Further characterization of Bacillus subtilis antibiotic biosensors and their use for antibacterial mode-of-action studies

We further examined the usefulness of previously reported Bacillus subtilis biosensors for antibacterial mode-of-action studies. The biosensors could not detect the tRNA synthetase inhibitors mupirocin, indolmycin, and borrelidin, some inhibitors of peptidoglycan synthesis, and most membrane-damaging agents. However, the biosensors confirmed the modes of action of several RNA polymerase inhibitors and DNA intercalators and provided new insights into the possible modes of action of ciprofloxacin, anhydrotetracycline, corralopyronin, 8-hydroxyquinoline, and juglone.     

Tricyclic compounds containing nonenolizable cyano enones. A novel class of highly potent anti-inflammatory and cytoprotective agents

Forty-four novel tricycles containing nonenolizable cyano enones (TCEs) were designed and synthesized on the basis of a semisynthetic pentacyclic triterpenoid, bardoxolone methyl, which is currently being developed in phase II clinical trials for the treatment of severe chronic kidney disease in diabetic patients. Most of the TCEs having two different kinds of nonenolizable cyano enones in rings A and C are highly potent suppressors of induction of inducible nitric oxide synthase stimulated with interferon-γ and are highly potent inducers of the cytoprotective enzymes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Among these compounds, (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile ((±)-31) is the most potent in these bioassays in our pool of drug candidates including semisynthetic triterpenoids and synthetic tricycles. These facts strongly suggest that an essential factor for potency is not a triterpenoid skeleton but the cyano enone functionality. Notably, TCE 31 reduces hepatic tumorigenesis induced with aflatoxin in rats. Further preclinical studies and detailed mechanism studies on 31 are in progress.     

Expression of b‐FGF and endostatin and their clinical significance in human osteosarcoma

Objective: To investigate the expression and the clinical significance of basic fibroblast growth factor (b‐FGF) and endostatin in osteosarcoma. Methods: From January 2003 to December 2005, expression of b‐FGF, endostatin and CD34 were detected in 30 osteosarcoma and 30 osteochondroma tissue specimens by the immunohistochemical Elivision method. All data were post‐processed with SPSS 13.0 software and prepared for investigation and analysis of these expressions and the relationships between the parameters. Results: (i) The rates of expression of b‐FGF, endostatin and CD34 protein in osteosarcoma were 76.7%, 93.3%, and 96.7%, respectively, and in osteochondroma 43.3%, 40.0% and 16.7%, respectively. Each of the three expressions showed obvious differences between the osteosarcoma and the osteochondroma group. (ii) In the osteosarcoma group, expression of endostatin was positively correlated with that of CD34 (P < 0.05, γs = 0.528), and expression of endostatin in poorly differentiated osteosarcoma was much greater than that in highly differentiated osteosarcoma (P= 0.004). Expression of endostatin correlated with osteosarcoma metastasis (P= 0.036). (iii) There was no correlation between b‐FGF and endostatin expression rates (P= 0.182) in the osteosarcoma group. Conclusion: Angiogenesis is the basis of tumor metastasis, as well as being an important factor in tumor growth. Expression of endostatin could be adopted as a parameter for the diagnosis of postoperative metastases and for assessing prognosis, and could act as an adjuvant indicator in the grading of osteosarcoma.     

Comparison of supine-only and REM-only obstructive sleep apnoea

ObjectivesThe effect of body position and sleep state on sleep apnoea have major clinical implications in the management of patients, yet are infrequently reported in the scientific literature. The aim of this study was to compare and contrast the prevalence and severity of supine-only and rapid eye movement (REM)-only obstructive sleep apnoea (OSA) in a population.MethodsProspective cohort analysis of the influence of supine body position and REM sleep on the severity of apnoea in 100 consecutive patients with OSA (apnoea–hypopnoea index [AHI] > 5) using attended polysomnography with continuous digital monitoring in an accredited sleep laboratory. Supine-only OSA was defined as a supine:non-supine AHI ratio of >2:1 and non-supine AHI <5 events/h. REM-only OSA was defined as an REM:non-REM ratio of >2:1 and non-REM AHI <5 events/h.ResultsSupine sleep time represented a greater proportion of total sleep time than REM sleep time (40% vs 13%). The prevalence of supine-only OSA was more than twofold greater than that of REM-only OSA (23% and 10%, respectively). The supine-only group had greater overall AHI (mean 12.6 ± 6.1 vs 7.2 ± 2.2 events/h; P < 0.01) than the REM-only group. No significant differences in gender, age, or sleepiness were found between the two groups.ConclusionsSupine-only OSA is more common and is associated with a greater AHI than REM-only OSA.     

Treatment options for rosacea with concomitant conditions

Patients with rosacea frequently present with coexisting skin conditions, such as seborrheic dermatitis, acne, perioral dermatitis, and melasma, which may complicate diagnosis and treatment. This article discusses the presentation, pathophysiology, and management of rosacea with common concomitant skin disorders.     

Severe bronchomalacia treated by combination of Nuss procedure and aortopexy: an unusual therapy combination

Aortopexy is the treatment of choice for clinically significant tracheobronchomalacia from external vascular compression. When a marked chest depression is present, aortopexy may be less effective. We report 2 patients with pectus excavatum and vascular compression of the trachea who, despite their young age, benefited from combined Nuss bar insertion and aortopexy.     

Natural chlorophyll inhibits aflatoxin B1-induced multi-organ carcinogenesis in the rat

Chemoprevention by chlorophyll (Chl) was investigated in a rat multi-organ carcinogenesis model. Twenty-one male F344 rats in three gavage groups (N = 7 rats each) received five daily doses of 250 microg/kg [(3)H]-aflatoxin B(1) ([(3)H]-AFB(1)) alone, or with 250 mg/kg chlorophyllin (CHL), or an equimolar amount (300 mg/kg) of Chl. CHL and Chl reduced hepatic DNA adduction by 42% (P = 0.031) and 55% (P = 0.008), respectively, AFB(1)-albumin adducts by 65% (P < 0.001) and 71% (P < 0.001), respectively, and the major AFB-N(7)-guanine urinary adduct by 90% (P = 0.0047) and 92% (P = 0.0029), respectively. To explore mechanisms, fluorescence quenching experiments established formation of a non-covalent complex in vitro between AFB(1) and Chl (K(d) = 1.22 +/- 0.05 microM, stoichiometry = 1Chl:1AFB(1)) as well as CHL (K(d) = 3.05 +/- 0.04 microM; stoichiometry = 1CHL:1AFB(1)). The feces of CHL and Chl co-gavaged rats contained 137% (P = 0.0003) and 412% (P = 0.0048) more AFB(1) equivalents, respectively, than control feces, indicating CHL and Chl inhibited AFB(1) uptake. However, CHL or Chl treatment in vivo did not induce hepatic quinone reductase (NAD(P)H:quinone oxidoreductase) or glutathione S-transferase (GST) above control levels. These results are consistent with a mechanism involving complex-mediated reduction of carcinogen uptake, and do not support a role for phase II enzyme induction in vivo under these conditions. In a second study, 30 rats in three experimental groups were dosed as in study 1, but for 10 days. At 18 weeks, CHL and Chl had reduced the volume percent of liver occupied by GST placental form-positive foci by 74% (P < 0.001) and 77% (P < 0.001), respectively compared with control livers. CHL and Chl reduced the mean number of aberrant crypt foci per colon by 63% (P = 0.0026) and 75% (P = 0.0004), respectively. These results show Chl and CHL provide potent chemoprotection against early biochemical and late pathophysiological biomarkers of AFB(1) carcinogenesis in the rat liver and colon.     

Identifying and managing acute coronary syndrome

Acute coronary syndrome (ACS) is a term used to describe the acute myocardial ischaemic syndromes of unstable angina, non ST-elevation myocardial infarction and ST-elevation myocardial infarction. Despite diagnostic and therapeutic developments over the past decade the quality of care for many patients suffering from ACS remains suboptimal. This paper describes the pathophysiology, assessment and management of patients with ACS.