In both cases, the bacilli found in their sputum were identified as M. abscessus by DNA hybridization. They were completely resistant to all anti-tuberculosis agents and many antibiotics with a high value of MIC. However, their symptoms, radiographic abnormalities and the results of sputum examination improved following chemotherapy. The results obtained by MIC measurement were inconsistent with the clinical outcomes. The measurement of the MIC value of antibiotics do not necessarily predict its therapeutic effect.     

Ulcerative colitis followed by the development of Behçet's disease

A 34-year-old man who had a history of ulcerative colitis (UC) was admitted to our hospital with complaints of arthralgia, erythema nodosum, recurrent oral aphthous ulcers and bloody stools. A colonoscopy revealed multiple aphthous ulcers on his cecum and colon and also revealed a transmural ulcer on his rectum consistent with a diagnosis of UC. The patient was HLA-B51 positive. Based on clinical evidence [recurrent oral ulcers, skin lesions (erythema nodosum), positivity for pathergy test] this patient was diagnosed as having Beh?et's disease with gastrointestinal involvement. We describe this rare case of Beh?et's disease with colitis and discuss the difficulties in making a differential diagnosis between Beh?et's disease and the inflammatory bowel diseases.     

Limited value of the international staging system for predicting long-term outcome of transplant-ineligible,newly diagnosed,symptomatic multiple myeloma in the era of novel agents

We retrospectively investigated clinical outcomes and prognostic factors of 131 patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) who received melphalan and prednisolone (MP) as first-line therapy from 2006 to 2013. Eighty-one patients received salvage therapies incorporating bortezomib, lenalidomide, and/or thalidomide. The overall response rate to MP was 54.2 %, including 9.2 % of better than very good partial response. With a median follow-up period of 30.2 months, median overall survival (OS) and median time to next treatment (TNT) were 54.4 and 19.0 months, respectively. Univariate analysis revealed that performance status and serum calcium level significantly associated with both OS and TNT, and multivariate analysis revealed that the higher serum calcium level had a significantly unfavorable impact on OS and TNT. Importantly, staging informed by the international staging system (ISS) was not predictive for OS or TNT in the analyzed cohort. Our study revealed that, in the context of first-line MP therapy for NDMM, the salvage therapy incorporating novel agents produced a survival period of >30 months after the initiation of second-line therapy, suggesting that the predictive value of ISS for OS and TNT may be limited in the era of novel agents.     

Helicobacter pylori infection is positively associated with gallstones: a large-scale cross-sectional study in Japan

Background

Our aim is to elucidate causative factors for gallstones, especially focusing on Helicobacter pylori (HP) infection.

Methods

We analyzed 15,551 Japanese adults who had no history of gastrectomy, cholecystectomy, HP eradication, and didn’t use proton pump inhibitors, anti-diabetic drugs, or anti-cholesterol drugs. 1,057 subjects who previously had HP eradication were analyzed separately.

Results

Gallstones were detected in 409 of 8,625 men (4.74 %) and 285 of 6,926 women (4.11 %) by ultrasonography. Among the 25 factors univariately analyzed, age, HP infection, alcohol intake, weight, body mass index (BMI), and 14 blood test values (AST, ALT, ALP, γ-GTP, T-Chol, HDL-Chol, LDL-Chol, TG, TP, Hb, HbA1c, pepsinogen I, pepsinogen II, and pepsinogen I/II ratio) displayed significant association with gallstones (p < 0.05), whereas gender, smoking, height, and three blood test values (Alb, T-Bil, MCV) did not. Multivariate analysis showed that age, gender, alcohol intake, BMI, γ-GTP, LDL-Chol, TP, and HP infection had significant association (p < 0.05). Successive multiple logistic regression analysis calculating odds ratio (OR) and standardized coefficients (β) showed that age (OR/β = 1.57/0.450), BMI (OR/β = 1.30/0.264), HP infection (OR/β = 1.51/0.206), lower alcohol intake (OR/β = 1.33/0.144), γ-GTP (OR/β = 1.15/0.139), and pepsinogen I/II ratio (OR/β = 1.08/0.038) have significant positive association with gallstones, whereas gender does not. The gallstone prevalence among HP-negative, HP-eradicated, and HP-positive subjects was 3.81, 4.73 and 6.08 %, respectively. The matched analysis controlling age, BMI, γ-GTP, alcohol intake, pepsinogen I/II ratio and gender also demonstrated that gallstone prevalence among HP-eradicated subjects was significantly lower compared with HP-positive subjects (p < 0.05).

Conclusions

HP infection is positively associated with gallstones. HP eradication may lead to prevention of gallstones.