Digoniodiol, deoxygoniopypyrone A, and goniofupyrone A: three new styryllactones from Goniothalamus amuyon

Three new styrylpyrone analogues, digoniodiol (2), deoxygoniopypyrone A (3), and goniofupyrone A (4), along with ten known styryllactones, were isolated from the aerial parts of Goniothalamus amuyon. Among these compounds, 2 is the first example of a bis-styrylpyrone. Compound 4 represents a new skeleton for styryllactones. All structures were established on the basis of spectroscopic data. The stereochemistry of 2 and 4 was determined by X-ray crystallographic analysis. The absolute configuration of 3 and 4 was further confirmed by Mosher ester derivatives. All styryllactones were subjected to cytotoxicity assays. Among them, goniothalamin, goniothalamin epoxide, and 8-chlorogoniodiol showed significant cytotoxicity against the HepG2 cancer cell line with IC50 in the range of 0.19 - 0.64 microg/mL, and moderate activity toward Hep3B, MDA-MB-231, and MCF-7 cancer cell lines.     

Peritonitis caused by Aspergillus sydowii in a patient undergoing continuous ambulatory peritoneal dialysis

We describe a patient who received continuous ambulatory peritoneal dialysis and developed catheter-related peritonitis caused by Aspergillus sydowii. Identification of A. sydowii was confirmed by the sequence analysis of the ribosomal RNA genes. The patient remained well after removal of the peritoneal catheter without administration of any anti-fungal agent.     

Increased Incidence of Fulminant Hepatic Failure in Previously Unrecognized HBsAg Carriers with Acute Hepatitis Independent of Etiology

Abstract Background: Previous studies have shown a high risk of fulminant hepatitis in HBsAg carriers with acute hepatitis. The etiology of acute hepatitis in HBsAg carriers was heterogeneous. This study aimed to correlate the incidence of fulminant hepatitis with the etiology in HBsAg carriers with acute hepatitis. Patients and Methods: The incidence of fulminant hepatitis was studied in 334 adults hospitalized for overt acute viral hepatitis. There were 12 patients with acute hepatitis A, 17 with acute hepatitis B, 70 with acute hepatitis C, five with acute hepatitis E, 53 with acute hepatitis non-A-E, and 177 previously unrecognized HBsAg carriers with acute hepatitis (patients who were positive for HBsAg but negative for IgM antibody against hepatitis B core antigen). Of the latter, 64 (36%) had serological evidence of non-B hepatotropic virus superinfection. Results: The incidence of fulminant hepatitis was 3.2% (5/157) in patients with acute hepatitis A, B, C, E or non-A-E, and 20.3% (36/177) in HBsAg carriers with acute hepatitis (p < 0.001). HBsAg carriers were at a 9-fold increased risk of fulminant hepatitis than noncarriers. Among HBsAg carriers with acute hepatitis, the incidence of fulminant hepatitis showed no significant difference between patients with viral superinfection (23% or 15/64) and those without (19% or 21/113). The incidence of fulminant hepatitis in HBsAg carriers with viral superinfection also showed no significant difference between different etiologies of virus superinfection. Conclusion: There is a 9-fold increased risk of fulminant hepatitis in HBsAg carriers with acute hepatitis, independent of the underlying etiology.     

Laparoscopic photodynamic diagnosis of ovarian cancer using 5-aminolevulinic acid in a rat model

OBJECTIVE: The objective of this study was to determine the efficacy and sensitivity of laparoscopic photodynamic diagnosis to detect 5-aminolevulinic acid (ALA)-induced fluorescent tumors in an animal model. METHODS: Cancer cells were injected into the peritoneum of rats to induce peritoneal carcinomatosis. After 3-4 weeks, ALA was administered to establish fluorescence in tumor nodules. All intraperitoneal surfaces were inspected using fluorescence and white light laparoscopy. Suspicious lesions were then biopsied in vivo under either fluorescence or white light laparoscopic guidance. Fluorescence intensities of the cancerous lesions compared to normal tissues were determined. A pathologist blinded to our clinical impression analyzed all biopsied specimens. We compared the sensitivity of fluorescence and white light laparoscopic-guided detection of cancerous lesions and determined the clinical utility of fluorescent photodynamic diagnosis in detecting metastatic ovarian cancer. RESULTS: Forty-three biopsies were performed in vivo under laparoscopic fluorescent guidance and 42 biopsies were taken using white light in various regions of the peritoneal surface from nine rats. Ten biopsies were also removed from nonfluorescent regions as nontumor controls. Cancerous lesions showed significantly higher fluorescent intensity compared to noncancerous lesions. Cancerous lesions that were difficult to differentiate from normal surrounding tissue under white light conditions were clearly detected by ALA-induced fluorescence. The average size of these metastatic lesions biopsied under fluorescent light was 1.0 mm (range: 0.3-2.5) compared to 1.5 mm (range: 0.5-2.9) with white light illumination (P < 0.05). CONCLUSIONS: Fluorescent laparoscopic detection of micrometastatic ovarian cancer using ALA is significantly more sensitive than white-light laparoscopy in detecting smaller cancerous lesions in an ovarian cancer rat model. Human trials are indicated.     

Detection and diagnosis of oral cancer by light-induced fluorescence

BACKGROUND AND OBJECTIVE: New techniques for non-invasive early detection and diagnosis of oral dysplasia and carcinoma are required. Our objective was to determine in the hamster cheek pouch model whether differentiation between the healthy tissue and the different stages of oral premalignancy and malignancy is possible using laser-induced fluorescence after tissue exposure to 5-Aminolevulinic acid (ALA). STUDY DESIGN/MATERIALS AND METHODS: DMBA carcinogenesis was applied to one cheek pouch in 18 hamsters for 0-20 weeks. Prior to sacrifice, 20% ALA was applied to the cheek tissues. Excised cheek tissues were cryosectioned and imaged using fluorescence microscopy with excitation at 405 nm, detection at 635 nm. After fluorescence measurement, H&E staining and histopathological evaluation were performed. RESULTS: Fluorescence intensity was significantly lower in healthy tissue than in pathological tissues. Significantly higher intensities and more "fluorescence hot spots" occurred in severe dysplasia and carcinoma than in healthy tissue, hyperkeratosis, mild and moderate dysplasia. CONCLUSIONS: Light-induced fluorescence after ALA exposure can differentiate between the different stages of premalignancy and malignancy. Its ability to differentiate between healthy tissue and early pathology is particularly interesting     

Polymorphisms in XRCC1 and glutathione S-transferase genes and hepatitis B-related hepatocellular carcinoma

Chronic infection with hepatitis B virus (HBV) causes DNA damage. An arginine (Arg)-to-glutamine (Gln) polymorphism at codon 399 in the XRCC1 gene is putatively associated with DNA damage. In a case-control study of 577 HBV surface antigen carriers with hepatocellular carcinoma (HCC) and 389 HBV carrier control subjects, we investigated the association between this polymorphism and the risk of HCC and assessed whether this association varied with glutathione S-transferase (GST) status; GSTs are involved in carcinogen metabolism. All statistical tests were two-sided. The XRCC1 Gln allele was associated with a dose-dependent increased risk of early-onset HCC (<50 years) but not with the risk of late-onset HCC (P(trend) =.01). The GSTT1-null genotype alone did not affect risk, but the GSTM1-null genotype was associated with a decreased risk for early-onset HCC. Various combinations of GSTM1 and GSTT1 genotypes differentially modified the association of XRCC1 with HCC (P(interaction) =.005); e.g., for individuals with the GSTT1-null/GSTM1-present genotype, the risk of HCC was greater for those with the Gln/Gln genotype (odds ratio = 8.07, 95% confidence interval = 1.67 to 38.93) than for those with the Arg/Arg genotype. Thus, GST status appears to affect the risk of HCC associated with this XRCC1 polymorphism.     

Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk

Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Estrogen may play some role in the development of HCC. We conducted a multicenter case-control study to evaluate the effects of reproductive factors on HCC risk, and to assess whether the association between each factor and HCC differs between hepatitis B surface antigen (HBsAg)-positive and -negative women, in which hepatitis C virus (HCV) is the major cause of HCC. The study included 218 women with HCC and 729 control women selected from nonbiological and first-degree female relatives of patients with HCC. The risk of HCC was inversely related to the number of full-term pregnancies (FTP) (P(trend) =.0216) and age at natural menopause (P(trend) =.0251 among women aged 45-55 without prior surgical menopause). Oophorectomy at age or=16 years), which increased HCC risk in HBsAg carriers (multivariate-adjusted OR, 6.96; 95% CI, 2.52-19.18) but posed no increased risk in noncarriers (P(interaction) =.0053). In conclusion, increased exposure to estrogen during adulthood may provide a protective effect against HCC. Nevertheless, an early menarche, which results in early estrogen exposure, does not confer protection for HBsAg carriers.     

Doctors' perceptions and attitudes to prescribing within the Authority Prescribing System

OBJECTIVE: To examine doctors' perceptions and attitudes to prescribing within the Authority Prescribing System (APS). DESIGN AND SETTING: Questionnaire survey of Australian doctors' responses to a number of statements and factorial vignettes, conducted between 1 May and 30 June 2001. PARTICIPANTS: A national random sample of 1200 doctors, stratified according to specialist/generalist, rural/urban and high/low prescriber: 669 (56%) responded. MAIN OUTCOME MEASURES: Self-reported perceptions of the APS and attitudes to prescribing within the APS. RESULTS: 72% of doctors agreed that the APS makes effective medications available to the socioeconomically disadvantaged members of the Australian public and 50% agreed that it compromises patient privacy. Fewer agreed that authority indicators were based on the highest quality of evidence quality (40%) or medication safety (12%). Doctors placed more emphasis on the doctor-patient relationship than on the criteria for authority prescribing in their decisions about prescribing APS medications. Doctors who used computers to prescribe were more likely to agree that computers can improve the authority prescribing process. CONCLUSIONS: This study suggests that authority-required prescribing is not achieving the stated aims of the National Medicines Policy in reducing variability in prescribing. Strategies to improve the quality of prescribing must consider the professional and ethical conundrum associated with prescribing outside of PBS/APS approved use for clinical and patient-centred reasons.     

Unintentional rechallenge resulting in a causative relationship between ketoconazole and acute liver injury

We present the case of a female patient in whom acute overt hepatitis developed after 60 days of ketoconazole administration (200 mg/day). A prompt renewed hepatic injury 48 hours after an unintentional rechallenge 30 months later provided definitive evidence for a causative relationship between ketoconazole and acute liver injury. Histological examination revealed acute hepatitis with bridging hepatic necrosis. Clinicians should be aware of this cause and effect relationship between ketoconazole and acute liver injury, which can result in prompt severe acute liver injury after rechallenge.     

Intravitreal VEGF and bFGF produce florid retinal neovascularization and hemorrhage in the rabbit

PURPOSE: Vascular endothelial growth factor (VEGF) causes widespread retinal vascular dilation, produces breakdown of the blood-retinal barrier, and is implicated in ocular neovascularization (NV). Basic fibroblast growth factor (bFGF) also has been implicated in the production of ocular NV. This study was performed to investigate the ability of simultaneous sustained intravitreal release of both VEGF and bFGF to induce robust retinal NV in the rabbit. METHODS: Intravitreal implantation of sustained-release Hydron polymeric pellets containing both 20 microg of VEGF and 20 microg of bFGF was performed on adult male Dutch belted rabbits. In other animals either 20 microg or 50 microg bFGF-containing pellets was implanted intravitreally; also, either 20 microg VEGF or 50 microg VEGF-containing pellets was implanted. Control rabbits received either blank polymeric pellets or a pellet containing 30 microg bovine serum albumin. Eyes were examined by indirect ophthalmoscopy after surgery at 24 hrs, 48 hrs, 4 days, 7 days, 14 days, 21 days, and 28 days. Findings were documented by color fundus photography and fluorescein angiography (FA). Eyes were enucleated and prepared for histologic analysis at 28 days following intravitreal implantation of the VEGF/bFGF-containing pellets. RESULTS: In all eyes implanted with VEGF/bFGF pellets, dilation and tortuosity of existing blood vessels were observed within 48 hrs after pellet implantation. The progression of retinal vascular changes was rapid and occurred over the entire optic disk and medullary rays between 4 and 7 days. Hemorrhage occurred as early as 14 days after VEGF/bFGF pellet implantation. In eyes with massive hemorrhage, total traction retinal detachment developed after the second week. The presence of abnormal tissues at the vitreo-retinal interface within 28 days was demonstrated by light microscopy while FA showed profuse leakage of dye from anomalous vessels within the first week. Neither bFGF-exposed eyes nor control eyes showed any vascular changes. Eyes that received only VEGF-containing pellets exhibited tortuosity of existing vessels, but neither hemorrhaging nor retinal detachment occurred. CONCLUSIONS: These results demonstrate that retinal vascular changes leading to hemorrhaging is produced rapidly in the rabbit by simultaneous intravitreal release of both VEGF and bFGF. Understanding how these growth factors induce retinal NV may suggest novel therapeutic treatment strategies.