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.     

Permeation of PEO-PBLA-FITC Polymeric Micelles in Aortic Endothelial Cells

Purpose. To determine aortic endothelial cells permeation ability and mechanisms of the aqueous block copolymeric micelles, poly(ethylene oxide)-poly ((-benzyl L-aspartate) (PEO-PBLA) chemically conjugated with fluroescein isothiocyanate (FITC) by transport study and confocal laser scanning microscopy. Methods. The block copolymers' PEO-PBLA-FITC was first synthesized and characterized by gel permeation chromatography (GPC) reflect index, UV, fluorescence detectors, and critical micelles concentrations (CMC), and atomic force microscopy (AFM). Permeation ability and mechanisms of polymeric micelles in aortic endothelial cells were evaluated by incubating with NaF, NaN₃, wortmannin, cytochalasin B inhibitors, at 20°C, and under reverse conditions. FITC and latex particles (40 nm) were also used for comparison of transport ability. The extent of localization of uptake polymeric micelles was established by confocal laser scanning microscopy. Results. The size of the aqueous PEO-PBLA-FITC polymeric micelles was detected at around 56 nm with unimodal distribution by AFM. The CMC test revealed the fluorescence intensity increased to around 0.01 0.05 mg/ml. NaF, NaN₃, wortmannin, cytochalasin B, 20°C, and reverse experiments inhibited the absorption of polymeric micelles through aortic endothelial cells with apparent permeability coefficients (P) of 18.07 ± 1.03 to 12.98 ± 0.93, 11.31 ± 0.77, 12.44 ±1.23, 6.40 ± 0.23, 11.11 ± 0.46, and 10.22 ± 1.09 X 10^–7 cm/sec, respectively. Also, the permeation of FITC and latex on aortic endothelial cells was 70.02 ±4.71, and 2.05± 0.41 X 10^–7 cm/sec, respectively. Confocal laser microscopy showed that fluorescent compounds were distributed in the intracellular cytoplasm and nucleus. Conclusions. PEO-PBLA-FITC copolymeric micelles in an aqueous system were transported by energy-dependent endocytosis with 18.07 X 10^–7 cm/sec penetrated range and were localized on intracellular and nucleus endothelial cells.     

Prevalence of antibodies to hepatitis C virus in the hemodialysis unit.

An enzyme immunoassay was used to detect antibodies to hepatitis C virus (anti-HCV) in 261 patients and 69 staff members of a hemodialysis unit. The prevalence of anti-HCV was 46.7% in patients and 2.9% in staff members (p less than 0.001). The prevalence of anti-HCV increased significantly with increasing duration of hemodialysis (p less than 0.001), but was not related to age, sex, history of blood transfusion, status of hepatitis B or hepatitis A virus infection, or serum ALT. Patients with hepatitis episode increased with increasing duration of hemodialysis and showed a significantly higher prevalence of anti-HCV than those without (63.1 vs. 34.7%, p less than 0.001). The prevalence of anti-HCV in patients with hepatitis also increased with increasing duration of hemodialysis (p = 0.05). Thus, HCV appears to be the major cause of hepatitis in hemodialysis patients. Besides strict infection control measures, further studies are needed to determine the mode of HCV infection and its prevention in the hemodialysis unit.     

Treatment of chronic hepatitis B virus infection: who,when, what for and how

Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its worldwide distribution and possible adverse sequelae. It is particularly important in the Asia–Pacific region where HBV infection is highly prevalent and usually acquired perinatally or in early childhood. It is now known that chronic HBV infection is a dynamic interaction between virus, hepatocyte and the host’s immune response. The natural history of chronic HBV infection can be divided into three phases: high replicative or viraemic ‘immune tolerance phase’ followed by ‘immune clearance phase’ and then the low replication ‘residual phase’. The clinical course of chronic HBV infection is characterized by a series of exacerbations and remissions during the ‘immune clearance phase’, which may lead to hepatic decompensation, progression of liver disease, development of cirrhosis and hepatocellular carcinoma (HCC). It is of paramount importance to arrest HBV replication as early as possible to reduce infectivity, improve hepatic injuries, prevent progression to cirrhosis or HCC and thereby prolong survival. There are many potentially effective agents with different mechanisms of action and there is substantial accumulated experience with these therapies, but there is also still a need for practical recommendations such as: (i) who should be treated; (ii) when to treat such patients; (iii) which drug(s) or strategy would be most cost‐effective for the patient under consideration; (iv) how the patient should be monitored; (v) what benefit the patient can expect from such treatments; (vi) what can be done for special groups of patients, such as decompensated cirrhosis immunocompromised patients or children; and (vii) what treatment of chronic HBV infection could be expected in the 21st century. The Asia–Pacific region not only has the greatest number of patients with chronic HBV infection, but also has conducted important clinical trials. It is relevant and mandatory to coordinate all current knowledge to reach a consensus and to make guidelines for the treatment of chronic HBV infection in this region.     

Subpopulations of intrathyroidal lymphocytes in Graves' disease

Subsets of T- and B-lymphocytes were immunophenotyped in frozen thyroid tissues from 20 patients with Graves' disease by using the avidin-biotin-complex peroxidase method. A panel of B- and T-cell monoclonal antibodies were employed to detect the subsets of T cells, activated T cells, natural killer cells and B cells. Serum thyroglobulin and microsomal antibodies were also measured simultaneously from both the thyroid vein and the peripheral vein in 9 patients. The quantitative results found that an almost equal ratio of lymphocytes stained positively for Leu 3a (CD4) and T8 (CD8) in almost all specimens. Activated lymphocytes expressing T9, T10, and Tac (CD25) were sporadically noted in the interstitial areas. The lymphoid aggregates and follicles were B cell clusters. Natural killer cells appear to play an insignificant role in Graves' disease. The thyroid epithelial cells expressed HLA-DR (Ia+) and HLA-ABC, suggesting a possible localized immune reaction between antigen-presenting thyroid epithelial cells and lymphocytes. The titers of serum thyroglobulin and microsomal antibodies from either the thyroid vein or the peripheral vein showed no definite correlation with the lymphoid distribution of the thyroid tissues, implying that the in situ or local immunologic reaction may not reflect the status of systemic antibody production. The immunologic mechanism and pathogenesis of Graves' disease is reviewed and discussed.     

Serum immunosuppressive acidic protein levels in blackfoot disease patients and cancer patients

Immunosuppressive acidic protein (IAP) was first found in the ascitic fluids of cancer patients. Its biochemical properties are significantly different from those of acidic protein in the serum of normal persons. Previous studies have indicated that the serum IAP concentration increases in most cancer patients and decreases to a normal level as such patients are cured. Therefore, it has been suggested as a useful marker for follow-up in operated cancer patients. In this study, analyses and comparisons of serum IAP concentrations have been made among 53 normal persons in Blackfoot disease endemic areas, 25 patients with diabetes, cataracts, hypertension and cardiovascular disease in Blackfoot disease endemic areas, 50 breast cancer patients, 13 colorectal cancer patients, and 18 Blackfoot disease patients. Serum IAP concentrations were found as follows: 454 +/- 138 micrograms/ml for normal subjects and 499 +/- 132 micrograms/ml for disease patients in Blackfoot disease endemic areas; 520 +/- 149 micrograms/ml for breast cancer patients; 864 +/- 341 micrograms/ml for colorectal cancer patients and 950 +/- 368 micrograms/ml for Blackfoot disease patients. Serum IAP concentrations were much higher in Blackfoot disease patients, than in normal persons in Blackfoot disease endemic areas (p less than 0.001), and as high as in colorectal cancer patients. In Blackfoot disease patients, the mean serum IAP concentration of 6 patients coming from the Blackfoot disease endemic areas was as high as 1,238 +/- 404 micrograms/ml, showing a positive rate of 100% to IAP (i.e. IAP concentration exceeds 500 micrograms/ml). We conclude that serum IAP assay of Blackfoot disease patients may be useful for prognosis and therapeutic monitoring.     

THR Simulator – the software for generating radiographs of THR prosthesis

Background  

Measuring the orientation of acetabular cup after total hip arthroplasty is important for prognosis. The verification of these measurement methods will be easier and more feasible if we can synthesize prosthesis radiographs in each simulated condition. One reported method used an expensive mechanical device with an indeterminable precision. We thus develop a program, THR Simulator, to directly synthesize digital radiographs of prostheses for further analysis.