Benign bilateral independent periodic lateralized epileptiform discharges.

Bilateral independent periodic lateralized epileptiform discharges (BIPLEDs) usually appear transiently in patients with severe disturbances of consciousness and are indicative of a poor prognosis. Recurrent BIPLEDs have not previously been reported in the literature. We report a 64-year-old patient with bilateral hippocampal lesions (cerebral infarction) who exhibited persistent periodic lateralized epileptiform discharges (PLEDs) (chronic PLEDs) associated with recurrent BIPLEDs. Electroencephalography was recorded for more than 6 months. Left hemispheric PLEDs appeared first. Next, PLEDs shifted to the right hemisphere and BIPLEDs occasionally developed. Brain magnetic resonance imaging and single-photon emission computed tomography with technetium-99-hexamethyl-propyleneamine oxime was performed before and after the appearance of BIPLEDs. The patient had no remarkable clinical symptoms aside from mild memory impairment for this period of time. This is the first case of recurrent 'benign' BIPLEDs, that is, BIPLEDs with a positive prognosis.

Insulin-like growth factor-I enhances choleretic action of FK506 in rats.

FK506 is an immunosuppressant for organ transplantation in the same clinical settings as cyclosporine (CsA). In the management of liver transplantation, FK506 has advantages over CsA, in terms of rejection and corticosteroid requirements. Recent clinical findings in liver transplant patients indicate that FK506, but not CsA, stimulates choleresis, suggesting that FK506 treatment may accelerate recovery from cholestatic dysfunction through its choleretic action. Recently, we demonstrated in rats that exogenous treatment with insulin-like growth factor I (IGF-I) results in an increase in bile flow and also that FK506 has the potential to increase hepatic production of IGF-I. However, circulating levels of IGF-I in FK506-treated rats were only 30% higher than in nontreated rats. In this study, we evaluated the combined effect of treatment with both IGF-I and FK506 on bile flow in rats to explore the possibility that combination treatment in liver transplant patients could enhance the choleretic action of FK506, benefiting the transplanted liver. Combination treatment of IGF-I with FK506 resulted in a potent and long-lasting increase in bile flow. Overall, this study demonstrated that IGF-I treatment enhanced the choleretic action of FK506, providing potential clinical utility for combination therapy using these two drugs, in treatment after liver transplantation.

Induction of bone loss by bile duct ligation in rats.

Metabolic bone loss is the most common complication of chronic liver disease. However, there is little information available about bone loss in rats with a ligated bile duct, a biliary-type of experimental cirrhosis model. Therefore, in this study, the effect of bile duct ligation (BDL) on bone mineral density (BMD) and plasma insulin-like growth factor-I (IGF-I) levels was examined in rats. Two weeks after BDL operation, the rats with a ligated bile duct showed a pronounced and significant decrease in both trabecular and cortical BMD of the femur. In these rats, decreases in food intake and plasma IGF-I levels plus elevated levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and bilirubin were also observed. When the effect of dietary restriction (30% or 50%) over 2 weeks was then investigated in normal rats, 50% food restriction resulted in a significant decrease in femoral trabecular bone density although BMD was unchanged by 30% dietary restriction. The plasma levels of IGF-I were also decreased in food-restricted rats. Thus, the decrease in femoral bone density in 50% food-restricted rats was less potent compared with BDL rats; nevertheless, the decrease in plasma levels of IGF-I was almost equally potent in both BDL and food-restricted rats. Overall, this study showed that BDL operation resulted in a pronounced bone loss in rats, but also that this bone loss might not be merely due to the decreases in food intake and plasma IGF-I levels. These results suggest that BDL in rats is a useful experimental cirrhosis model for evaluating the bone loss associated with chronic liver disease.

Induction of choleresis by immunosuppressant FK506 through stimulation of insulin-like growth factor-I production in the liver of rats.

FK506 (Tacrolimus) is an effective immunosuppressant currently used worldwide in organ transplantation. Based on our recent findings that insulin-like growth factor-I (IGF-I) is important for the stimulation of choleresis in vivo, in this study we investigated the effect of FK506 on bile flow and the plasma and hepatic levels of IGF-I in rats. Intravenous treatment of rats with FK506 resulted in a significant increase in bile flow, whereas cyclosporin A induced a significant decrease. A significant increase in plasma levels of IGF-I was observed in rats 30 min after a single intravenous administration of FK506. Oral treatment of rats with FK506 for 1 week also resulted in an increase in both plasma and hepatic levels of IGF-I. Overall, this study showed that FK506 treatment increased bile flow and also induced an increase in the plasma and hepatic levels of IGF-I in rats, suggesting that a stimulation of hepatic IGF-I production by FK506 may contribute to its choleretic profile.

Stimulation of choleresis by insulin-like growth factor-I in rats.

Insulin-like growth factor-I (IGF-I) is an endogenous growth factor which is mainly produced in the liver. The functions of IGF-I can be summarized as growth-promoting and insulin-like metabolic actions. In the present study, the effect of IGF-I on bile flow and bile acid secretion was investigated in rats. In normal rats bile flow was significantly increased by single exogenous administration of IGF-I, and by 1 week treatment of IGF-I, both bile flow and bile acid secretion were significantly increased. Moreover, to further understand the relationship between IGF-I and bile acid secretion, hypophysectomized rats were next used. We found that the decreases in bile flow and bile acid secretion observed in rats after hypophysectomy, as well as the decrease in the endogenous level of IGF-I in the blood, were partially reversed by 1 week exogenous IGF-I treatment. Overall, this study showed that IGF-I stimulates choleresis associated with an elevation of bile acid secretion in both normal and hypophysectomized rats when exogenously administered, suggesting the importance of IGF-I in the stimulation of choleresis in vivo.

Membranous and soluble forms of Fas antigen in cutaneous lupus erythematosus.

The role of Fas-mediated apoptosis in cutaneous lupus erythematosus (LE) is still unclear, although the Fas/FasL system has been investigated in autoimmune diseases in relation to impaired apoptosis. In order to elucidate the connections between acute cutaneous LE (ACLE) and chronic cutaneous LE (CCLE), we determined the expression of membranous Fas antigen (mFas) on peripheral blood mononuclear cells (PBMC) by flow cytometry and the levels of the soluble form of the Fas antigen (sFas) in sera. The ratio and the mean fluorescence intensity of mFas were much higher in ACLE patients than in others, including patients with CCLE and atopic dermatitis and normal healthy controls. The levels of sFas in ACLE and CCLE patients were also elevated, and there was a significant increase in sFas levels in ACLE patients over that in CCLE patients. Immunohistochemical studies revealed that Fas antigen was predominantly expressed on infiltrating cells around blood vessels and appendages in ACLE and CCLE patients. Based on these findings, it is suggested that the expression of Fas antigen is closely associated with the activation of circulating lymphocytes, especially in ACLE patients, but is not directly associated with keratinocyte damage.

A negative component on event related potential recorded in the drowsy state.

Behavior of event related potential (ERP) components in the drowsy state was examined in nine subjects using oddball paradigm. A component with peak latency of 300 msec, N300, was superimposed on ERP in the drowsy state. N300 appeared also in stage 1 of NREM sleep and closely resembled vertex sharp wave evoked by sound stimulation in both scalp distribution and peak latency. It was suggested that N300 recorded in the drowsy state and vertex sharp wave recorded in stage 1 of NREM sleep are generated by the identical synchronizing mechanism in the brain.

Some sensory stimuli generate spontaneous K-complexes.

The present study was performed in order to determine whether spontaneous K-complex are induced by sensory stimuli. Electroencephalogram (EEG) segments in stage 2 sleep containing an evoked K-complex or spontaneous K-complex were separately averaged with respect to the peak of N300, one of the main components constituting the K-complex. Small negative and positive components were found immediately before the main components of spontaneous K-complex in averaged EEG. These two components were judged to correspond to N100 and P200 induced by the sound stimulus. The present findings suggest that the spontaneous K-complex is not a spontaneous phenomenon but that it is induced by sensory stimuli.

Cortical activity of REM sleep often occurs earlier than other physiological phenomena.

N300 appearing in response to sound stimulus was used as an index to determine the occurrence of cortical activity characterizing REM sleep. In 5/10 subjects, marked reduction of N300 amplitude occurred even in the period of 0.5-2.5 min immediately preceding the appearance of muscle atonia characterizing REM sleep. Neither muscle atonia nor rapid eye movements appeared prior to the marked reduction of N300 amplitude in any subject. This suggests that the cortical activity characterizing REM sleep sometimes occurs a few minutes (or less) earlier than other physiological phenomena.

Marked suppression of cortical auditory evoked response shortly before the onset of REM sleep.

In 10 of 12 subjects examined, the amplitude of N300, a component of the cortical auditory evoked potential, was evidently smaller in rapid eye movement (REM) sleep than in non-REM sleep. The start of the reduction associated with the onset of the first episode of REM sleep was examined in these 10 subjects. In five of these, a marked reduction of N300 amplitude occurred 0.5-2.5 min before the appearance of muscle atonia of REM sleep. In two subjects, a similarly marked reduction of the N300 amplitude occurred 0.5-1.0 min before the disappearance of sleep spindles or K-complexes. This suggests that a suppression of the synchronizing mechanism in the cerebrum sometimes occurs briefly prior to the occurrence of other physiological phenomena associated with REM sleep.

Evaluation of angiogenic inhibitors with an in vivo quantitative angiogenesis method using agarose microencapsulation and mouse hemoglobin enzyme-linked immunosorbent assay.

In the present work, using a previously reported in vivo quantitative tumor-angiogenesis model, we attempted to ascertain whether this animal model is suitable for practical use in monitoring inhibitors of tumor angiogenesis. Mouse sarcoma-180 cells, human A431 cells or rat C6 cells microencapsulated in agarose beads were implanted s.c. into C57BL/6 mice. The level of blood vessel induction at the agarose pellet site was evaluated using mouse hemoglobin enzyme-linked immunosorbent assay on day 10 after implantation. Hydrocortisone, tetrahydro-S, medroxyprogesterone acetate, pentosan polysulfate and suramin inhibited blood vessel growth in our in vivo tumor-angiogenesis assay system, and heparin enhanced the antiangiogenic effects of hydrocortisone and tetrahydro-S. These results are almost entirely consistent with those observed in common assay systems, and suggest that this method may be useful for the identification and quantitative evaluation of inhibitors of tumor angiogenesis.

Eosinophilic pustular folliculitis effectively treated with recombinant interferon-gamma: suppression of mRNA expression of interleukin 5 in peripheral blood mononuclear cells.

Eosinophilic pustular folliculitis (EPF) is characterized clinically by pruritic grouped follicular papules and pustules on the trunk, limbs, and face, and, histologically, by follicular infiltration with eosinophils. The blood eosinophil count is elevated in most patients. Oral minocycline, nonsteroidal anti-inflammatory drugs, diaminodiphenylsulphone, and corticosteroids may induce remission. We report two Japanese men with EPF who responded poorly to the usual therapy. Intravenous injections of recombinant interferon-gamma (rIFN-gamma), 5 x 10(5) to 2 x 10(6) Japan Reference Unit (JRU) (1 JRU roughly corresponds to 4 NIH units) daily for 7 days, cleared the skin lesions and returned the peripheral eosinophil counts to normal in both patients. However, the lesions recurred 2-3 days after rIFN-gamma was stopped. Both patients have received intravenous rIFN-gamma once or twice a week for nearly 1 year without systemic side-effects. Reverse transcriptase-polymerase chain reaction revealed a decreased expression of interleukin 5 (IL-5) mRNA in peripheral mononuclear cells after the rIFN-gamma therapy. rIFN-gamma may become the treatment of choice in recalcitrant EPF, although further studies are needed. It may work by interfering with the immunological function of type 2 T-helper cells, including IL-5 production responsible for the growth and differentiation of eosinophils.

Varicella pneumonia in a healthy adult presenting with severe respiratory failure.

We describe a case of varicella pneumonia in a 24-year-old healthy man presenting with severe respiratory failure. A chest radiograph showed diffuse, bilateral airspace consolidation; additional complications included liver dysfunction and thrombocytopenia. However, treatment with intravenous acyclovir and gamma-globulin improved his clinical symptoms and signs. A greater than four-fold change in paired titers of the varicella-zoster virus antibody was observed. Bronchoalveolar lavage performed during the recovery phase revealed increased total cell and lymphocyte counts and a decreased CD4:CD8 ratio of T lymphocytes. Transbronchial lung biopsy findings were compatible with a diagnosis of interstitial pneumonia.

A quantative in vivo method of analyzing human tumor-induced angiogenesis in mice using agarose microencapsulation and hemoglobin enzyme-linked immunosorbent assay.

This study was conducted to develop a quantitative assay system for use in the in vivo evaluation in mice of angiogenesis induced by human tumor cells. The human epidermoid carcinoma cells, A431 cells, were cultured on microcarriers. Microcarrier-attached A431 cells (A431-MC) were microencapsulated with agarose hydrogel to isolate them from the immune system of the C57BL/6 mice after subcutaneous dorsal midline implantation. The agarose hydrogel-microencapsulated A431 cells (Aga-A431 cells; diameter=300 micron) survived for at least 10 days in vitro, and the proliferation profile of the Aga-A431 cells was indistinguishable from that of non-microencapsulated A431 cells. The Aga-A431 cells were subcutaneously injected into mice with an 18-gauge needle. Ten days later, few vessels had formed at the site implanted with cell-free agarose beads, whereas notable angiogenesis was observed at the site implanted with Aga-A431 cells. The degree of angiogenesis was evaluated by measurement of the hemoglobin content in the implanted site using a mouse hemoglobin (mHb) enzyme-linked immunosorbent assay (ELISA) system. This mHb-ELISA system has the advantages of great simplicity and reproducibility. The measured mHb-content of new blood vessels at the site implanted with agarose beads was in good agreement with the amount of angiogenesis observed under a stereoscopic microscope. This assay system enabled us to evaluate the angiogenesis induced by xenogeneic cells, such as human tumor cells. Thus, our novel method may be useful for the study of the angiogenic potential of various human tumor cells and in research on the anti-angiogenic properties of various agents.

Malignant hemangioendothelioma.

BACKGROUND: The administration of interleukin-2 (IL-2) has recently been reported to be favorable for treating malignant hemangioendothelioma (MHE). METHODS: Two patients with MHE responded well to intralesional injections of recombinant IL-2 (rIL-2) without major side effects. The purpose of this study was to characterize cells infiltrating the regressing tumor following rIL-2 treatment. Immunohistochemical studies were performed on biopsy specimens taken from rIL-2-injected lesional skin. RESULTS: It was shown that CD8+ lymphocytes and CD56+ natural killer (NK) cells infiltrated at the rIL-2-injection sites, suggesting that these cells contributed to the tumor regression. In addition, MHE cells bore intercellular adhesion molecule-1 (ICAM-1) whose expression was augmented by rIL-2 injections. CONCLUSIONS: These findings suggested, that rIL-2 not only induces lymphokine-activated killer (LAK) cells and NK cells, but also facilitates these cytotoxic cells to adhere to MHE cells by enhancing ICAM-1 expression of tumor cells.

K-complex evoked in NREM sleep is accompanied by a slow negative potential related to cognitive process.

Evoked cortical responses to two kinds of auditory stimuli (rare and frequent) were analyzed to determine whether or not a K-complex evoked in stage 2 of NREM sleep is accompanied by some endogenous cognitive components of the event-related potential. All the 7 subjects examined in this sleep state failed to provide the correct behavioral response to auditory stimuli, but a K-complex was evoked more frequently by rare stimuli than by frequent stimuli. EEG segments in stage 2 were averaged separately according to the presence or absence of K-complexes emerging just after the stimulation. In cases where K-complexes did not emerge, a long-lasting negative potential of relatively low voltage appeared in the difference wave, which was obtained by subtracting the averaged EEG for frequent stimuli from that for rare stimuli. In cases where K-complexes emerged, a similar long-lasting negative potential of large amplitude appeared in the difference wave. These data may indicate that a K-complex evoked by an external stimulus is accompanied by a potential related to a cognitive process, which appears with greater amplitude in cases where a K-complex is evoked.

Essential region for transforming activity of human c-Ha-ras-1.

An SstI fragment of 2.9 kb carrying all four coding exons of the human melanoma c-Ha-ras-1 oncogene could not transform mouse NIH 3T3 cells. Preparation of plasmid clones carrying the 2.9 kb SstI DNA and adjacent regions and analyses of the biological activities of the clones revealed that, for transforming activity of c-Ha-ras-1, a nucleotide sequence of 0.85 kb adjacent to the 2.9 kb DNA in the upstream region was required.