The licorice pentacyclic triterpenoid component 18ß-glycyrrhetinic acid enhances the activity of antibiotics against strains of methicillin-resistant Staphylococcus aureus.

This study aimed to identify compounds that enhance the activity of current antibiotics against multidrug-resistant bacteria. Screening of a 350+ compound proprietary small molecules library revealed that the Glycyrrhiza glabra (licorice)-derived triterpenoid 18ß-glycyrrhetinic acid (18ß-GA) potentiated the antibacterial activity of certain antibiotics against Staphylococcus aureus. Here, we evaluated the ability of pentacyclic triterpenoids to potentiate the activity of antibiotics against strains of methicillin-resistant S. aureus (MRSA). Checkerboard assays were used to assess the minimum inhibitory concentration (MIC) of tobramycin and ten pentacyclic triterpenoids against S. aureus. The effect of 18ß-GA on the MIC of different antibiotics against MRSA was also determined in an in vitro airway MRSA infection model. 18ß-GA enhanced the bactericidal activity of the aminoglycosides tobramycin, gentamicin and amikacin, and of polymyxin B against two MRSA strains, reducing the MIC of these antibiotics 32-64-fold [fractional inhibitory concentration index (FICI) of 0.12-0.13]. Other ß-amyrin triterpenoids and α-amyrin triterpenoids did not exert such synergistic effects. 18ß-GA did not enhance the activity of antibiotics from other structural classes against the MRSA strains. In an air-exposed airway epithelial cell culture, 18ß-GA enhanced the bactericidal activity of tobramycin and polymyxin B against the MRSA strain. These data demonstrate the potential of 18ß-GA to synergise with certain types of antibiotics to eliminate strains of MRSA.

Interleukin 13 exposure enhances vitamin D-mediated expression of the human cathelicidin antimicrobial peptide 18/LL-37 in bronchial epithelial cells.

Vitamin D is an important regulator of the expression of antimicrobial peptides, and vitamin D deficiency is associated with respiratory infections. Regulating expression of antimicrobial peptides, such as the human cathelicidin antimicrobial peptide 18 (hCAP18)/LL-37, by vitamin D in bronchial epithelial cells requires local conversion of 25(OH)-vitamin D(3) (25D(3)) into its bioactive metabolite, 1,25(OH)(2)-vitamin D(3) (1,25D(3)), by CYP27B1. Low circulating vitamin D levels in childhood asthma are associated with more-severe exacerbations, which are often associated with infections. Atopic asthma is accompanied by Th2-driven inflammation mediated by cytokines such as interleukin 4 (IL-4) and IL-13, and the effect of these cytokines on vitamin D metabolism and hCAP18/LL-37 expression is unknown. Therefore, we investigated this with well-differentiated bronchial epithelial cells. To this end, cells were treated with IL-13 with and without 25D(3), and expression of hCAP18/LL-37, CYP27B1, the 1,25D(3)-inactivating enzyme CYP24A1, and vitamin D receptor was assessed by quantitative PCR. We show that IL-13 enhances the ability of 25D(3) to increase expression of hCAP18/LL-37 and CYP24A1. In addition, exposure to IL-13 resulted in increased CYP27B1 expression, whereas vitamin D receptor (VDR) expression was not significantly affected. The enhancing effect of IL-13 on 25D(3)-mediated expression of hCAP18/LL-37 was further confirmed using SDS-PAGE Western blotting and immunofluorescence staining. In conclusion, we demonstrate that IL-13 induces vitamin D-dependent hCAP18/LL-37 expression, most likely by increasing CYP27B1. These data suggest that Th2 cytokines regulate the vitamin D metabolic pathway in bronchial epithelial cells.

Altered hemoglobin-oxygen affinity with long-term propranolol therapy in patients with coronary artery disease.

Pharmacologic agents that alter hemoglobin affinity for oxygen may affect systemic or myocardial oxygen delivery. In vitro, and in normal man propranolol shifts the oxyhemoglobin equilibrium curve to the right, thus increasing the partial pressure of oxygen at which hemoglobin is 50% saturated (P50) and enhancing oxygen delivery. The effect of propranolol on hemoglobin P50 was evaluated in 12 patients with angina pectoris and documented coronary artery disease. Determinations were made during oral propranolol therapy (mean daily dose 152 mg) of at least 3 months' duration and after administration of propranolol had been discontinued for at least 4 days. Hemoglobin P50 and erythrocyte 2,3-diphosphoglycerate (DPG) were measured. Data in 12 patients were: the mean P50 after discontinuation of propranolol was 28.2 mm Hg+/-0.9 (standard error of the mean) and during propranolol therapy 31.7+/-0.7; P less than 0.001; red blood cell 2,3-DPG did not change to explain the increase in P50. This demonstrated shift could increase systemic oxygen delivery and thus benefit marginally perfused myocardium while sparing coronary flow. Propranolol, in addition to its negative chronotropic and inotropic effects, may increase tissue oxygen delivery in patients with the anginal syndrome.

Bronchial matrix and inflammation respond to inhaled steroids despite ongoing allergen exposure in asthma.

BACKGROUND: Inflammatory and structural changes of the airway mucosa are chronic features of asthma. The mechanisms underlying these changes and their modulation by steroid prophylaxis have not been clarified. OBJECTIVE: We postulated that asymptomatic ongoing allergen exposure could drive airway inflammation as well as changes in the extracellular matrix (ECM), and that inhaled steroids could prevent this. METHODS: Therefore, we exposed patients with mild asthma to 2 weeks of repeated low-dose allergen, with concomitant inhaled steroid or placebo treatment. Bronchial biopsies, which were taken before and after this exposure, were stained and digitally analysed. The ECM proteins in asthmatics were also compared with a normal control group. RESULTS: Low-dose allergen exposure alone resulted in a significant increase of bronchial epithelial macrophages. Despite ongoing allergen exposure, inhaled steroids reduced the numbers of mucosal eosinophils, neutrophils and T lymphocytes. At baseline, the mean density of the proteoglycans (PGS) biglycan and decorin were, respectively, higher and lower in the bronchial mucosa of asthmatics as compared with normal controls. Steroid treatment, during allergen exposure, increased the mean density of the PGS biglycan and versican. CONCLUSION: We conclude that chronic allergen exposure induces inflammatory changes in the bronchial mucosa. Despite ongoing allergen exposure, steroid treatment decreases mucosal inflammatory cells while altering PG density. The latter observation highlights the need to examine steroid-induced changes closely in the airway structure in patients with asthma.

Cerebral echinococcal cyst demonstrated on radionuclide angiogram: case report.

A cerebral echinococcal cyst was detected by cerebral radionuclide angiography as a large avascular mass. Static brain scans did not show the abnormality, emphasizing the diagnostic value of the dynamic phase of the study.

Bleeding simulated by the distal internal pudendal artery stain.

A capillary and venous phase blush in the region of the distal branches of the internal pudendal artery that simulates bleeding can sometimes be seen on arteriograms of male patients who are not bleeding. We describe five such cases. Correct identification of this pooling of contrast material is important to avoid unnecessary treatment by transcatheter embolization or by infusion of vasoactive drugs.

Computed tomography of focal hepatic lesions: a blind clinical evaluation of the effect of contrast enhancement.

Hepatic CT scans in 61 consecutive patients with proved liver metastasis performed both before and after administration of contrast medium were subjected to blind analysis by two observers. In 10 patients (16%) hepatic lesions were better defined before CE and focal hepatic lesions were diagnostically visible only before CE in 8 patients (13%). Lesions were better defined following CE in 16 patients (26%) but in only 2 cases (3%) were lesions diagnostically visible only after CE. The majority of lesions [35 (58%)] were equally well visualized before and after CE.

Correlation of early neurologic outcome and CT findings in neonatal brain hypoxia and injury.

Ninety cranial computed tomography scans were analyzed in 56 high risk neonates (30 premature and 26 term). Neurologic follow-up averaging 18 months in length was obtained. Four types of intracranial hemorrhage were seen: subdural (with three subtypes), germinal matrix--intraventricular, primary subarachnoid, and cerebellar. The four types differ in age of occurrence, mechanism, and prognosis. Mild periventricular low density was present in most of the neonates and did not correlate with future neurologic deficit. Severe periventricular leukomalacia (16%) and cortical low density zones (12%) at 40 weeks did correlate with abnormal motor and mental development.