Retreatment with interferon for chronic hepatitis C after transient response.

Approximately half of all patients with chronic hepatitis C show an initial biochemical response to interferon, but only 15% to 20% of patients achieve a sustained response. We studied the efficacy of retreatment with interferon for patients with chronic hepatitis C who showed transient biochemical responses to initial treatment. Thirty patients who relapsed were retreated 1 to 52 months (median 14) after the end of initial treatment, according to the previously used regimens. The responses were correlated with the pre-retreatment patient data. The liver histologic grades, compared with those found before the initial treatment, were better in eight (27%) patients but worse in six (20%), whereas the fibrosis stage was improved in five (17%) but worsened in eight (27%). All patients displayed end-of-retreatment biochemical responses. Of the 30 patients, 10 (33%) achieved sustained aminotransferase normalization and serum hepatitis C virus (HCV) RNA clearance, but the remaining 20 patients showed relapse within 1 year after cessation of retreatment. Univariate analysis associated the sustained response with low pre-retreatment viral loads (0.8 +/- 0.7 MEq/mL vs. 9.1 +/- 6.5 MEq/mL; p = 0.006), short treatment intervals (13 +/- 13 months vs. 22 +/- 14 months; p = 0.031), and low histologic grades (1.3 +/- 0.7 vs. 1.9 +/- 0.7; p = 0.039). However, multivariate analysis indicated that only the pre-retreatment viral load was predictive of the sustained response (p = 0.049). These findings suggest that transient responders to interferon are likely to respond to retreatment but the achievement of a sustained response depends on the HCV viral load before retreatment.

A novel strategy for cancer therapy by mutated mammalian degenerin gene transfer.

Mammalian degenerin (MDEG) is a member of the amiloride-sensitive sodium ion channel family, and its site-directed active mutant (MDEG-G430F) induces massive Na+ influx into cells, leading to cell ballooning and cell bursting. We attempted a novel therapeutic approach for gastric cancers by transferring MDEG-G430F into cancer cells using tumor-specific promoters. In carcinoembryonic antigen (CEA)-producing gastric cancer cells, the level of cell death observed when MDEG-G430F was used with a CEA promoter was similar to that observed when using a potent nonspecific promoter such as the cytomegalovirus promoter. In an in vivo study, fusogenic liposome complexes containing MDEG-G430F driven by the CEA promoter were injected intraperitoneally into CEA-producing gastric cancer cells in a mouse peritoneal dissemination model. Although all 15 of the control mice were dead by 50 days postinoculation, 13 of the 15 mice treated with MDEG-G430F survived. These results indicate that transferring MDEG-G430F into cancer tissues using tumor-specific promoters can achieve striking and selective cancer cell death irrespective of the transcriptional efficiency of the promoters used in vivo, and suggest that this approach is a promising new strategy for cancer gene therapy.

The clinical usefulness of liquid human growth hormone (hGH) (Norditropin SimpleXx in the treatment of GH deficiency.

Human growth hormone (hGH) is an essential therapeutic drug for the treatment of GH deficiency. The development of recombinant GH using a pen injection system has enabled easy and safe treatment of GH-deficient patients; however, the process of dissolving hGH in the powder form is complicated and dangerous. In this study, we investigated the usefulness of a newly developed liquid form of hGH (Norditropin((R)) SimpleXx(TM)) in the treatment of 51 patients with GH deficiency. Fifteen previously untreated patients with GH deficiency were treated with liquid hGH (group A), and 36 patients who had previously used hGH in the powder form were changed to the liquid form (group B). Both groups were treated with liquid hGH 0.5 IU/kg per week for 6 months. The growth rate of patients in group A increased from 4.0 +/- 2.4 cm/year to 9.2 +/- 2.9 cm/year. The patients in group B continued to grow at the same rate as before using the liquid hGH therapy. Questionnaires to the patients in group B demonstrated that 85% preferred the convenience of using the new liquid form of hGH. Our results indicate that liquid hGH has similar efficacy to that of powder hGH, but its improved convenience may have a beneficial effect on patient compliance.

Examination of synovial fluid and serum hyaluronidase activity as a joint marker in rheumatoid arthritis and osteoarthritis patients (by zymography).

OBJECTIVE: Hyaluronic acid (HA) is an important joint marker and the substrate for hyaluronidase (HAase). Synovial fluid (SF) and serum HAase were measured to investigate the potential use of HAase as a joint marker in rheumatoid arthritis (RA) and osteoarthritis (OA) patients. METHODS: The subjects were 39 patients with RA and 42 patients with OA. HAase activity was measured by zymography and its relation with various parameters examined statistically. RESULTS: In RA SF a positive correlation (r = 0.458, p = 0.0186) was found between SF HAase activity and the concentration of serum C reactive protein. A positive correlation (r = 0.45, p = 0.024) was also found between SF HAase activity and platelet count in the RA group. Serum HAase activity in the RA group was significantly higher than in the OA group (p < 0.0001) and normal controls (p < 0.0001). CONCLUSION: The results suggest that SF HAase activity could be used as a marker of synovial inflammation.

Thrombotic thrombocytopenic purpura developed suddenly during interferon treatment for chronic hepatitis C.

A 57-year-old man had abnormal hepatic function identified in April 1994. In October 1994, chronic hepatitis C was diagnosed. Based on the findings of a liver biopsy, administration of recombinant interferon (rIFN)-alpha2b was begun. In the 16th week of treatment, the patient experienced headache and fever and developed a markedly decreased, platelet count and hemolytic anemia. He was admitted on May 19, 1995 and thrombotic thrombocytopenic purpura (TTP) was diagnosed. He died on the 3rd hospital day. The causes of TTP have yet to be elucidated, but in this patient the occurrence of TTP appeared to be related to the IFN treatment for chronic hepatitis C.

New familial nephropathy involving glomerular and tubular basement membranes.

We describe two siblings, an 8-year-old boy and a 9-year-old girl, with severe mental retardation, dwarfism, optic atrophy and nephropathy. Laboratory examination showed beta 2-microglobulinuria, decreased creatinine clearance, hypercholesterolaemia and elevated serum levels of muscle enzymes. Renal biopsy from one of the patients demonstrated characteristic ultrastructural changes involving both the glomerular and tubular basement membrane. This group of symptoms and laboratory findings is quite distinct and differs from those of other reported familial nephropathy syndromes. We conclude that this disorder may represent a new syndrome of autosomal recessive inheritance.

Neurophysiologic dysfunction in hypomelanosis of Ito: EEG and evoked potential studies.

To evaluate neurological involvements in hypomelanosis of Ito (HI), we conducted electroencephalographic and evoked potential studies in 3 children with HI. Patient 1 presented with the West syndrome, and was severely handicapped. Patient 2 had mild mental retardation. Patient 3 appeared neurologically normal, but chromosome analysis showed a 46,XX/46,XX,12p + mosaic karyotype. EEGs of Patient 1 initially showed asymmetric hypsarrhythmia, and later diffusely increased fast waves, occipital dominant alpha rhythm plus multifocal spikes. Patients 2 and 3 had minimal and no EEG abnormalities, respectively. Brainstem auditory evoked potentials showed prolongation of wave I latency as well as I-III and I-V interpeak latencies in Patient 1, and prolonged wave I latency in Patient 3. Flash visual evoked potential studies disclosed a significant difference between the right and left latencies of wave IV in Patient 2. The fact that there were no specific EEG or evoked potential findings for HI seems to be consistent with the pathogenetically heterogeneous nature of this disorders. We emphasize the usefulness of neurophysiologic examinations in evaluating diverse CNS dysfunctions in HI patients.

Repair of bone defect with cultured chondrocytes bound to hydroxyapatite.

Cultured chondrocytes were bound to hydroxyapatite (HA) and implanted in surgically created bone defects in the ulna of the rabbit. Chondrocytes were obtained from the iliac crest cartilage of the rabbit and were cultured on the HA block for two weeks before implantation. Scanning electron micrographs showed that pores of the HA surface and the inside of the block were filled with cultured cells. After cultivation for two weeks, the expression of chondrocyte-specific characteristics was confirmed in these cells by an implanted diffusion of chondrocyte-specific characteristics was confirmed in these cells by an implanted diffusion chamber experiment. The HA without chondrocytes served as a control. At two weeks postimplantation, proliferating chondrocytes were observed on the surface and in the inside pores of the HA-chondrocyte blocks but not the HA controls. At four and six weeks postimplantation, in the central region of the implants, there was a significant increase in the amount of bone formation in the HA with cultured chondrocytes. At 13 weeks post-implantation, the implants were partially resorbed and completely enveloped in lamellar bone, including bone marrow.

Zonal and age-related difference in the amounts of creatine kinase subunits in cartilage.

Energy metabolism in cartilage may affect the morphogenetic events of skeletal growth. Investigating enzymes responsible for energy metabolism in cartilage, such as creatine kinase (CK), can provide clues to an understanding of pathogenesis and treatment of osteochondrodysplasias. In this study levels of CK subunits M (muscle type) and B (brain type) were measured by a highly sensitive enzyme immunoassay system in growth and resting cartilages of the rat rib at various ages. CK-M was predominant, but there was no statistically significant difference in its quantity of CK among cartilages of various ages or between resting and growth cartilage. In contrast, although CK-B levels were low, they showed a significant decrease with advancing age and a significant increase in growth cartilage as compared with resting cartilage. The results of this study suggest that CK in cartilage, especially CK-B, may play an important role in skeletal growth.

Longitudinal clinicoelectrophysiologic study of a case of Lafora disease proven by skin biopsy.

A longitudinal clinicoelectrophysiologic study was undertaken of a 15-year 2-month-old girl with Lafora disease who was diagnosed by skin biopsy and an immunohistochemical method with antisera against Lafora bodies. From age 10 years 5 months, 4 months after onset, EEG disclosed progressive deterioration of background activity and incremental increase in epileptic discharges. Photosensitivity was unique: Occipital spikes and diffuse spike-wave discharges were provoked by low-frequency repetitive photic stimuli but without elicitation of myoclonic seizures. Photosensitivity completely disappeared after age 13 years 10 months. High-voltage somatosensory evoked potentials (SEPs) and high-voltage flash visual evoked potentials (F-VEPs) were seen before age 13. After age 13, progressive prolongation of I-III and I-V interpeak latencies of auditory brainstem responses (ABRs), progressive prolongation of latencies of photoevoked eyelid microvibrations, delayed latencies of pattern-reversal visual evoked potentials, and a decrease in the V/I amplitude ratio of ABRs and the previously high F-VEP amplitudes were observed.

Histopathologic and biochemical analysis of classic Pelizaeus-Merzbacher disease.

An autopsy study of an 11-year-old boy with the classic type of Pelizaeus-Merzbacher disease is presented. He developed normally until 5 years of age when he began to deteriorate with scanning speech and gait abnormality. Auditory brainstem responses were normally preserved. At the age of 11 years, 8 months, he died of pneumonia while in a vegetative state. The neuropathologic findings suggested a typical classic type of Pelizaeus-Merzbacher disease and biochemical analysis of cerebral white matter demonstrated a decreased ratio of long-chain fatty acids (greater than or equal to C19) to short- and medium-chain fatty acids (less than C19). These findings suggested defective myelin synthesis as the etiology of Pelizaeus-Merzbacher disease; comprehensive classifications of the disease are expected to include both pathologic and biochemical parameters.