Elevated intracellular IFN-gamma levels in circulating CD8+ lymphocytes in patients with fulminant hepatitis.

BACKGROUND/AIMS: Fulminant hepatitis usually takes a rapidly progressive course, terminating in death within a short period. Experimental studies have demonstrated that immunological mechanisms play an important role, especially those involving virus-specific CD8+ cytotoxic T lymphocytes and their production of interferon-gamma (IFN-gamma). However, there are no immunological markers for prediction of the development of fulminant hepatitis in man. METHODS: Peripheral blood lymphocytes from four patients with fulminant hepatitis, six with acute hepatitis and 11 healthy volunteers as normal controls were analyzed. Intracellular IFN-gamma production in both CD8 positive and negative T lymphocytes was assessed by flow cytometry. RESULTS: Populations of CD8+ IFN-gamma+ T lymphocytes were significantly increased in patients with fulminant hepatitis, as compared with those with acute hepatitis and normal controls. Production of IFN-gamma in CD8+ T lymphocytes of patients with fulminant hepatitis was also elevated, furthermore significantly correlating with the prothrombin time (r=-0.64, p<0.01). CONCLUSIONS: The capacity for IFN-gamma production by CD8+ lymphocytes is up-regulated in fulminant hepatitis, and this may be important for the development of fulminant hepatitis.     

Prevention of renal damage by angiotensin II blockade, accompanied by increased renal hepatocyte growth factor in experimental hypertensive rats.

Hepatocyte growth factor (HGF) is a unique growth factor that has many protective functions against renal damage. Our previous study demonstrated that HGF stimulated the growth of endothelial and epithelial cells without the replication of mesangial cells. Moreover, angiotensin (Ang) II significantly decreased local HGF production in mesangial cells. Therefore, we examined the effects of Ang II blockade on renal HGF expression and renal damage in experimental hypertensive rats. An angiotensin-converting enzyme inhibitor (cilazapril; 10 mg. kg(-1). d(-1)), an Ang II type 1 receptor antagonist (E-4177; 30 mg. kg(-1). d(-1)), hydralazine (8 mg. kg(-1). d(-1)), and vehicle were administered to 16-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) for 3 weeks. Renal damage was evaluated with a computer analysis system, and renal HGF mRNA was measured by Northern blot analysis. Blood pressure of SHR-SP was significantly decreased by all drug treatments compared with vehicle. Moreover, cilazapril, E-4177, and hydralazine significantly decreased the thickening and necrosis of blood vessels compared with vehicle. Similarly, degeneration and necrosis of glomeruli were also markedly improved by cilazapril and E-4177 (P<0.01). We next examined the effects of Ang II blockade on renal HGF expression in SHR-SP. Renal HGF mRNA was markedly decreased in SHR-SP compared with Wistar-Kyoto rats, although Ang II blockade by cilazapril and E-4177 but not hydralazine significantly increased renal HGF mRNA in SHR-SP. Ang II blockade significantly increased renal HGF (a protective growth factor for tubular epithelial cells); thus, we examined tubular histological appearance. Degeneration and necrosis of tubules were significantly improved by cilazapril and E-4177 treatment (P<0.01). In addition, cell infiltration into the glomeruli and hemorrhage were also significantly reduced in SHR-SP treated with cilazapril or E-4177. The present data demonstrated the prevention of renal damage by Ang II blockade in SHR-SP, which was accompanied by a significant increase in renal HGF mRNA. Given the strong mitogenic activity and antiapoptotic actions of HGF on endothelial and epithelial cells, we believe that increased local HGF production by the blockade of Ang II may improve renal function in hypertension.     

Activation of the brain angiotensin system by in vivo human angiotensin-converting enzyme gene transfer in rats.

The possibility of the brain-specific expression of a component of the renin-angiotensin system was evaluated in the present study. We used the hemagglutinating virus of Japan-liposome complex to transfect human angiotensin-converting enzyme (ACE) cDNA, driven by the cytomegalovirus enhancer and beta-actin promoter, into the lateral cerebroventricle of male Sprague-Dawley rats. We evaluated the time course of hemodynamics, the tissue levels of angiotensin (Ang) II and vasopressin, and ACE activity. Intracerebroventricular transfection of the human ACE gene increased both blood pressure and heart rate. Transfected rats exhibited higher concentrations of brain Ang II and increased brain ACE activity. This activation of the brain angiotensin system was accompanied by increased vasopressin production. The increases in blood pressure and heart rate were abolished by intracerebroventricular administration of an ACE inhibitor or Ang II type 1 receptor antagonist. The expression of the transgene was widely distributed in the periventricular cell layer, the cortex, the hypothalamic nuclei, and the brain stem. Expression in the neuronal cells persisted for up to 14 days. Thus, this hemagglutinating virus of Japan-liposome method is a highly efficient system for gene delivery and is extremely useful for functional gene transfection. This novel hypertensive model may enable characterization of the functions of the renin-angiotensin system in the brain and determination of its role in the pathogenesis of hypertension.     

Massive rectal bleeding due to ileal tuberculosis

A patient with massive rectal bleeding due to ileal tuberculosis is reported. Technetium-99m labelled red blood cell scintigraphy indicated hemorrhage from the ileum, and laparotomy was then carried out. A 70-cm segment of ileum containing ulcers and erosions was resected, and epitheloid granuloma with Langhans-type giant cell was found in the resected specimen. Massive rectal bleeding is considered a rare presenting symptom of intestinal tuberculosis. Intestinal tuberculosis, including small intestinal tuberculosis, although uncommon, should be taken into consideration as a cause of rectal bleeding. Received: September 16, 1998 / Accepted: February 26, 1999     

Statistical analysis of localized non-Hodgkin's lymphomas of the head and neck--multivariate analysis of prognostic factors and evaluation of therapeutic modalities]

Prognostic factors and treatment outcome of 48 patients with Stage I (29) or II (19) non-Hodgkin's lymphoma of the head and neck were analyzed retrospectively. There were 26 males and 22 females, aged from 15 to 89 years old, with an average age of 57. The primary lesion was located in Waldeyer's ring in 25 patients, the nasal cavity and paranasal sinuses in 13, cervical lymph nodes in 8, and others in 2. Histologically, 2 had low grade lymphoma, 42 had intermediate grade disease, and 1 had high grade disease. The patients were treated with radiation alone (5 patients), chemotherapy according to a cyclophosphamide, doxorubicin, vincristine, prednisone- (CHOP) regimen (8 patients), or a combination of both treatments (35 patients). In univariate analyses, an unfavorable prognosis was associated with age > or = 60, Stage I disease, and extralymphatic lesion. Multivariate analysis showed that an extralymphatic lesion was a significant independent risk factor for death (p = 0.0093). The overall five-year survival rate was 73.5%. Differences in the treatment was not reflected in the outcome. Our results suggest that a combination of chemotherapy (CHOP) and radiation is an appropriate treatment for lymphatic stage I and II non-Hodgkin's lymphoma of the head and neck. However, more intensive therapy is necessary for patients with extralymphatic head and neck NHL.     

Immunocytochemical staining patterns for parathyroid hormone and chromogranin in parathyroid hyperplasia, adenoma, and carcinoma

Parathyroid glands (PGs) contain less secretory granules with presumably less stored parathyroid hormone (PTH) than many other endocrine glands. Immunocytochemical staining for PTH has been hindered by the lack of commercially available, reliable antibodies against human PTH. By treating deparaffinized tissue sections with an antigen-retrieval procedure, immunocytochemical staining for PTH and chromogranin A (CHA) was performed using commercially available monoclonal antibodies to investigate the functional activity of hyperfunctioning PGs, including chief cell hyperplasia (CCH), adenoma, and carcinoma, compared with that of normal PGs. In normal PGs, PTH and CHA immunostaining was diffusely granular in the chief cell cytoplasm, but was weak in oxyphil cells. The immunostaining in hyperfunctioning PGs was less dense in CCH, and adenomas were less intensely stained than the densely stained peripherally located normal rim. The one carcinoma case studied showed less staining at the periphery and in the mid-portion of the tumor. Thus, immunocytochemical staining for PTH and CHA provides further information on stored, immunoreactive PTH status and will improve functional analysis of hyperfunctioning parathyroid glands.     

B-cell activation in the mesenteric lymph nodes of resistant BALB/c mice infected with the murine nematode parasite Trichuris muris

Immune responses in resistant BALB/c mice infected with the murine nematode parasite Trichuris muris were examined. Following the establishment of infection, worm burdens of T. muris were expelled by BALB/c mice by day 21 postinfection (p.i.). Specific immunoglobulin G₁ (IgG₁) antibodies to T. muris excretory/secretory (E/S) antigens were detected in sera from infected mice, though specific IgG_2a antibodies were not observed during infection. Ig-producing cells increased in the mesenteric lymph nodes (MLN) of infected mice on days 7, 14, and 21 p.i., with the greatest increase in numbers of IgG- and IgA-producing cells occurring on day 14. Marked increases in the relative percentages of B220⁺ and surface Ig⁺ (sIg⁺) cells were observed in the MLN of infected mice on days 14 and 21 p.i. Furthermore, cellular expansion of the MLN in infected mice resulted in an increase in the absolute numbers of B220⁺ and sIg⁺ cells. The levels of interleukin 2 (IL-2), IL-4, and interferon-γ (IFN-γ) detected in the supernatants from concanavalin A-stimulated MLN cells of infected mice were higher than those found in normal mice. Consequently, the expulsion of T. muris in resistant BALB/c mice was concomitant with cytokine production and B-cell activation in the MLN of infected mice. These results suggest the involvement of B-cell responses in protective immunity to T. muris infection. Received: 12 May 1998 / Accepted: 5 August 1998     

Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease.

Families bearing mutations in the presenilin 1 (PS1) gene develop early onset familial Alzheimer's disease (FAD). Further, some PS1 mutants enhance secretion of the longer form of amyloid beta protein (Abeta42). We constructed cDNAs encoding human PS1 harboring 28 FAD-linked mutations, and examined the effects of the expressed PS1 mutants on Abeta42 secretion in beta amyloid precursor producing COS-1 cells. All the mutants significantly enhanced the ratio of Abeta42 to total Abeta compared with wild-type PS1. However, the increase in Abeta42 ratio in cells with each PS1 mutation did not correlate with the reported age of onset of FAD caused by that mutation. These results suggest that increased Abeta42 secretion is important for the development of Alzheimer's disease (AD), but may not be the only factor contributing to the onset of AD.