Identification of the key interactions in structural transition pathway of FtsZ from Staphylococcus aureus.

The tubulin-homolog protein FtsZ is essential for bacterial cell division. FtsZ polymerizes to form protofilaments that assemble into a contractile ring-shaped structure in the presence of GTP. Recent studies showed that FtsZ treadmilling coupled with the GTPase activity drives cell wall synthesis and bacterial cell division. The treadmilling caused by assembly and disassembly of FtsZ links to a conformational change of the monomer from a tense (T) to a relaxed (R) state, but considerable controversy still remains concerning the mechanism. In this study, we report crystal structures of FtsZ from Staphylococcus aureus corresponding to the T and R state conformations in the same crystal, indicating the structural equilibrium of the two state. The two structures identified a key residue Arg29, whose importance was also confirmed by our modified MD simulations. Crystal structures of the R29A mutant showed T and R state-like conformations with slight but important structural changes compared to those of wild-type. Collectively, these data provide new insights for understanding how intramolecular interactions are related to the structural transition of FtsZ.

A low psoas muscle volume correlates with a longer hospitalization after radical cystectomy.

BACKGROUND: Recently, sarcopenia has been reported as a new predictor for patient outcomes or likelihood of post-operative complications. The purpose of this study was to evaluate the association of the psoas muscle volume with the length of hospitalization among patients undergoing radical cystectomy. METHODS: A total of 63 (80.8%) male patients and 15 (19.2%) female patients who underwent radical cystectomy for their bladder cancer in our institution from 2000 to 2015 were analyzed. The psoas muscle index (PMI) was calculated by normalizing the psoas muscle area calculated using axial computed tomography at the level of the umbilicus (cm2) by the square of the body height (m2). Longer hospitalization was defined as hospitalization exceeding 30 days after surgery. RESULTS: The median PMIs (mean ± standard deviation) were 391 (394 ± 92.1) and 271 (278 ± 92.6) cm2/m2 in men and women, respectively. Thus, the PMIs of male patients were significantly larger than those of females (p < 0.001). Based on the differences in gender, we analyzed 63 male patients for a further analysis. In male patients, those hospitalized longer showed a significantly smaller PMI than those normally discharged (377 ± 93.1 vs. 425 ± 83.4; p = 0.04). Similarly, male patients with a small PMI (<400) had a significantly worse overall survival (p = 0.02) than those with a large PMI (≥400). CONCLUSIONS: The presence of sarcopenia was found to be associated with significantly longer hospitalization after radical cystectomy in male patients. Furthermore, in men, a PMI <400 may suggest a significantly worse prognosis.

[Severe Hyponatremia after Cisplatin-Based Chemotherapy : Two Case Reports].

Hyponatremia is one of the common electrolyte disorders associated with cisplatin (CDDP) administration. We report here two cases of hyponatremia associated with CDDP. Case 1 : A 75-year-old man with urothelial carcinoma of bladder (cT3N1M0) underwent neoadjuvant chemotherapy with CDDP and gemcitabine. He lost consciousness on the eighth day after the chemotherapy. Blood tests showed severe hyponatremia (Na 113 mEq/l), low plasma osmolality and high level of plasma vasopressin. Urine tests showed low osmolality. These findings were consistent with the syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH). His consciousness level was improved after saline infusion and fluid restriction. Case 2 : A 54-year-old man with penile cancer (cT3N2M0) underwent neoadjuvant chemotherapy with CDDP, paclitaxel and fluorouracil. He lost consciousness on the seventh day after the chemotherapy. Blood tests showed hyponatremia(Na 121 mEq/l) with renal dysfunction. We concluded that the hyponatremia is due to the renal salt wasting syndrome (RSWS) based on renal dysfunction and high urinary sodium excretion. His consciousness level was improved after saline infusion. Although it is difficult to distinguish between SIADH and RSWS, correct evaluation is necessary for appropriate management of hyponatremia after CDDP administration.

Self-assessment of pediatric basic life support among nursery teachers in a rural area of Japan.

•Serious injury and deaths can occur in childcare settings.•School teachers in Japan have low confidence about managing serious injuries.•With appropriate education we can increase confidence of childcare workers.•We evaluate the confidence of nursery teachers in pediatric basic life support.

Structural Flexibility of an Inhibitor Overcomes Drug Resistance Mutations in Staphylococcus aureus FtsZ.

In the effort to combat antibiotic resistance, inhibitors of the essential bacterial protein FtsZ have emerged as a promising new class of compounds with clinical potential. One such FtsZ inhibitor (TXA707) is associated with potent activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) that are resistant to current standard-of-care antibiotics. However, mutations in S. aureus FtsZ (SaFtsZ) that confer resistance to TXA707 have been observed, with mutations in the Gly196 and Gly193 residues being among the most prevalent. Here, we describe structural studies of an FtsZ inhibitor, TXA6101, which retains activity against MRSA isolates that express either G196S or G193D mutant FtsZ. We present the crystal structures of TXA6101 in complex with both wild-type SaFtsZ and G196S mutant SaFtsZ, as well the crystal structure of TXA707 in complex with wild-type SaFtsZ. Comparison of the three structures reveals a molecular basis for the differential targeting abilities of TXA6101 and TXA707. The greater structural flexibility of TXA6101 relative to TXA707 enables TXA6101 to avoid steric clashes with Ser196 and Asp193. Our structures also demonstrate that the binding of TXA6101 induces previously unobserved conformational rearrangements of SaFtsZ residues in the binding pocket. In aggregate, the structures reported in this work reveal key factors for overcoming drug resistance mutations in SaFtsZ and offer a structural basis for the design of FtsZ inhibitors with enhanced antibacterial potency and reduced susceptibility to mutational resistance.

A case of tubulocystic carcinoma of the kidney with aggressive features.

Tubulocystic carcinoma of the kidney is rare and typically indolent. Our case involved an aggressive tubulocystic carcinoma as well as the radiological confirmation of its relation to papillary renal cell carcinoma. A 46-year-old male presented with renal multiloculated cysts with a solid part. On computed tomography and magnetic resonance imaging, the solid part showed the characteristics of papillary renal cell carcinoma. Contrast enhancement of the solid part was fluffy and sparse because of the coexistence of cysts. Perirenal fat invasion resulted in exophytic cysts, and renal-hilar cystic lymph node metastasis existed. The histopathological diagnosis was tubulocystic carcinoma associated with areas of papillary renal cell carcinoma and poorly differentiated carcinoma with metastasis. Our case suggests that the solid part enhancement of tubulocystic carcinoma tends to be fluffy and sparse, and exophytic cysts and cystic lymph nodes may show radiologically aggressive findings.

Invasive urothelial carcinoma, lymphoma-like/plasmacytoid variant, successfully treated by radical cystectomy with adjuvant chemotherapy: a case report.

BACKGROUND: Invasive urothelial carcinoma, lymphoma-like/plasmacytoid variant, is a rare histological type of bladder cancer similar to plasma cells and is an aggressive variant of urothelial carcinoma associated with a poor prognosis. CASE PRESENTATION: A 41-year-old Asian man was referred to our hospital due to macroscopic hematuria. Cystoscopy detected a non-papillary tumor, and a transurethral resection of the bladder tumor revealed pT1N0M0 bladder cancer. A pathological examination showed high-grade invasive urothelial carcinoma and a component of signet ring cell carcinoma. A follow-up of the transurethral resection with radical cystectomy was carried out, and a pathological examination showed infiltrating urothelial carcinoma, with partial features of the plasmacytoid variant. We added chemotherapy treatment with gemcitabine and cisplatin for two cycles. Our patient has been free from recurrence for 2 years. CONCLUSIONS: We herein report the case of a patient with a plasmacytoid variant of urothelial carcinoma controlled with radial cystectomy and subsequent chemotherapy.

Lack of an Association between Neutrophil-to-Lymphocyte Ratio and PSA Failure of Prostate Cancer Patients Who Underwent Radical Prostatectomy.

Introduction. The neutrophil-to-lymphocyte ratio (NLR), which can be easily calculated from routine complete blood counts of the peripheral blood, has been suggested to serve as a prognostic factor for some solid malignancies. In the present study, we aimed to determine the relationship between NLR in prostate cancer patients undergoing radical prostatectomy (RP) and their prognosis. Materials and Methods. We assessed NLR in 73 men (patients) who received RP for their prostate cancer. We also performed immunohistochemistry for CD8 and CD66b in a separate set of RP specimens. Results. The median NLR in the 73 patients was 1.85. There were no significant correlations of NLR with tumor grade (p = 0.834), pathological T stage (p = 0.082), lymph node metastasis (p = 0.062), or resection margin status (p = 0.772). Based on the area under the receiver operator characteristic curve (AUROC) to predict biochemical recurrence after RP, potential NLR cut-off point was determined to be 2.88 or 3.88. However, both of these cut-off points did not precisely predict the prognosis. There were no statistically significant differences in the number of CD66b-positive neutrophils or CD8-positive lymphocytes between stromal tissues adjacent to cancer glands and stromal tissues away from cancer glands and between different grades or stages of tumors. Conclusions. There was no association between NLR and biochemical failure after prostatectomy.

Epidermal Cyst in the Scrotum Successfully Treated while Preserving the Testis: A Case Report.

A 66-year-old male was referred to our hospital for further examination of a scrotal mass. Because of the risk of testicular cancer, we first clamped the vessels as a course of higher orchiectomy. Then, we approached the tumor through the scrotum and successfully resected it while preserving the testis. A histopathological diagnosis revealed an epidermal cyst. We herein report a rare case of an intrascrotal epidermal cyst successfully treated while preserving the testis.

Retroperitoneal Schwannoma in the Renal Hilum: A Case Report.

A 73-year-old male was referred to our department for further treatment of a right retroperitoneal tumor. Contrast CT showed a tumor mass measuring 33 × 26 mm in size with poor contrast enhancement. Because we were unable to rule out tumor malignancy, we planned an operation. The tumor was easily separated and removed without nephrectomy. Histological study revealed a schwannoma. It is rare for this kind of tumor to arise from the retroperitoneum (approximately 0.7% of all cases), in particular at the renal hilum. We herein report a rare case of retroperitoneal schwannoma arising from the renal hilum.

Ureteroscopy-Assisted Biopsy for a Retroperitoneal Tumor: A Case Report.

INTRODUCTION: Retroperitoneal tumor is often seen in urology clinical practice. To diagnose the tumor, tumor specimens must be obtained. However, in some cases, the tumor is penetrated by vessels around the ureter, and it may be difficult to detect the optimal spot for obtaining a specimen, even when performing open surgery. CASE PRESENTATION: A 53-year-old male patient was referred to our hospital for further examination of left back pain due to hydronephrosis. Enhanced computed tomography demonstrated ureter stenosis in front of the ilium, which was surrounded by a retroperitoneal tumor. The tumor was penetrated by blood vessels; therefore, we performed an open surgical biopsy on the suspicion of a retroperitoneal tumor using ureteroscopic assistance. The diagnosis of idiopathic retroperitoneal fibrosis was made according to the biopsy. CONCLUSION: We herein report the first case of a ureteroscopy-assisted biopsy for the pathological diagnosis of a retroperitoneal tumor.

Scavenger receptor type BI potentiates reverse cholesterol transport system by removing cholesterol ester from HDL.

High-density lipoprotein (HDL) plays an important role in reverse cholesterol transport by removing accumulated cholesterol from extrahepatic tissues. Subsequently, cholesterol ester (CE) on HDL in humans is transported to apolipoprotein B-containing lipoproteins by cholesteryl ester transfer protein (CETP). CETP deficiency, which is common in the Japanese population, leads to a marked increase in HDL-cholesterol levels due to impaired CE transport from HDL to LDL. It has been reported that the HDL observed in CETP deficiency is an atherogenic lipoprotein, as it contains a large amount of CE. Scavenger receptor class B type I (SR-BI) has been found to be an authentic HDL receptor that mediates the selective uptake of HDL CE and the bi-directional transfer of free cholesterol between HDL and cells. In the present study, the interaction between SR-BI and CE-rich HDL from CETP-deficient patient was studied in order to evaluate the anti-atherosclerotic role of SR-BI in relation to CE uptake and reverse cholesterol transport. When CE-rich HDL was added to the medium of SR-BI-transfected CHO (SR-BI CHO) cells, more CE accumulated in SR-BI CHO cells compared to control HDL. In contrast, the amount of cholesterol efflux from SR-BI CHO cells into HDL was almost the same between the two HDLs. Therefore, when CE-rich HDL was added to the medium of SR-BI CHO cells, the intracellular CE content increased significantly. Moreover, the particle size of HDL in CETP-deficient patient decreased significantly when the HDL was added to the medium of SR-BI CHO cells, and this HDL showed an increment of CE efflux from foam cells. These results indicate that SR-BI reduces the cholesterol content and size of the CE-rich HDL from CETP deficiency, which ultimately activate reverse cholesterol transport system.

Induction of sister chromatid exchanges and chromosome aberrations in cultured mammalian cells treated with aminophenylnorharman formed by norharman with aniline.

Aminophenylnorharman (APNH) is a newly identified mutagenic heterocyclic amine formed by coupling of norharman with aniline in the presence of S9 mix. Furthermore, mutagenic amino-3'-methylphenylnorharman (AMPNH) and aminophenylharman (APH) have been identified from a reaction mixture of norharman and o-toluidine and that of harman and aniline, respectively, with S9 mix. Among these three heterocyclic amines, APNH shows most potent mutagenic activity towards Salmonella typhimurium TA98 and YG1024 with S9 mix. In the present study, the induction of sister chromatid exchanges (SCEs) by APNH was examined in Chinese hamster lung (CHL) cells in vitro, comparing it to those of AMPNH and APH. On incubation with rat S9 for 6h, followed by a recovery culture period of 18h, a dose-dependent effect was found at concentrations between 0.00125 and 0.01 microg/ml for APNH and between 0.3125 and 5 microg/ml for AMPNH and APH. The approximate chemical concentrations leading to a three-fold of control SCE levels calculated from slopes of the linear regressions of induced SCEs were 0.005 for APNH, 0.51 for AMPNH and 1.7 microg/ml for APH. Because of the very strong SCE-causing ability of APNH, we further explored its genotoxicity by examining the induction of chromosome aberrations in CHL cells. A dose-dependent effect was found for chromosome aberrations at concentrations between 0.00125 and 0.04 microg/ml of APNH. The aberrations observed were primarily chromatid exchanges (cte) and breaks (ctb). In conclusion, the potency of SCE induction and clastogenic activity induced by APNH is stronger than Actinomycin D, Mitomycin C (MMC) or 1,8-dinitropyrene which are considered to be the potent clastogens in the literature. Further studies are needed for elucidating mechanisms of the genotoxic actions of these compounds and for evaluating their potential hazards to human health.

Protective effects of Polygalae root in experimental TNBS-induced colitis in mice.

In this study, the protective effect of Polygalae root was evaluated in a murine model of experimental colitis by intrarectal injection with 2,4,6-trinitrobenzene sulfonic acid (TNBS). Polygalae root, given orally at 2, 4 g/kg body weight of herbs once a day consecutively for 9 days, could recover the lost body weight and decrease the gross rectal bleeding. Polygalae root also reduced the degree of inflammation and improved significantly the histological changes such as infiltration by polymorphonuclear leukocytes and multiple erosive lesions. Furthermore, the cytokine production of intraepithelial lymphocytes was analyzed. The results showed that IFN-gamma was increased, but IL-4 was decreased in TNBS-induced colitis, when those were compared with the sham controls. But the administration of Polygalae root to TNBS-induced colitis mice showed lower production of IFN-gamma and higher production of IL-4 than the TNBS-induced colitis. These results suggest that the protective effects of Polygalae root against the TNBS colitis may be associated with the regulation of cytokine production of intraepithelial lymphocytes.

International airport and emergency medical care.

The Nippon Medical School New Tokyo International Airport Clinic (Airport Clinic) was opened in 1992 as Japan's first 24-hour international airport clinic. To date, it has provided medical services to a total of 117,953 patients. Of these, 85,545 (72.5%) were airport employees, 28,662 (24.3%) were passengers, and 3,746 (3.2%) were others. Of the total, non-Japanese patients accounted for 8,485 (7.2%). In the year to March 31, 2001, the Clinic treated an average of 43.9 cases per day. The number of emergency patients was 2,969 or 2.3% of the total, of whom 500 (0.4%) were non-Japanese. There were 47 deaths, with age ranging from 14 to 84 (average age 64.0). The ratio of males to females who died was 28:19. Of the 47 deaths, 18 were non-Japanese. Pulmonary thromboembolism is considered to have played a role in 25 of the deaths. Based on more than 8 years of airport clinical experience, we believe that a first-class international airport should have excellent medical facilities that can provide quality emergency medical services to travelers and disaster victims.

Crystal structure of FtsA from Staphylococcus aureus.

The bacterial cell-division protein FtsA anchors FtsZ to the cytoplasmic membrane. But how FtsA and FtsZ interact during membrane division remains obscure. We have solved 2.2 Å resolution crystal structure for FtsA from Staphylococcus aureus. In the crystals, SaFtsA molecules within the dimer units are twisted, in contrast to the straight filament of FtsA from Thermotoga maritima, and the half of S12-S13 hairpin regions are disordered. We confirmed that SaFtsZ and SaFtsA associate in vitro, and found that SaFtsZ GTPase activity is enhanced by interaction with SaFtsA.