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Introduction: The role of vascular endothelial growth factor in macular edema (ME) due to branch retinal vein occlusion (BRVO) by enhancing vascular permeability has been well studied. ME due to BRVO often recurs; however, there has been no report on the relationship between this recurrence and choroidal thickness (CT), considering the high vascularity of the choroid. This study was designed to investigate this relationship., Methods: In this retrospective consecutive case series, patients with recurrence of ME within 6 months of receiving intravitreal aflibercept injection treatment for naive ME due to BRVO at Juntendo University Urayasu Hospital were included. Retinal thickness (RT) and CT were measured in the fovea and on the occlusion, non-occlusion, nasal, and temporal sides at baseline, after the first intravitreal aflibercept administration, and before and after recurrence. We also examined the change for each side before and after reinjection., Results: This study included 11 patients and 11 eyes. The subfoveal CT and RT at baseline were 261.9 ± 93.4 μm and 691.5 ± 254.4 μm, respectively, which significantly decreased to 208.5 ± 70.3 μm and 188.6 ± 33.8 μm, respectively, at 1 month after the first injection (p = 0.001 and p < 0.01, respectively). These values also significantly decreased at all the other sites after treatment. There were 14 recurrences within the 6 months following intravitreal aflibercept injection; RT significantly changed at all sites before and after recurrence and reinjection. CT significantly changed at the subfovea and on the occlusion and non-occlusion sides; however, there was no significant change on the nasal and temporal sides., Conclusion: In patients with BRVO, the CT around the macula after initial treatment was significantly reduced; however, at the time of ME recurrence and reinjection, there were site-dependent differences in the changes observed in the CT. These findings suggest that the pathologies of ME at initial occurrence and at the time of recurrence are different., (© 2020 The Author(s). Published by S. Karger AG, Basel.)

Background and Purpose: Lymphotoxin alpha (LTA), one of the tumor necrosis factor family proteins, is an important proinflammatory cytokine and appears to play a putative role in the inflammatory process of atherosclerosis. Recent genetic studies have suggested that variations in the gene encoding LTA, which affect its expression and biological function, may contribute to the development of vascular diseases. We conducted a case-control study to clarify the association of LTA gene polymorphisms with ischemic stroke in a large Japanese population., Methods: Genotyping for LTA A252G and C804A polymorphisms was achieved by a rapid-cycle polymerase chain reaction and melting curve analysis using fluorescent probes in 1,044 incident cases of ischemic stroke recruited from the Fukuoka Stroke Registry and 1,044 age- and sex-matched control subjects recruited from the Hisayama Study., Results: The overall distribution of allele and genotype for each polymorphism was similar between stroke patients and control subjects. The allele frequencies of 252G and 804A were slightly lower in stroke patients than in control subjects; however, conditional logistic regression analysis adjusted for potential risk factors found no association between the risk of ischemic stroke and either polymorphism. In terms of stroke subtype, we also found no association of these polymorphisms with any subtypes of ischemic stroke., Conclusions: Neither the A252G nor C804A polymorphism of the LTA gene was associated with stroke overall and any subtypes of ischemic stroke in the Japanese population., ((c) 2008 S. Karger AG, Basel.)

Background: Autoimmune bullous diseases are characterized by autoantibodies against specific adhesion molecules of the skin and/or mucous membrane. While these autoantibodies are known to play a primary role in the disease manifestation, it remains unknown how disease-specific autoreactive B cells and autoantibodies are induced. Recent studies have indicated the importance of the CD40 and CD40 ligand (CD40L) receptor-ligand pair in the immunopathogenesis of autoimmune diseases. CD40L circulates in soluble form, and some reports suggest that serum soluble CD40L (sCD40L) levels are increased in various autoimmune diseases., Objectives: To determine serum sCD40L levels in patients with pemphigus vulgaris (PV) and bullous pemphigoid (BP), and to determine their correlation with clinical findings and laboratory findings., Patients and Methods: Sera from 10 PV patients, 35 BP patients and 12 normal controls were subjected to ELISA assays to measure serum levels of sCD40L, anti-desmoglein-3 antibody and anti-BP180 antibody., Results and Conclusions: Circulating sCD40L levels were significantly elevated in BP patients, but not in PV patients. Serum sCD40L levels increased in the early stage of disease onset and recurrence in BP patients. In conclusion, circulating sCD40L levels may be a useful marker for early activation of autoimmune diathesis and, furthermore, an effective therapeutic target in patients with BP., (Copyright 2007 S. Karger AG, Basel.)

Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe disease with multiorgan failure. Recently, the association of the human herpesvirus (HHV) family, particularly of HHV-6, with DIHS has been reported. We report a 43-year-old female diagnosed as having DIHS based on the clinical course and laboratory examinations. The HHV-6 reactivation was demonstrated by significantly increased levels of the specific antibody in her paired sera and by polymerase chain reaction of HHV-6 DNA. Notably, transient hypogammaglobulinaemia was detected in the early stage of the disease, which was associated with the disease activity. By contrast, the serum IgE level and eosinophils were increased 2 or 3 weeks later. In addition, serum levels of interferon gamma, interleukin (IL)-4 and soluble IL-2 receptor, which were increased in the early phase of the disease, decreased gradually after the corticosteroid therapy., (2005 S. Karger AG, Basel)

Background: Psoriasis features an increased level and activity of tumor necrosis factor alpha (TNF-alpha). The TNF-alpha gene has single nucleotide polymorphisms (SNPs) at positions -308 (-308G>A) and -238 (-238G>A) in the promoter region, and the -238G>A SNP has been reported to be associated with psoriasis vulgaris (PV) and psoriatic arthritis in Caucasians., Objective: To examine whether these SNPs are associated with susceptibility to PV in Japanese patients, we investigated the genotype and allele frequencies at each SNP in Japanese PV patients and in controls., Methods: We examined 163 PV patients and 96 healthy individuals. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method., Results: No significant association between the genotypes or alleles of these SNPs and susceptibility to PV was observed., Conclusion: These SNPs themselves are not associated with susceptibility to PV in the Japanese., (Copyright 2003 S. Karger AG, Basel)

Multiple eruptive dermatofibromas (MEDF) are rare and have been thought to be associated with altered immunity. It has been reported that dermatofibromas (DFs) are positive for factor X IIIa but not for CD34. In this report, we describe a 34-year-old Japanese woman with MEDF and persistent hypertriglyceridemia. Histopathological examination revealed that several areas in larger nodules, showing higher cellularity and storiform growth pattern, had CD34+ cells. Our case and the review of previous reports suggest that hyperlipidemia, including hypertriglyceridemia, could induce MEDF and that highly cellular areas in DFs are sometimes positive for CD34., (Copyright 2003 S. Karger AG, Basel)

Background: Trichoblastoma is a rare benign skin appendage tumor constituted mostly of follicular germinative cells. It can arise on any part of the body except the palms, soles, nail units and mucosal membranes. No case of it in breast skin has been reported before. Furthermore, fine needle aspiration cytology findings on this lesion have not been described before., Case: A 76-year-old female presented with a firm nodule in her left breast. The tumor was well demarcated, about 1.5 cm in diameter. Fine needle aspiration cytology revealed clusters composed of relatively uniform cells with a high nuclear/cytoplasmic ratio. In the midst of some clusters, the tumor cells had a more abundant cytoplasm. Fibrocellular interstitium or dense cyanophilic acellular material occasionally was attached to them. The tumor cells had oval or fusiform nuclei that had fine, evenly dispersed chromatin. To exclude a diagnosis of breast cancer, it is important to recognize that the clusters are composed of basaloid cells with focal squamous eddies and that there is at least focally peripheral palisading. The histopathologic diagnosis was trichoblastoma., Conclusion: Fine needle aspiration cytology can distinguish trichoblastoma from malignant diseases of the breast and may be used to diagnose the lesion in conjunction with clinical findings.

Background: Topical corticosteroids are commonly applied in atopic dermatitis (AD) treatment. However, their chronic use may be associated with significant side effects at the application site. Skin atrophy and other undesirable effects are frequently seen after long-term corticosteroid treatment. In addition, when application of corticosteroids is discontinued, a rebound phenomenon in the facial lesions can occur within several days. Topical tacrolimus, an immunosuppressant currently used to prevent rejection after solid-organ transplantation, presents a potential alternative therapeutic agent for AD., Objective: The present study is the first trial designed to evaluate the efficacy and safety of topically applied tacrolimus ointment after corticosteroid discontinuation without a washout phase in severe, long-term facial AD., Patients/methods: Forty-seven patients with facial refractory AD were recruited, of whom 38 had undergone topical corticosteroid treatment for at least 4 weeks before enrollment (group 1) and the other 9 had not received steroid treatment (group 2). All 47 patients received 0.1% tacrolimus ointment, and the severity index and pruritus score were assessed as an AD clinical activity index every week and compared with baseline data., Results: Both the severity index and pruritus score improved significantly in group 1 after 1 and 2 weeks of application (p < 0.01, respectively). Group 2 showed the greatest improvement at 4 weeks (p < 0.05). In this trial, none of the patients experienced a rebound phenomenon associated with tacrolimus treatment. A transient sensation of burning at the application site was the only adverse event in 31 of the 47 (66%) enrolled patients, but this condition improved after several days. Spectrophotometric assessment of the facial lesion following treatment revealed significant improvement in group 1 (p < 0.05)., Conclusion: The present results indicate that topical tacrolimus treatment following corticosteroid discontinuation is safe and effective in refractory facial AD., (Copyright 2001 S. Karger AG, Basel)

Recent studies have demonstrated that macrolide antibiotics have anti-inflammatory as well as antibacterial effects. Therefore, macrolide antibiotics have been successfully used to treat patients with various inflammatory diseases. We evaluated the effect of macrolide antibiotics in 4 patients with prurigo pigmentosa who were treated with either 400 mg of clarithromycin or 300 mg of roxythromycin daily. Eruption and pruritus disappeared within a week in all the patients while those symptoms were unresponsive to other drugs. Although the mechanism of this effect remains unclear in patients with prurigo pigmentosa, macrolide antibiotics can be considered as an alternative treatment for prurigo pigmentosa.

Background and Methods: Recent studies have shown that RANTES plays a role in the pathogenesis of inflammatory skin diseases. We examined the production of RANTES by human keratinocytes (KCs) when cultured with various cytokines., Results: IFN-gamma (100 ng/ml) or IL-1beta (100 ng/ml) significantly induced RANTES production by KCs in 48-hour culture. These cytokines synergistically increased RANTES production by KCs. TNF-alpha (100 ng/ml), IL-4 (100 ng/ml) or IL-13 (100 ng/ml) markedly enhanced the RANTES production by KCs induced by IFN-gamma (100 ng/ml) although none of those cytokines significantly enhanced that induced by IL-1beta (100 ng/ml) in 48-hour culture. Dexamethasone (10(-8) M) strongly inhibited RANTES production by KCs induced by the combination of IFN-gamma and IL-4, while tacrolimus (FK-506, 10(-8) and 10(-6) M) showed partial inhibition., Conclusions: These results revealed that RANTES production by KCs is regulated by inflammatory cytokines, such as IFN-gamma, IL-1beta, TNF-alpha, IL-4 and IL-13, and can be modulated by immunosuppressive drugs. Our data suggest that RANTES is involved in skin inflammation., (Copyright 2001 S. Karger AG, Basel)

Background: Platelet-derived growth factor BB (PDGF-BB) and transforming growth factor beta are known to enhance the growth of neurofibroma-derived cells from neurofibromatosis type 1 (NF-1) patients., Objective: This study aims to elucidate whether these growth factors and their receptors are up-regulated in NF-1 patients., Methods: Tissues and culture cells from neurofibroma in NF-1 patients, nontumor lesions in NF-1 patients, and the skin of normal controls were collected. To evaluate the expressions of growth factors and their receptors, reverse-transcriptase polymerase chain reaction and immunohistochemistry were performed., Results: PDGF-beta receptor subunit was expressed in the neurofibroma tissues from NF-1 patients, but not in the nontumorous tissues from NF-1 patients or skin from normal controls. As for the other factors, there were no significant differences among these tissues. Neurofibroma sections also stained positive for the PDGF-beta receptor subunit., Conclusions: The interaction of PDGF and PDGF-beta receptor subunit may be important in the tumorigenesis of NF-1., (Copyright 2000 S. Karger AG, Basel.)

A 64-year-old male was treated continuously with rifampin, isoniazid and streptomycin for pulmonary atypical mycobacteriosis, Mycobacterium kansasii. Five weeks after beginning the treatment, the patient suddenly developed acute renal failure. A renal biopsy showed crescentic lesions characteristic of rapidly progressive glomerulonephritis with moderate interstitial changes. Serum antirifampin antibody was detected, and the cessation of rifampin treatment was followed by a rapid spontaneous recovery of the patient's renal function. This is, to our knowledge, the first case of rapidly progressive crescentic glomerulonephritis associated with rifampin treatment where circulating antirifampin antibody is demonstrated and the renal function spontaneously improved after discontinuing rifampin treatment.

Generalized melanosis occurs very rarely as a complication of malignant melanoma, and the pathogenesis of this condition is still unclear. Histological examination of pigmented skin and measurements of the DOPAquinone metabolites 5-S-cysteinyldopa (5-S-CD) and 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C) in the patient's serum and urine were carried out. Histological examination revealed basal hyperpigmentation, discrete melanoma cells and melanophages around the blood vessels and an unusual melanin deposition within collagen bundles in the dermis. The levels of 5-S-CD and 6H5MI2C were dramatically increased both in the patient's serum and urine. The deposition of DOPAquinone metabolites secreted by the melanoma cells may contribute to the unusual melanin deposition within collagen bundles in the affected dermis.

The present study demonstrated the elevated synthesis and gene expressions of transforming growth factor beta (TGF-beta) or latent TGF-beta binding protein (LTBP) in an irreversible glomerulosclerosis rat model induced by two consecutive injections of monoclonal antibody (MoAb) 1-22-3. The rats were intravenously injected with 500 microg of MoAb 1-22-3 either once or twice at an interval of 2 weeks. The rats were sacrificed at 24 h, 1 week, 2 weeks or 16 weeks after the last injection. At 24 h, the mesangiolytic changes in the rats with two injections of MoAb 1-22-3 were similar to those in the rats with one injection. The glomerular matrix score in the rats with two injections was significantly higher than that in the rats with one injection at weeks 1, 2 or 16. An increased LTBP localization in the glomeruli of the rats at week 1 after either one or two injections was detected in the segmentally expanded mesangial matrix. Moreover, LTBP in the glomeruli of rats at week 1 after two injections appeared to be more strongly stained in the enlarged mesangial matrix than that in the rats after one injection. A TGF-beta bioassay using mink lung epithelial cells revealed that the total TGF-beta in the glomerular culture conditioned medium in the rats at week 1 after two injections was significantly larger than that in the rats after one injection. A Northern blotting analysis of the glomeruli showed that both the expressions of TGF-beta and LTBP mRNA in the rats after two injections were higher than those in the rats after one injection. These findings suggested that the elevated TGF-beta or LTBP may thus be related to the irreversible glomerulosclerosis that was induced by two injections of MoAb 1-22-3 into rats.

We report a 50-year-old Japanese woman with a 3-year history of systemic lupus erythematosus treated with prednisolone, who had diffuse plane yellowish macules mainly on the upper arm. The lesion was clinically diagnosed as diffuse plane xanthomatosis. However, the histopathological findings from both the yellowish macules and the normal-appearing skin revealed a heavy degeneration of collagen fibers with membranocystic structure throughout the entire dermis and the collagenous septum of the subcutaneous tissue. Ultrastructurally, the membranocystic structure was not due to the degenerative change of fat cells as seen in membranous lipodystrophy but was caused by the degenerative change of collagen fibers with fat deposit.

Background: Cutaneous manifestations of systemic lupus erythematosus (SLE) in men have not been precisely investigated., Objective: The purpose of this study is to define the clinical features of SLE in men, focusing on skin lesions., Methods: The clinical and laboratory manifestations of 28 male and 111 female patients were compared., Results: Widespread discoid lupus erythematosus (DLE) and papular and nodular mucinosis (PNM) were significantly more common in men than in women. Serum sex hormone levels were within the normal range in all make patients examined., Conclusion: This study suggests that gender differences exist in SLE and that male patients tend to present with atypical cutaneous manifestations.

Endothelins (ETs) have been known to have a variety of biological functions such as mitogenic stimulation, natriuresis and the stimulation of the proteolytic activity in addition to vasoconstrictive action, which may participate in the process of glomerular diseases pathophysiologically. In this study, the effects of ET-1 on fibrinolysis, plasminogen activator inhibitor 1 (PAI-1) synthesis and PAI-1 mRNA expression were examined in cultured rat mesangial cells (MCs). The addition of ET-1 (10(-11) to 10(-7) M) into MC cultures reduced fibrinolytic activities assayed by fibrin autography in a dose-dependent manner. For the assay of PAI-1 synthesis, MC culture media metabolically labeled with 35S-methionine were analyzed by SDS-PAGE with fluorography and immuno-precipitation using rabbit antirat PAI-1 antibody. Exposure to ET-1 for 24 h produced a clear dose-dependent effect on the PAI-1 release from the MCs. PAI-1 mRNA expression was also enhanced in parallel with the concentration of ET-1 in the conditioned media. These findings indicate that ET-1 participates in fibrinolysis and the PAI-1 synthesis by MCs, which may thus regulate the degradation of the extracellular matrix in the glomerular microenvironment.

Background: Juvenile temporal arteritis has been proposed as an entity but remains controversial., Case Report: A 39-year-old male, who was otherwise asymptomatic, developed painless bilateral nodules in the temporal areas. His eosinophil blood count was 2,660/mm3 (31%), while the erythrocyte sedimentation rate was normal. Histologic examination of the lesion revealed non-giant-cell granulomatous inflammation with abundant eosinophil infiltration. The clinical and pathologic manifestations in our patient were different from those in classic temporal arteritis, which occurs almost exclusively in individuals over the age of 50 years, allergic granulomatosis and angiitis, and thromboangiitis obliterans. Eight cases of this disease have previously been reported in the literature., Conclusion: We consider that 'juvenile temporal arteritis with eosinophilia' is a distinct clinical and pathologic entity. The prognosis of the diseases is considered to be good.

A 71-year-old Japanese woman had two dome-shaped tumors on her right buttock with several surrounding papules. Histological examination revealed that large anaplastic cells and atypical lymphoid cells densely infiltrated the entire dermis. On immunohistochemical examination, Ki-1, HLA-DR, CD25 (IL-2 receptor alpha), CD122 (IL-2 receptor beta), CD4, CD11c and CD68 were all positive in the tumor cells, whereas CD1a, CD3, CD5, CD8 and CD19 were negative. Neither rearrangement of the T-cell receptor beta, T-cell receptor gamma nor the immunoglobulin heavy-chain was seen. Ultrastructurally, most of the tumor cells contained thick bundles of intermediate filaments in the perinuclear cytoplasm. Thus, this patient was diagnosed as having Ki-1-positive lymphoma of non-T, non-B origin. No recurrence or metastasis of the tumor has been observed in the last 2 years, although surgical resection was required 3 times before control was achieved.

The effects of a high salt diet on glomerular hypertrophy and sclerosis were examined in a focal glomerular sclerosis rat model. Sprague-Dawley rats were injected twice with Adriamycin (ADR, 2.5 mg/kg body weight) and then divided into 3 groups: (1) ADR rats fed a 1% sodium chloride (NaCI) diet (control ADR rats); (2) ADR rats fed an 8% NaC1 diet (ADR-NaC1 group), and (3) ADR rats fed a 10% sodium bicarbonate (NaHCO3) diet (the ADR-NaHCO3 group), and were then observed for 8 weeks. There were no differences in the blood pressure levels between the control ADR and ADR-NaC1 groups. The urinary protein excretion was significantly less in the ADR-NaC1 and ADR-NaHCO3 groups than in the control ADR group. However, a progressive increase in the blood urea nitrogen and serum creatinine associated with extensive glomerular sclerosis and hypertrophy was only observed in the ADR-NaC1 group. An increase in the glomerular diameter preceded the development of glomerulosclerosis in this group. Furthermore, a daily administration of amiloride, a Na+/H+ exchanger inhibitor, to the ADR-NaC1 rats prevented the development of glomerular hypertrophy and sclerosis. These results therefore suggest that the aggravated effect of a high salt diet on glomerular sclerosis may be related to glomerular hypertrophy which is associated with the stimulation of the Na+/H+ exchanger.

We measured regional cerebral blood flow (rCBF) in young and old Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats by a minimally invasive microsphere technique. Blood flows to the cerebrum, diencephalon, mesencephalon, cerebellum and pons-medulla during normocapnia were determined. To test the ability of the vessels to dilate, rCBF was also measured during hypercapnia. Reactivity to CO2 was calculated as delta rCBF/delta paCO2. In the old SHR, blood flow to the pons-medulla (88 +/- 8 ml/min/100 g, mean +/- SEM) was markedly lower than that in the young SHR (107 +/- 4 ml/min/100 g, p < 0.05), whereas the difference of those values in the old and young WKY rats was slight (0.05 < p < 0.1). There were no differences in the values of blood flow to the cerebrum, diencephalon, mesencephalon or cerebellum between the young and old rats in both species. Cerebrovascular CO2 reactivity was markedly impaired in the old SHR (p < 0.05) compared to that in the young SHR, but the difference in reactivity in the WKY rats was not significant. The results indicate that blood flow to the pons-medulla is reduced in association with age, particularly in the hypertensive animals, and that the ability of the cerebral vessels to dilate is impaired homogeneously by the combination of chronic hypertension and aging.

We report a Japanese case of Darier's disease with brown and white papules or maculae distributed on the neck, trunk and dorsa of hands. Both brown papules and leukoderma showed typical histological features of Darier's disease. Moreover, there were much fewer melanocytes and melanosomes in the epidermis of both lesions. The corneal layer of the brown papules was far thicker than that of the leukoderma. Therefore, the thick corneal layer of the brown papules may prolong the retention of a few melanosomes or a little melanin to induce hyperpigmentation, while the thin corneal layer of leukoderma may not do so, thereby producing hypopigmentation. The difference in clinical and histological courses after involvement of melanocytes was proposed to be the cause of the discrepancy between the previous reports. We conclude that leukoderma was the primary lesion, the postinflammatory depigmented spots, or the atypical or subclinical eruption of Darier's disease.

The accumulation of extracellular matrix (ECM) is an important feature of most forms of progressive glomerular diseases. In order to examine the relationship between ECM synthesis and glomerulosclerosis, we evaluated fibronectin synthesis by glomeruli with the immunoprecipitation of conditioned media from isolated glomeruli in 5/6 nephrectomized spontaneously hypertensive rats (5/6N-SHR). There was no difference in blood pressure between 5/6N-SHR and control SHR throughout the experiment. Two weeks after the nephrectomy, most of the glomeruli were intact and no difference in the synthesis of fibronectin was observed between either groups. Twenty weeks after the nephrectomy, marked glomerulosclerosis associated with an increase in urinary protein was revealed in 5/6N-SHR but no glomerular lesions in control SHR. The synthesis of fibronectin by isolated glomeruli increased in 5/6N-SHR compared to control SHR. The administration of enalapril or hydralazine + reserpine + hydrochlorothiazide markedly attenuated the glomerular sclerosis and urinary protein excretion to a comparable degree, although the later therapy reduced blood pressure more effectively. These antihypertensive therapies also suppressed fibronectin synthesis in the 5/6N-SHR group at week 20. In conclusion, increased synthesis of glomerular fibronectin appeared to contribute to the glomerulosclerosis caused by subtotal nephrectomy and hypertension.

One of the HLA class II genes, HLA-DQA1, was typed from 290 unrelated healthy Japanese using the oligonucleotide typing method. The HLA-DQA1 gene was enzymatically amplified and typed by dot-blot hybridizations with 10 sequence-specific oligonucleotide probes labeled nonradioactively. Using this method, the HLA-DQA1 genotype was theoretically classified into 36 genotypes: 8 homozygous and 28 heterozygous ones. Actually, 26 genotypes were observed in the present study, and the gene frequency of each allele was calculated. The observed numbers were in accordance with the numbers expected under the Hardy-Weinberg equilibrium. The HLA-DQA1 genotype was also determined in aged bloodstains. Since the genotype is polymorphic in the Japanese population and a very small amount of blood is required for determination, this typing is particularly useful for forensic analysis.

Cerebrospinal fluid (CSF) lactate and pyruvate concentrations were determined in 16 patients with hepatic encephalopathy before and/or after treatment. CSF lactate was significantly increased to 1.92 +/- 0.11 mmol/l in hepatic encephalopathy before the treatment in comparison to 1.40 +/- 0.05 mmol/l in control subjects. In 9 of 11 patients with moderate or stage 2 encephalopathy, CSF lactate levels were below 2 mmol/l. In contrast, in 4 of 5 patients with stage 3-4 encephalopathy, CSF lactate levels were higher than 2 mmol/l. CSF lactate was decreased with the recovery of neurological symptoms by the treatment. These findings indicate that CSF lactate levels reflect the severity of metabolic impairment of the brain. Hypocapnia was frequently observed in these encephalopathic patients, and arterial PCO2 correlated inversely with CSF lactate and linearly with CSF HCO3-, suggesting that CSF lactic acidosis contributes to hyperventilation in hepatic encephalopathy. It is concluded from present results that metabolic disorder of neuronal cells might be one of the important factors for the development of hepatic encephalopathy.