2'-,5'-Oligoadenylate synthetase response ratio predicting virological response to PEG-interferon-alpha2b plus ribavirin therapy in patients with chronic hepatitis C.

OBJECTIVE: Although all the mechanisms of elimination of hepatitis C virus (HCV) by Interferon (IFN) have not been fully elucidated, the 2'-5'-oligoadenylate (2-5A) system is one of the mechanisms of the antiviral effect of IFN. Consequently, the measurement of 2'-5'-oligoadenylate synthetase (2-5AS) activity could be useful for the evaluation of IFN treatment. This retrospective study was aimed at assessing whether 2-5AS activity functions as a clinical marker of virological response to PEG-interferon-alpha2b (PEG-IFN) plus ribavirin therapy of chronic hepatitis C. METHODS: The 32 patients included in this study had high viral loads of serum HCV-RNA of genotype 1b with chronic hepatitis C. All the patients received a regimen of PEG-IFN plus ribavirin for 48 weeks, and were then divided into two groups: one group (effective group) with undetectable serum HCV-RNA levels at 24 weeks (n = 22) of therapy, the other group (ineffective group) with persistent presence of HCV-RNA in serum at 24 weeks (n = 10). The 2-5AS activity in serum was measured 2, 8 and 12 weeks before initial administration. RESULTS: The 2-5AS response ratio (measured value/measured value of baseline 2-5AS) at 2, 8 and 12 weeks after the administration in the effective group was significantly higher than that in the ineffective group. CONCLUSIONS: These results suggest that the ratio of 2-5AS is closely related to the antiviral effect, and that the measurement of 2-5AS response ratio may be a useful clinical parameter of virological response to PEG-IFN plus ribavirin therapy of chronic hepatitis C.

Liver transplantation from an identical twin without immunosuppression, with early recurrence of hepatitis C.

Hepatitis C virus reinfection after liver transplantation is universal and more severe than in nontransplant patients. Rejection episodes and immunosuppressive agents are considered risk factors for deterioration of recurrent hepatitis C. We report 2 cases of living donor liver transplantation for patients with hepatitis C-related cirrhosis who received right-lobe grafts from an identical twin. Thanks to genetic identity, no immunosuppressive drugs were administered during or after transplantation without rejection. Hepatitis C virus RNA kinetics showed a rapid increase following transplantation and liver biopsies 1 month after transplantation showed acute lobular hepatitis in both cases. Antiviral therapy using interferon alpha and ribavirin was started immediately, and both cases showed virological and histological response. In conclusion, avoidance of immunosuppression did not delay hepatitis C recurrence following transplantation, while early antiviral therapy without risk of rejection or immunosuppression led to successful viral eradication.

Interferon-beta induction/interferon-alpha2b plus ribavirin therapy in patients with chronic hepatitis C.

Treatment of chronic hepatitis C virus (HCV) infection with interferon (IFN) and ribavirin improves the rate of eradication of the virus by less than 20% in patients with genotype 1b and a high viral load. In this study we assessed whether IFN-beta induction/IFN-alpha2b plus ribavirin enhances the efficacy of the therapy in patients with chronic hepatitis C. The efficacy of IFN-beta induction/IFN-alpha2b plus ribavirin therapy (group A, n=7) was compared with that of IFN-alpha2b plus ribavirin (group B, n=7) in 14 patients with high levels of HCV-RNA (> 100 K/U/ml). No significant differences were observed in the clearance of HCV-RNA between the two groups (A and B, respectively) 2 weeks after the start of the treatment (0% and 14.3%), at the end of the treatment (71.4% and 100%) and 6 months after the end of the treatment (28.6% and 14.3%). Recovery was complete in 28.6% and 14.3%, transient in 42.9% and 85.7% and absent in 28.6% and 0% in groups A and B, respectively. Early log changes in the viral load from the baseline after 2 weeks of treatment were 2.41 +/- 0.91 and 2.77 +/- 0.20 in groups A and B, respectively, with no significant difference between the two groups. In the present study, we were not able to demonstrate that IFN-beta induction/IFN-alpha2b plus ribavirin therapy was superior to IFN-alpha2b plus ribavirin therapy in patients with genotype 1b and high viral loads.

The effectiveness of anti-retroviral drug therapy for HIV-1 is associated with HIV-1 proviral DNA levels and viral selection.

The effect of combination anti-retroviral therapy regimens on HIV-1 proviral DNA levels in peripheral blood mononuclear cells was examined in 12 HIV-1-positive patients, using endpoint dilution polymerase chain reaction and serial cloning, and sequencing of the gag region of HIV-1. The major clone was defined as the most numerous of 10 analysed clones, and observation periods ranged from 8 months to 32 months (mean 19.7 +/- 10.2 months). In five patients (one with primary-stage HIV-1 infection) receiving three anti-retroviral drugs, HIV-1 RNA reduced to undetectable levels (i.e. < or = 100 copies/ml). HIV-1 proviral DNA and the number of major clones reduced in four of these patients. HIV-1 RNA levels reduced, but remained detectable, in five other patients. In the two remaining patients (both receiving two rather than three anti-retroviral drugs), HIV-1 RNA levels increased. These results suggest that the population of major clones may be affected when HIV-1 RNA levels reduce following combination regimens of anti-retroviral therapy.

A reduction in the number of peripheral CD28+CD8+T cells in the acute phase of influenza.

Influenza patients show a high incidence of T lymphocytopenia in the acute phase of the illness. Since CD8+ T cells play an important role in influenza virus infection, we investigated which subset of CD8+ T cells was involved in this lymphocytopenia. CD8+ T cells from eight patients with influenza A were studied for lymphocyte count, surface marker, and intracellular IFN-gamma production in the acute (days 1-3) and recovery phases (days 9-12). Total and T lymphocyte counts in the acute phase were approximately three times less than in the recovery phase; however, the CD4/8 ratio was the same in both phases. The cell count reduction in the acute phase was attributed predominantly to the CD28+ CD8+ subset, compared with the CD28- CD8+ subset. The memory/activation marker CD45RO on the CD8+ T cells was assessed. The CD28+ CD45RO- subset, a naive phenotype, was reduced significantly in number in the acute phase compared with the recovery phase. The CD28+ CD45RO+ subset, a memory phenotype, was also reduced in the acute phase, but the reduction was not statistically significant. Intracellular IFN-gamma in the CD8+ subset after mitogenic stimulation was measured by flow cytometry; the percentage of CD28+ IFN-gamma-/CD8+ subset in the acute phase was significantly less than in the recovery phase. These results indicated that the predominant reduction of peripheral CD8+ T cells in the acute phase of influenza was from naive-type lymphocytes, suggesting that these quantitative and qualitative changes of CD8+ T cells in influenza are important for understanding the immunological pathogenesis.

[Surgical treatment for symptomatic arachnoid cysts].

During the period from 1983 to 1999, 12 patients with symptomatic arachnoid cyst were treated. The mean patient age was 20.6 years. The most common location was the middle fossa (10 cases). Initial CT scan revealed associated subdural hygroma in 7 patients and hydrocephalus in one. Clinical symptoms were related to increased intracranial pressure, cranio-megaly and seizure. One infant with a huge arachnoid cyst was treated, using a cystoperitoneal (CP) shunt. Four patients underwent membraectomy. Combination CP shunt and membraectomy was performed in 5 patients. The remaining 2 arachnoid cysts were complicated with subdural hygroma and, initially, they were observed conservatively, but hygroma gradually changed to hematoma. One was treated by irrigation and the other hematoma was spontaneously absorbed. Significant complications included extensive subdural effusion in one patient, contralateral chronic subdural hematoma in two, intracranial hypotension in two, and shunt dependency in one. There were no recurrences during the follow-up period (mean 3.6 years).

Migration of a lumboperitoneal shunt catheter into the spinal canal--case report.

A 50-year-old female suffered upward migration of a lumboperitoneal (LP) shunt catheter into the spinal canal, manifesting as disturbance of short-term memory. Revision of the shunt confirmed that the tube had migrated into the spinal canal. The tube was pulled back into the peritoneal cavity and attached firmly to the fascia with a new anchoring device. LP shunts have the advantages of technical simplicity and extracranial procedure, but firm fixation is recommended since movements of the spine may cause proximal tube migration.

TI-201 SPECT compared with histopathologic grade in the prognostic assessment of cerebral gliomas.

PURPOSE: Although TI-201 SPECT has been used to evaluate the malignant grade of cerebral gliomas, the gold standard continues to be histopathologic examination. The authors assessed and compared the prognostic abilities of the two studies using survival analysis. MATERIALS AND METHODS: Twenty-nine patients underwent 34 sessions of TI-201 SPECT plus surgery for primary or recurrent cerebral gliomas 12 to 78 months before this analysis. Using conventional survival analyses, such as the log-rank test, Cox regression, and the Akaike cross-tab method, the authors evaluated the prognostic significance of 10 variables: histopathologic grade, TI-201 SPECT, Tc-99m HMPAO SPECT, tumor cell viability, radionecrosis, neurologic defects, clinical improvement, surgery, chemotherapy, and external beam radiotherapy. RESULTS: TI-201 SPECT was most strongly related to prognosis, followed by histopathologic grade. The other variables had little prognostic value. The Cox stepwise selection procedure indicated that TI-201 SPECT was the only independent predictor of outcome, whereas histopathologic analysis was eliminated from the prognostic model. However, the Kaplan-Meier survival curve and the Akaike method indicated that histopathologically low-grade tumors were more closely associated with longer-term survival than were TI-201 low uptake tumors. CONCLUSIONS: TI-201 SPECT is not only closely correlated with the histopathologic grade of tumor but is a significantly better predictor of outcome than histopathologic grade. However, histopathologic examination may provide additional information on longer-term survival. TI-201 SPECT is a valuable procedure, especially in patients in whom a histologic diagnosis of possible glioma cannot be made.

[A case of severe adult measles pneumonia--efficacy of combination of steroid pulse therapy, high-dose vitamin A and gamma globulins].

A 33 year-old female was admitted with facial, trunk and limb eruptions, conjunctiva intrahemorrhage, Koplik's spots in the pharynx and severe hypoxemia after fever and upper respiratory tract symptom. Infiltrative shadow of the whole right lung was seen on chest radiography. Fine crackles were seen in the lower left lung and in the whole right lung. Severe inflammation and liver dysfunction were indicated by blood test. Measles antibody IgM was high. The abnormal interstitial shadows were confirmed in greater detail by chest computed tomography. Her condition was diagnosed as measles pneumonia. A combination therapy with steroid pulse, high dose vitamin A, and gamma globulin was started, after which the patient gradually improved, indicating the effectiveness of this combination therapy for severe adult measles pneumonia.

[A case of intravascular malignant lymphomatosis presenting as cerebral infarction].

A case of intravascular malignant lymphomatosis (IML) presenting as progressive cerebral infarction is reported. A 62-year-old previously healthy male developed progressive dementia. MRI of the brain at the nearest hospital revealed multiple infarcts with unknown etiology. His level of consciousness deteriorated rapidly, and then he was transferred to our hospital for further evaluation. High grade fever, raised serum C reactive protein (CRP), and raised lymphoma markers (serum LDH and soluble IL-2 receptor (sIL-2R)) were observed. Repeated brain MRI disclosed progression of multifocal cerebral infarctions. We considered IML most likely, and we performed muscle biopsy. However muscle biopsy didn't demonstrate any proliferation of neoplastic cells of lymphoid origin within small vessels. Thereafter IML was diagnosed by brain biopsy. The patient underwent chemotherapy, but died of pneumonia due to severe myelosuppression. IML is a rare disease but most commonly shows neurological symptomatology as its clinical manifestation. Dementia is the most common neurological symptom, and progressive multiple infarction is the most common of the MRI findings. Rapidly progressive dementia associated with multiple infarction, when elevated CRP, LDH and sIL-2R are observed in the laboratory data, is suggestive of IML.

[Clinical problems in the treatment of primary central nervous system malignant lymphoma].

While the treatment of extracerebral lymphomas with the combination of chemotherapy and radiotherapy has drastically improved outcomes, the treatment of primary central nervous system malignant lymphoma(PCNSML) has been disappointing. Because of the variety of clinical presentations, progression of disease, and treatment modalities, careful inspection of factors which influence survival may suggest possible approaches for a more effective management in each case. In this report, clinical problems in the treatment of PCNSML was discussed with presenting cases experienced at Tenri hospital since 1983. There were twenty-one cases of histologically proven PCNSML. Surgical resection was undertaken in 11 patients. The remaining patients underwent biopsy only. All patients received radiation therapy. Various modality of chemotherapy was performed in 14 cases. Tumor recurrence was occurred at one or more CNS sites, including 3 patients who had meningeal relapse and one patient who also relapsed outside the CNS. The median survival time was estimated to be 15 months. Among the 9 patients alive at last contact the median length of follow up was 31.5 months(range 4 to 56 months). The following problems were presented and discussed; 1) varieties of initial clinical presentations, 2) variable recurrence patterns, metastases including CSF dissemination and extracranial metastases, 3) treatment-related leukoencephalopathy.

[A case of psoriatic arthropathy complicated with spinal fracture and epidural hematoma].

A 78-year-old man with psoriatic arthropathy complicated with traumatic spinal fracture and epidural hematoma is reported. He had fallen down the stairs. On admission one hour after injury, he developed an incomplete C6 quadriparesis. CT revealed a C6-7 fracture and dislocation on sagittal reconstruction. MR imaging disclosed the compression of the spinal cord between the posterior margin of the vertebral body and an epidural hematoma. The patient had had the skin lesion, psoriasis vulgaris, for about 20 years and been previously treated for uveitis. Serological tests for rheumatoid factor and HLA B-27 were negative. Emergent laminectomy and evacuation of the epidural hematoma were carried out because of progressive neurological deterioration. Osteoporotic laminar bone and ossified yellow ligament were observed to have been fractured. Conservative therapy was selected for spinal instability. Although a respiratory complication occurred postoperatively, he was transferred to the rehabilitation facility in an improved neurological condition.

The efficacy of conventional radiation therapy in the management of pituitary adenoma.

PURPOSE: To evaluate the efficacy of conventional radiotherapy for reducing tumor size and endocrine hypersecretion of pituitary adenomas. METHODS AND MATERIALS: We reviewed the records of 91 patients with pituitary adenoma, who were first treated between 1969 and 1994 and had been followed for more than 2 years (median, 8.2 years.) Of these patients, 86 had received postoperative radiotherapy, and 5 had received radiotherapy alone. The median total dose was 51 Gy. Clinical symptoms related to mass effects or endocrine hypersecretion were assessed. The efficacy of radiotherapy was evaluated before treatment and during the follow-up period (1-14 years; median, 3 years) by estimating tumor size on computed tomography or magnetic resonance imaging in 56 patients, as well as by endocrine testing in the 22 patients who had secreting adenomas. Local control rate, prognostic factors, and side effects were analyzed. RESULTS: Mass-effect symptoms improved in 72% and 79% of patients who had such symptoms due to nonsecreting adenomas and secreting adenomas, respectively. Symptoms of endocrine hypersecretion abated in 67% of patients who had such symptoms. Excessive hormone levels normalized in 74% of patients who showed endocrine hypersecretions. The greatest size reduction was seen 3 years after the completion of radiotherapy (24% CR, 62% PR, 12% NC, and 3% PD in nonsecreting adenomas, and 32% CR, 36% PR, 27% NC, and 5% PD in secreting adenomas). Three patients with secreting adenomas (2 with prolactinoma and 1 with Cushing's disease) showed a mismatch between reduction in tumor size and normalization of endocrine hypersecretion. The 10-year local control rates were 98%, 85%, 83%, and 67% for nonsecreting adenoma, growth-hormone-secreting adenoma, prolactinoma, and Cushing's disease, respectively. Univariate analyses showed that disease type and radiation field size were significant prognostic factors. Brain necrosis occurred in 1 patient who received a 60-Gy dose of irradiation. CONCLUSION: We conclude that conventional external radiotherapy with 50 Gy is safe and sufficient to control pituitary adenoma. Careful observation is required in the management of secreting adenomas because the effects on tumor size and endocrine hypersecretion may be mismatched in some secreting adenomas.

Influenza in three patients with human immunodeficiency virus infection.

Three Japanese outpatients with human immunodeficiency virus (HIV) infection on anti-retroviral therapy showed evidence of influenza in January 1999. CD4+ T cell counts of these patients prior to the diagnosis of influenza were 72, 248, and 152/mm3, and HIV RNA levels were 19,953, 1,259, and 1,585 copies/ml, respectively. Fever continued 4 to 5 days with no severe complications. One patient showed post-influenzal bronchitis which was effectively treated by antibiotics. None of these patients showed increased serum HIV RNA levels during and after influenza, however, in one patient, a transient reduction of CD4+ and CD8+ cells was seen during the active phase of influenza. Although symptoms of influenza in HIV carriers are generally mild and similar to those in healthy adults, careful follow-up is needed as symptoms of influenza in some HIV-infected patients can be prolonged and serious.

Magnetic resonance imaging of calvarial eosinophilic granuloma with pericranial soft tissue reaction--case report.

A 4-year-old girl presented with an eosinophilic granuloma in the cranial vault. Magnetic resonance (MR) imaging showed the mass as slightly low intensity on T1- and high intensity on T2-weighted images. The pericranial soft tissue was densely enhanced after gadolinium-diethylenetriaminepenta-acetic acid infusion. The mass was soft and successfully removed. Histological examination disclosed Langerhans' cell histiocytosis. MR imaging is useful for the diagnosis of calvarial eosinophilic granuloma with soft tissue involvement.

Increased frequency of interferon-gamma-producing peripheral blood CD4+ T cells in chronic hepatitis C virus infection.

OBJECTIVES: To determine the profile of cytokine secretion by CD4+ T helper (Th) cells in chronic hepatitis C virus (HCV) infection, we used flow cytometry to determine the percentage of interferon (IFN)-gamma and interleukin (IL)-4 producing cells from CD4+ T lymphocytes in peripheral blood obtained from patients chronically infected with HCV. METHODS: Peripheral blood mononuclear cells isolated from 89 HCV infected subjects (22 asymptomatic carriers, 56 patients with chronic hepatitis, and 11 patients with liver cirrhosis) and 24 healthy controls were stained with surface CD4 and intracellular IFN-gamma and IL-4. Serum soluble IL-2 receptor (sIL-2R) levels were analyzed by ELISA. RESULTS: The frequency of IFN-gamma producing CD4+ cells in asymptomatic HCV carriers, patients with chronic hepatitis, and patients with liver cirrhosis were significantly higher than those of healthy controls (p<0.01, respectively). In contrast, the percentages of IL-4-producing CD4+ cells were very low, and there were no significant correlations with disease progression. A significant elevation in serum sIL-2R levels was found in chronic HCV infection compared to healthy controls, and serum sIL-2R levels significantly correlated with the frequency of IFN-gamma-producing cells. CONCLUSIONS: In HCV infected subjects, both serum sIL-2R and IFN-gamma are increased in chronic HCV infection no matter the stage of disease, meaning they are no different in asymptomatic carriers, patients with chronic hepatitis, and patients with liver cirrhosis, and that Th1 cytokine or Th1 cells may participate in the pathogenesis of liver damage in chronic HCV infection.

[Combined modality therapy for malignant lymphoma of the primary central nervous system: a preliminary report of a new chemotherapeutic regimen with "PEACE"].

Between 1994 and 1998, a total of 5 patients with primary central nervous system malignant lymphoma (PCNSML) were enrolled in this study. There were one man and four women, with a median age of 53 years. These patients were treated with a new systemic chemotherapeutic regimen "PEACE" therapy. After undergoing surgery (biopsy or resection), the patients received radiotherapy followed by adjuvant chemotherapy with combination of procarbazine (P) (100 mg/day, p.o., day 1 to day 5), cyclophosphamide (E) (200 mg/sqm/day, day 4), doxorubicin hydrochloride (A) (20 mg/sqm/day, day 4 and day 5), carboplatin (C) (300 mg/sqm/day, day 1), and etoposide (E) (30 mg/sqm/day, day 1 to day 3). This regimen was repeated for at least three cycles every 4 to 6 weeks. Intrathecal injection of methotrexate was also administrated in conjunction with systemic chemotherapy except in one case. Complete response was seen in one, and partial response in four patients. Toxicity was tolerable. Median survival time was 31.5 months. The results suggest the efficacy of this chemotherapeutic regimen and further emphasize a role for adjuvant chemotherapy in the initial treatment of PCNSML.

[Clinical study of symptomatic Rathke cleft cyst].

The clinical, radiographic findings in 12 patients with symptomatic Rathke cleft cysts (RCC) are presented. The mean age of these patients was 52 years, and 9 of the patients were female. Visual disturbance was the most common symptom, followed by headache. Magnetic resonance images (MRIs) were reviewed in 11 cases. In two cases, the cyst fluid had low signal intensity on T1-weighted images and high intensity on T2-weighted images. In eight cases the cyst fluid had iso-to-high intensity on both T1 and T2-weighted images. On dynamic MRI study using Gd-DTPA, normal anterior pituitary gland was seen superior to the RCC in 4 cases, anterior in 4, and inferior in 2 cases. In accordance with the MRI findings, transcranial approach was chosen in 4 cases and the transsphenoidal route was used in eight cases. Most symptoms and signs improved or resolved following surgery with the exception of those cases with a long-standing history of hypopituitarism. We experienced two cases of recurrence at 7 months, and 65 months respectively requiring a second operation, and the mean follow-up period for all cases was 78 months. Differential diagnosis between RCC and craniopharyngioma should be carefully made in the recurrent cases by surgical specimens of the cyst wall. Partial resection of the cyst wall and drainage of the contents via the transsphenoidal route is a safe and effective procedure in the majority of cases, but the transcranial approach is the treatment of choice in cases in which the cyst is entirely located in the suprasellar region.

T-Cell hyporesponsiveness induced by activated macrophages through nitric oxide production in mice infected with Mycobacterium tuberculosis.

In active tuberculosis, T-cell response to Mycobacterium tuberculosis is known to be reduced. In the course of Mycobacterium tuberculosis infection in mice, we observed that T-cell proliferation in response to M. tuberculosis purified protein derivative (PPD) reached the maximum level on day 7, then declined to the minimal level on day 14, and persisted at a low level through day 28 postinfection. The frequency of PPD-specific CD4 T cells in the spleen on day 28 decreased to one-sixth on day 7. To further investigate the mechanism of this T-cell hyporesponsiveness, we next analyzed the suppressive activity of spleen macrophages on T-cell function. The nonspecific proliferative response of naive T cells and the PPD-specific proliferative response of T cells were suppressed by day 28 macrophages, but not by day 7 macrophages or naive macrophages. This reduction of proliferative response was restored by addition of nitric oxide synthesis inhibitor, NG-monoethyl-L-arginine monoacetate, but not by monoclonal antibody against interleukin 10 or transforming growth factor beta. These data indicate that the macrophages from mice chronically infected with M. tuberculosis suppress T-cell response through production of nitric oxide, suggesting that nitric oxide-induced elimination mediated by activated macrophages may reduce the T-cell response and the number of mycobacterium-specific CD4 T cells in vivo.

[Fibrous dysplasia of the skull presenting interesting neuroradiological findings].

A case of fibrous dysplasia of the frontal bone in a 51 year-old male is described. He was admitted to our hospital with a hard, painless growing mass in the left frontal region. A symmetrical protrusion of his forehead has been observed since several years before. Neurological examination and laboratory data revealed no abnormalities. Skull x-rays demonstrated two different lesions. One showed a ground glass appearance in the supraorbital region, and the other showed a radiolucent lesion with marginal sclerosis crossing the left coronal suture CT scan revealed an intradiploic multilocular mass. T1 and T2 MR images showed an abnormal low-intensity mass, and heterogeneous gadolinium-enhancement was noticed in both lesions. Selective external carotid angiography showed tumor stain in the left coronal mass fed by middle meningeal and superficial temporal arteries mimicking intraosseous meningioma. On the other hand, a supraorbital hyperostotic lesion showed no apparent vascularity. An operation was performed on the left coronal lesion to verify the nature of the progressively enlarging mass, which was histologically confirmed to be a fibrous dysplasia rich in numerous vessels. Postoperative course was uneventful. Correlation with clinical activity and enhancement pattern was not known, however, careful observation is required in hypervascular fibrous dysplasia such as was observed in this case.