Kiyohito Ishikawa

Increased Urinary Neutrophil Gelatinase Associated Lipocalin Levels in a Rat Model of Upper Urinary Tract Infection

PURPOSE Recurrent upper urinary tract infection is a common complication of vesicoureteral reflux that often leads to irreversible renal scarring. In our previous study of a rat model of renal bacterial infection we performed global gene expression profiling of the kidney during the onset of renal scarring. We have further investigated the product of an up-regulated gene product, NGAL, in this animal model to evaluate its potential usefulness as a biomarker of renal scarring. MATERIALS AND METHODS Renal NGAL mRNA and protein levels were examined by real-time polymerase chain reaction, Western blot and immunohistochemistry. Urinary NGAL levels were monitored by direct enzyme-linked immunosorbent assay. RESULTS Rat renal NGAL mRNA and protein levels were found to be increased soon after bacterial injection. They then decreased rapidly but subsequently persisted at high levels until the 6-week time point after injection. On histological analysis we found that NGAL protein was overproduced in macrophages and renal tubular cells 2 weeks after injection. However, renal tubular cells continued to produce NGAL 6 weeks after injection, whereas this expression was lost in infiltrating cells. Rat urinary NGAL levels were also markedly increased at the early stages of infection and they persisted at high levels throughout the latter stages of the experiment. CONCLUSIONS Urinary NGAL may be a potential noninvasive diagnostic biomarker of renal scarring.

Genetic Profiles of Fluoroquinolone-Resistant Escherichia coli Isolates Obtained from Patients with Cystitis: Phylogeny, Virulence Factors, PAIusp Subtypes, and Mutation Patterns

The low virulence of quinolone- and fluoroquinolone-resistant Escherichia coli strains is known, although the reasons for this remain unclear. We surveyed the mutation patterns of quinolone resistance determining regions (QRDRs), phylogenetic distribution, prevalence of 18 urovirulence genes, and PAIusp subtypes in 89 fluoroquinolone-resistant E. coli (FQREC) isolates obtained from patients with cystitis and compared them with those of their fluoroquinolone-susceptible counterparts (FQSEC). Phylogenetic group B2 was significantly less prevalent in FQREC than in FQSEC (49% versus 78%; P = 0.0138), but it still dominated, followed by phylogroup D (35%), in FQREC. When the prevalences of virulence factor (VF) genes were compared between FQREC and FQSEC, sfa/foc, cnf1, hly, kpsMT, ompT, ibeA, usp, and iroN showed significantly lower prevalences in FQREC than in FQSEC (1.1% versus 24% [P < 0.0001], 0% versus 29% [P < 0.0001], 7.9% versus 33% [P < 0.0001], 74% versus 90% [P = 0.01], 71% versus 87% [P = 0.017], 5.6% versus 37% [P < 0.0001], 54% versus 82% [P < 0.0001], and 7.9% versus 32% [P = 0.0001], respectively), whereas aer, iha, and ETTT showed significantly higher prevalences in FQREC (85% versus 36% [P < 0.0001], 66% versus 29% [P < 0.0001], and 53% versus 16% [P < 0.0001], respectively). Furthermore, a similar difference in prevalences of uropathogenic VF genes was seen between FQREC and FQSEC in phylogroup B2. This indicated that the low virulence in FQREC was intimately correlated with a lesser distribution of VFs in phylogroup B2, which dominated in FQREC and FQSEC. It was interesting that the mutation pattern of Ser83Leu and Asp87Asn encoded in gyrA and Ser80Ile and Glu84Val encoded in parC was frequently found in FQREC isolates that belonged to phylogroup B2 and that most of these isolates showed PAIusp subtype 2a. PAIusp subtypes 1a, 1b, and 2b, which were frequently seen in FQSEC, were rarely found in FQREC. These results suggested that the acquisition of fluoroquinolone resistance, e.g., mutations in QRDRs, might be a specific event in limited strains, such as those that possess PAIusp subtype 2a in phylogroup B2.

Nationwide survey of antibacterial activity against clinical isolates from urinary tract infections in Japan (2008)

In this study, the causative bacteria and their sensitivity to various antimicrobial agents as well as risk factors for quinolone-resistant Escherichia coli were investigated in patients with acute uncomplicated cystitis or complicated cystitis by isolation and culture of bacteria from urine samples. In total, 1312 strains were isolated from 1009 patients with acute uncomplicated cystitis, including E. coli (63.3%), Enterococcus faecalis (12.8%) and Streptococcus agalactiae (4.6%). In addition, 994 strains were isolated from 725 patients with complicated cystitis, including E. coli (36.4%), E. faecalis (19.2%), Klebsiella pneumoniae (5.0%), S. agalactiae (4.7%) and Pseudomonas aeruginosa (4.5%). At least 90% of E. coli isolates from acute uncomplicated cystitis showed sensitivity to fluoroquinolones and cephems, whilst 70.4-88.4% of E. coli isolates from complicated cystitis were sensitive to fluoroquinolones and 85.4-89.5% were sensitive to cephems. Factors associated with quinolone-resistant E. coli included two or more episodes of cystitis within 1 year, failure of quinolone therapy, underlying urinary tract disease, prior quinolone treatment within 1 month and age ≥ 75 years. It is important to confirm the sensitivity of causative bacteria for optimal antimicrobial therapy, and empirical antimicrobial agents should be selected by considering patient characteristics and other factors.

Japanese guideline for clinical research of antimicrobial agents on urogenital infections: the first edition

In the 1970s, clinicians and researchers specializing in urinary tract infections (UTIs) established and published the first-ever Criteria for Clinical Evaluation of Drug Efficacy on UTI. There had so far been no uniform criteria for the evaluation of drug efficacy, and different criteria for determining drug efficacy had been used in the development of drugs, which had caused problems in determining drug efficacy and had made it impossible to compare efficacy between drugs. To resolve these challenges, the Criteria for Clinical Evaluation of Drug Efficacy on UTI were established on the basis of the results of a large number of studies. The late Dr. Masaaki Ohkoshi, the late Dr. Joji Ishigami, the late Dr. Tsuneo Nishiura, Dr. Toyohei Machida, Dr. Yoshiaki Kumamoto, Dr. Joichi Kumazawa, Dr. Yukimichi Kawada, Dr. Sadao Kamidono, and other senior physicians made efforts to create the world’s first Criteria for Clinical Evaluation of Drug Efficacy on UTI, which had contributed enormously to the development of antimicrobial agents for UTIs. In 1989, an International Symposium entitled ‘‘Clinical Evaluation of Drug Efficacy on UTI’’ was held in Tokyo and offered opportunities to get international recognition of the Criteria for Clinical Evaluation of Drug Efficacy on UTI. Thereafter, the International UTI Symposium was established and came to be held biennially in conjunction with the International Congress on Chemotherapy. The joint symposium has been held ten times to date. In Japan, the Criteria for Evaluation of Clinical Efficacy of Antimicrobial Agents on UTI were created by the UTI study group. The Criteria, which were those of the revised 3rd edition, involved various urological infections, including prostatitis, epididymitis, and urethritis, in addition to UTIs. Meanwhile, Infectious Diseases Society of America (IDSA)/ Food and Drug Administration (FDA) guidelines and the Criteria for Clinical Evaluation of Drug Efficacy were established in theUnitedStates andEurope, respectively,which led to an increased need for international harmonization aswell as globalization of the development of antimicrobial agents. To move with the times and to allow compatibility between data accumulated in Japan and data fromother countries, the Study Group on Urology, the Committee of Clinical Evaluation Methods, and the Japanese Society of Chemotherapy discussed and created the 4th edition of Criteria for Evaluation of Clinical Efficacy of Antimicrobial Agents on UTI (tentative) and its supplement in 1996. However, further international harmonization was needed, as international drug development, extrapolation of clinical data from other countries, and bridging studies had been increasing. In bringing about international M. Yasuda S. Takahashi H. Kiyota K. Ishikawa A. Takahashi S. Yamamoto S. Arakawa K. Monden T. Muratani R. Hamasuna H. Hayami T. Matsumoto UTI Subcommittee of the Clinical Evaluation Guidelines Committee, Japan Society of Chemotherapy, Tokyo, Japan

Essential Japanese guidelines for the prevention of perioperative infections in the urological field: 2015 edition.

After publication of the initial version of the Japanese guidelines for urological surgery in 2007, new surgical techniques have been introduced. Furthermore, several important issues, such as criteria for use of single‐dose antimicrobial prophylaxis and control of hospitalized infection, were also established, which led to alterations of the methods used for antimicrobial prophylaxis as well as perioperative management. The purpose of antimicrobial prophylaxis is to protect the surgical wound from contamination by normal bacterial flora. Antimicrobial prophylaxis should be based on penicillins with beta‐lactamase inhibitors, or first‐ or second‐generation cephalosporins, though penicillins without beta‐lactamase inhibitors should not be prescribed because of the high prevalence of antimicrobial resistance. As an adequate intratissue concentration of the antimicrobial at the surgical site should be accomplished by the time of initiation of surgery, antimicrobial prophylaxis should be started up to 30 min before beginning the operation. Antimicrobial prophylaxis should be terminated within 24 h in clean and clean‐contaminated surgery, and within 2 days of surgery using the bowels, because a longer duration is a risk factor for surgical site infection development. Importantly, possible risk factors for surgical site infections include the antimicrobial prophylaxis methodology used as well as others, such as duration of preoperative hospitalization, hand washing, the American Society of Anesthesiologists score, diabetes and smoking history. These guidelines are to be applied only for preoperatively non‐infected low‐risk patients. In cases with preoperative infection or bacteriuria that can cause a surgical site infection or urinary tract infection after surgery, patients must receive adequate preoperative treatment based on the individual situation.

Mycobacterium tuberculosis infection of bilateral cervical lymph nodes after renal transplantation

We report the case of a 52‐year‐old man who underwent a renal transplantation and subsequently developed extrapulmonary tuberculosis. The immunosuppressive agent was intravenously administered continuously together with antituberculosis drugs. The tuberculosis improved and renal function has been well preserved for more than 3 years post transplantation.

Testicular Cancer in Father and Son

The occurrence of testicular tumors in closely related family members is rare. We report a case of testicular cancers in a father and son. The father had pure seminoma, and his son developed a mixed nonseminomatous germ cell tumor. The peripheral blood lymphocytes in both patients were tested for 52 HLA specificities, and the patients were found to have six in common. The son was homozygous for HLA A24. The association between certain HLA antigens, other genetic factors, and testicular cancer requires further study to improve the care and counseling of patients and their families.

Emergence of Salmonella Strain That Produces IMP-1-Type Metallo-β-Lactamase in a Japanese Patient

1Department of Joint Research Laboratory of Clinical Medicine and 2Department of Quality and Safety in Healthcare, Fujita Health University Hospital, Toyoake 470-1192; 3Department of Pediatrics, Fujita Health University School of Medicine, Toyoake 470-1192; 4Department of Bacteriology II, National Institute of Infectious Diseases, Tokyo 208-0011; and 5Department of Microbiology and Medical Zoology, Aichi Prefectural Institute of Public Health, Nagoya 462-8576, Japan

A proposal of subcategorization of bacterial prostatitis: NIH category I and II diseases can be further subcategorized on analysis by therapeutic and immunological procedures

Aim:  We propose preliminarily that acute (category I of the NIH consensus definition) and chronic prostatitis (category II) can be subcategorized into primary and recurrent diseases based on the precise analysis of the clinical course and the immunological parameters in prostatic secretions of our cases.

Receptors for Escherichia coli adhesins in the genitourinary tract in a non-human primate.

Objective: To study the expression of receptors allowing adhesin-mediated binding of Escherichia coli to urogenital tissues ranging from the kidney to the vagina in cynomolgus monkeys using an in situ assay. Material and Methods: Receptors specific for four relevant adhesins were investigated: PapG and PrsG of P-fimbriae binding to gal-α(1–4)gal glycosphingolipids (preferentially globoside and the Forssman antigen, respectively); and two variants of FimH of type 1 fimbriae, one binding to monomannose/trimannose and the other to trimannose only. To ascertain the specificity of the observed bindings we used adhesion inhibition by receptor analogues as well as E. coli adhesin knockout mutants. Results: The distributions of PapG and FimH receptors in monkey tissues showed great similarities to available data in humans. Whilst monomannose receptors were expressed on the surface epithelium in both the monkey bladder and ureter, trimannose receptors were not. The different distribution of FimH isoreceptors and the heterogeneity of FimH adhesin variants among E. coli may explain contradictory earlier findings in type 1 fimbriae-mediated adhesion to the human bladder and to renal tissues. We also found evidence of a hitherto unknown type of host–aggressor interaction on vaginal and urethral mucosa, which was not discovered until type 1 fimbriae had been eliminated. Conclusions: A precise molecular fit between host receptors and bacterial lectins is important in infectious pathogenesis. We conclude that urinary tract infection in the cynomolgus monkey is a relevant model of the human disease because of the similarity in the expression of receptors for E. coli adhesins on epithelial surfaces in the two species.