Downregulation of cytochrome P450scc as an initial adverse effect of adult exposure to diethylstilbestrol on testicular steroidogenesis

Reproductive toxicities and endocrine disruptions caused by chemicals in adult males are still poorly understood. It is our objectives to understand further details of the initial adverse effects leading severe testicular toxicities of a pharmaceutical endocrine disruptor, diethylstilbestrol (DES). Downregulations of both testicular regulatory proteins, such as the steroidogenic acute regulatory protein (StAR) and the peripheral benzodiazepine receptor (PBR), which play important roles in the transport of cholesterol into the mitochondria, and cytochrome P450 mediating the cholesterol side chain cleavage reaction (P450scc), were observed in the rat orally administered DES (340 μg/kg/2 days) for 2 weeks. We found that after only 1 week treatment with DES, the blood and testicular testosterone (TS) levels were drastically decreased without abnormalities of the StAR and PBR; however, the protein and mRNA levels of P450scc were diminished. Decrease in the conversion rate of cholesterol to pregnenolone was delayed in the in vitro assay using the testicular mitochondrial fraction from the rat treated with DES for 1 week. When the precursors in TS biosynthesis containing the testis were identified and determined by liquid chromatography‐mass spectrometry analysis, decreased levels of all precursors except cholesterol were observed. In conclusion, suppressed cytochrome P450scc expression in adult male rat was identified as an initial target of DES in testicular steroidogenesis disorder leading reproductive toxicities. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1452–1459, 2014.     

Beta-blocker stress echocardiography in an aortic stenosis patient with associated left ventricular outflow tract obstruction

An 80-year-old man visited our hospital because of dyspnea on exertion from 6 months ago. Echo Doppler study showed severe calcification in the aortic valve with restricted movement and the sigmoid septum causing obstruction at the LV outflow tract (LVOT). Considering the aortic valve area (AVA) might have been inaccurately estimated, we carried out beta-blocker stress echocardiography. The transaortic pressure gradient and AVA were respectively calculated as 52 mmHg and 0.90 cm² before propranolol administration and as 64 mmHg and 0.86 cm² after propranolol administration. Thus, beta-blocker stress echocardiography may provide an accurate assessment of AS if the LVOT obstruction is concomitant.     

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.     

Asymptomatic colorectal cancer detected by screening

PURPOSE: Colorectal cancer screening has become prevalent. To discuss the efficacy of screening, we studied the characteristics of asymptomatic Colorectal cancer detected by screening. METHODS: This is a retrospective review of patients with colorectal cancer treated at our institution. During the past 20 years, 96 of 1,046 cases of colorectal cancer were asymptomatic and detected by screening. Sixty-one of these cases were detected in the recent five years. The initial screening procedures were fecal occult blood test in 51 cases, sigmoidoscopy or colonoscopy in 18, barium enema in 9, and other tests in 18. RESULTS: Thirteen lesions (14 percent) were smaller than 1.0 cm and 32 (33 percent) were 1–2 cm in size. There were 34 Tis, 21 T1, and 8 T2 tumors. Of the 55 Tis or T1 lesions, 14 showed nonpolypoid growth (5 flat-elevated, 7 flat-elevated with depression, 1 flat, 1 depressed), and 12 of these were detected on endoscopy. Thirty-four cases were TNM Stage 0, 25 were Stage I, 16 were Stage II, 12 were Stage III, and 9 were Stage IV. Sixty-one percent of those detected by screening were in either Stage 0 or Stage I compared with 16 percent in the symptomatic group. Cumulative five-year disease-free survival rates were 100 percent for both Stage 0 and Stage I, 94 percent for Stage II, and 52 percent for Stage III. Overall cumulative five-year survival rate was 87 percent for those detected by screening, compared with 57 percent in symptomatic patients. CONCLUSIONS: Asymptomatic cancers detected by screening were at a less advanced stage. In particular, many nonpolypoid early cancers were detected by endoscopic screening.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Montreal, Quebec, Canada, May 7 to 12, 1995.     

Identification of an Anti–Integrin αvβ6 Autoantibody in Patients With Ulcerative Colitis

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Evaluation of Streptococcus pneumoniae-urinary antigen detection kit in patients with community acquired pneumonia

We evaluated a new rapid urinary antigen detection kit. NOW Streptococcus pneumoniae (Binax Inc., USA) that detected S. pneumoniae antigen by immunochromatographic membrane assay, with 66 Japanese adult patients of community acquired pneumonia. Twenty-two (33.3%) patients were found to be positive with the kit and S. pneumoniae was isolated from six patients (27.3%) of these 22 patients. S. pneumoniae was not isolated from eight of the 22 patients by blood or sputum culture. Analysis of clinical laboratory data showed that the levels of C-reactive protein (CRP) in the serum were significantly higher in the urine-antigen positive group than those in the urine-antigen negative group. There were no significant difference between the two groups including renal function, urinalysis, clinical symptom, and severity of pneumonia. Our study suggests that more cases of community acquired pneumonia are caused by S. pneumoniae than conventional tests can currently confirm. Since it is not technically complex, does not require equipment, and detects within as quickly as in 15 minutes, the S. pneumoniae urinary antigen kit is useful for rapid diagnosis of community acquired pneumonia in adults.     

Elevated Fibroblast Growth Factor 23 Exerts Its Effects on Placenta and Regulates Vitamin D Metabolism in Pregnancy of Hyp Mice

Fibroblast growth factor 23 (FGF23) functions in an endocrine fashion and requires α‐Klotho to exert its effects on the target organs. We have recently demonstrated that the human placenta also expresses α‐Klotho, which led us to hypothesize that FGF23 may exert effects on the placenta. Immunohistochemical analysis demonstrated the expression of FGF receptor 1 (FGFR1) as well as that of α‐Klotho in the feto‐maternal interface of both mouse and human normal‐term placentas, which suggested that these areas might be receptive to FGF23. Therefore, we next investigated whether FGF23 has some roles in the placenta using Hyp mice with high levels of circulating FGF23. Hyp and wild‐type (WT) females were mated with WT males, and the mothers and their male fetuses were analyzed. FGF23 levels in Hyp mothers were elevated. FGF23 levels were about 20‐fold higher in Hyp fetuses than in Hyp mothers, whereas WT fetuses from Hyp mothers exhibited low levels of FGF23, as did fetuses from WT mothers. We analyzed the placental gene expression and found that the expression of Cyp24a1 encoding 25OHD‐24‐hydroxylase, a target gene for FGF23 in the kidney, was increased in the placentas of fetuses from Hyp mothers compared with fetuses from WT mothers. In an organ culture of WT placentas, treatment with plasma from Hyp mothers markedly increased the expression of Cyp24a1, which was abolished by the simultaneous addition of anti‐FGF23 neutralizing antibody. The direct injection of recombinant FGF23 into WT placentas induced the expression of Cyp24a1. The increase in the placental expression of Cyp24a1 in fetuses from Hyp mothers resulted in decreased plasma 25‐hydroxyvitamin D levels. These results suggest that increased levels of circulating FGF23 in pathological conditions such as Hyp mice exerts direct effects on the placenta and affects fetal vitamin D metabolism via the regulation of Cyp24a1 expression. © 2014 American Society for Bone and Mineral Research.