HLA-DQB1 0602 allele is associated with splenomegaly in Japanese sarcoidosis.

OBJECTIVES: The association between HLA class II alleles and susceptibility to sarcoidosis is well documented. Further, the HLA-DRB1 15 and DQB1 0602 haplotype has been considered as a marker for both chronic and severe disease. Splenomegaly has been proposed as a marker for severity and activity in sarcoidosis, although its functional mechanism is unknown. In other diseases, HLA class II alleles can be markers for splenomegaly. We therefore set out to test the hypothesis that the primary DRB1 15-DQB1 0602 link in sarcoidosis would be to splenomegaly. DESIGN AND SUBJECTS: We performed abdominal ultrasonography to evaluate the prevalence and extent of splenomegaly and genotyped for HLA-DRB1 and DQB1 using allele or allele group specific primers in polymerase-chain-reaction on 138 Japanese sarcoidosis patients as case comparison study. Furthermore, we explored their relationship with other clinically important indices, e.g. chest radiograph stage, serum angiotensin-converting enzyme (ACE) concentration and duration of disease. RESULTS: Splenomegaly was detected in 37 (26.8%) sarcoidosis patients. DQB1 0602 showed associations with splenomegaly (P < 0.0001) and longer disease duration (P = 0.007). In addition, higher chest radiograph staging was associated with both DQB1 0602 (P = 0.02) and splenomegaly (P = 0.003). The presence of splenomegaly was associated with higher serum ACE concentration (P < 0.0001). CONCLUSION: We conclude that in the Japanese population the primary association of HLA class II DQB1 0602 is with splenomegaly. This allele is also a marker for chronicity and lung disease severity. On the other hand, the presence of splenomegaly is a marker for severity and activity. Further studies are needed to explore the relationship between splenomegaly and sarcoidosis in other ethnic groups and its association with HLA-DQB1 0602.

Liver targeting of interferon-beta with a liver-affinity polysaccharide based on metal coordination in mice.

Frequent and high-dose i.v. injections of interferon-beta (IFN-beta) have been used clinically to treat patients with viral hepatitis despite various side effects. Because side effects are caused by the systemic effects of IFN-beta, the purpose of this study was to target the drug specifically to the liver, thus reducing the adverse events. A chelating residue, diethylenetriaminepentaacetic acid (DTPA), was introduced to pullulan, a water-soluble polysaccharide with a high affinity for the liver. Murine IFN-beta could be coordinately conjugated with the DTPA-pullulan by simple mixing in an aqueous solution containing zinc ion (Zn2+). Intravenous injection of the IFN-beta-DTPA-pullulan conjugate with Zn2+ coordination enhanced liver induction of an antiviral enzyme, 2',5'-oligoadenylate synthetase (2-5AS), to a greater extent than that by free IFN-beta, although the 2-5AS levels in the liver depended on the mixing ratio of the IFN-beta/DTPA residue of DTPA-pullulan/Zn2+. In addition, the duration of the liver 2-5AS induction by the IFN-beta-DTPA-pullulan conjugate with Zn2+ coordination was longer than that by free IFN-beta. The liver targeting of IFN-beta by DTPA-pullulan with Zn2+ coordination may be a promising IFN therapy.

Ultrasonographic arterial portography with second harmonic imaging: evaluation of hepatic parenchymal enhancement with portal venous flow.

Ultrasonographic arterial portography was evaluated with second harmonic and conventional gray scale imaging after the administration of 0.001 to 0.1 ml/kg of FS069 (Optison) in 10 dogs (four dogs with ligation of the portal vein branch) and two woodchucks with hepatocellular carcinomas. Harmonic imaging was required to obtain good liver parenchymal enhancement for ultrasonographic arterial portography to be useful. The tumors were visible as regions of greater enhancement after intravenous injection and as hypoechoic regions after superior mesenteric artery injection. The segments with portal vein ligation were not detected after intravenous injection but were clearly seen after superior mesenteric artery injection. Doppler signal measurement verified a significant difference between the portal vein and hepatic vein after superior mesenteric artery injection and in the femoral artery after intravenous versus superior mesenteric artery injection, demonstrating that minimal levels of FS069 pass through the liver.

A bioassay for serum interferon based on induction of 2'5'-oligoadenylate synthetase activity.

We have developed a bioassay for interferons (IFN) based on measuring the amounts of 2',5' oligoadenylate synthetase (2-5AS) induced in cells of the THP-1 monocyte line in response to IFN. The assay can be completed in 20 h, gives reproducible results, and is at least 50 times more sensitive to IFN-alpha than conventional cytopathic effect inhibition antiviral assays. It is, respectively, less and much less sensitive to IFN-beta and IFN-gamma. The presence of preexisting 2-5AS activity in a sample does not influence the results. We have used this assay to measure very low levels (0.1-0.5 IU/ml) of endogenously formed IFN-alpha in serum samples from patients with various diseases and also to measure the residual small amounts of IFN-alpha still present in the serum as late as 48 h after an i.m. injection of 3 million IU, which is appreciably later than in previous methods. Thus, our highly sensitive assay offers considerable advantages, not least in relation to the clinical use of IFN.

Sonographic detection of tumor blood flow using a new contrast agent in woodchuck hepatomas.

The aim of this study was to assess the ability of perfluoropropane-filled albumin microspheres to visualize tumor blood flow in woodchuck hepatomas. Ten tumors in five woodchucks with hepatomas were imaged before and after intravenous injection (dosages of 0.01 ml/kg to 2.0 ml/kg) of an agent using color Doppler sonography and gray scale ultrasonography. Both enhanced imaging modalities demonstrated blood flow around and within all tumors. Enhanced gray scale ultrasonography demonstrated sonographic "tumor blush" in seven tumors (70%). In conclusion, tumor blood flow in woodchucks was visualized more clearly using the agent on both color Doppler and gray scale ultrasonography.

Gray-scale second harmonic imaging of the liver with galactose-based microbubbles.

RATIONALE AND OBJECTIVES: The authors evaluate the efficacy of SHU 508A, a galactose-based contrast agent used in gray-scale second harmonic imaging in vitro and in vivo experiments. METHODS: A Toshiba prototype harmonic imaging system (2.5/5.0 MHz) was used with SHU 508A in a phantom experiment and to image the liver in five healthy rabbits and one rabbit that had VX-2 tumors in the liver. RESULTS: In the second harmonic imaging, most of the fundamental components of the backscattered echo were eliminated, and good images with high contrast were obtained in the phantom experiment. Liver parenchyma was enhanced clearly in all rabbits at 0.3 mL/kg, an effect that lasted for 90 seconds. The tumor, which was mostly necrotic, was depicted clearly as a negative enhanced area surrounded by enhanced healthy liver. CONCLUSIONS: Gray-scale second harmonic imaging is a promising new method for visualization of perfusion of organs.

Gray scale second harmonic imaging of the liver: a preliminary animal study.

Gray scale second harmonic imaging (2.5 MHz/5.0 MHz) was evaluated in preliminary animal studies with a new ultrasound contrast agent (FS069). FS069 was administered intravenously in 10 rabbits (6 with normal liver, and 4 with implanted VX-2 tumors) and two woodchucks with hepatocellular carcinomas. The vasculature (including tumor vessels) and liver parenchyma were clearly enhanced at a low dosage (optimal dose was from 0.1 to 0.2 mL/kg) in all cases. Enhancement was reproducible and generally dose-dependent. Tumors were enhanced well during the early phase and tumor enhancement disappeared earlier than that of surrounding normal liver. Arterial phase and portal phase were easily distinguished and patterns of enhancement were diagnostic of the tumors. Gray scale second harmonic imaging is useful in the detection of hepatic tumors and in diagnosis of their hemodynamics.

Influence of spontaneous portosystemic collateral pathways on portal hemodynamics in living-related liver transplantation in children. Doppler ultrasonographic study.

We investigated the influence of spontaneous portosystemic collateral pathways on the portal hemodynamics and examined the necessity for ligating these vessels in pediatric liver transplantation from living donors. We assessed portal blood flow before, during, and after surgery in 82 pediatric recipients (mean age, 4.2 years), using Doppler ultrasonography. When blood flow in the reconstructed portal vein was decreased (< 10 ml/min/kg body weight) and portosystemic collaterals persisted during surgery, those vessels were ligated and Doppler flowmetry was examined again. Spontaneous portosystemic collaterals were detected at one or more sites in 67 patients before transplantation. These collaterals had been ligated in 17 patients before intraoperative flowmetry. Among the remaining 50 patients, initial Doppler studies revealed a decrease in portal blood flow in 22 patients. Nine patients had hepatofugal splenic venous flow and 6 had no significant flow signals from the intrahepatic portal vein. Ligation of collaterals resulted in a remarkable increase in portal blood flow in 20 patients, all of whom are alive. The remaining 2 patients died of graft failure due in part to portal hypoperfusion. On the other hand, the collaterals were not ligated in 24 patients because adequate portal blood flow was confirmed by intraoperative flowmetry. Postoperatively, flow signals from the unligated collateral vessels gradually diminished, but they still persisted in 3 patients at 12 months after transplantation. Hepatofugal blood flow through the portosystemic collateral pathways may persist after implantation of a normal graft. If the patent collaterals significantly reduce the effective portal blood flow, these vessels should be ligated in order to avoid graft failure.