Comparison of antiemetic efficacy between single and repeat treatment with dexamethasone in patients receiving carboplatin-based combination chemotherapy.

A retrospective study was carried out to compare the preventive effects of single and repeat treatment with dexamethasone (DEX) on delayed nausea and emesis in patients who had received carboplatin (CBDCA)-based combination chemotherapy. Sixty-four patients were evaluated. Efficacy was assessed using the nausea and emesis score, food intake score and the requirement for antiemetic medication. These forward scores were categorized as three-grade during the first 5 days after chemotherapy. Acute nausea and emesis were well controlled in both groups on day 1. Mean values of the nausea and emesis score on day 3 evening and the food intake score on day 4 morning in the repeat-treatment group was 1.31 ± 0.93 and 3.46 ± 1.03, respectively, which were significantly better when compared with the single-treatment group (2.00 ± 1.52; P = 0.028 and 2.79 ± 1.12; P = 0.018, respectively). Multivariate logistic regression analysis revealed that less frequent dispensing of antiemetic medication was significantly associated with the repeat-treatment group (adjusted odds ratio, 0.153; 95% confidence interval, 0.026-0.734; P = 0.018). These results suggest that repeat-dose DEX may be more effective than single-dose DEX for the prevention of delayed nausea and emesis after CBDCA-based combination chemotherapy.

Chemokines in synovial inflammation in rheumatoid arthritis: basic and clinical aspects.

Abstract Rheumatoid arthritis (RA) is a chronic, multisystem autoimmune disease characterized by persistent synovitis. Since chemotactic cytokines (chemokines) may play critical roles in the recruitment of leukocytes in RA, analyses of chemokines and their receptors should provide insight into events in synovial inflammation in RA. The production of chemokines is regulated by cytokines such as tumor necrosis factor (TNF)-α produced in the inflamed joint, suggesting that the efficacy of anti-TNF-α therapy is mediated at least partly by the reduction of chemokine production. Chemokines have a role in joint inflammation not only by inducing leukocyte chemotaxis, but also by activating immune cells and angiogenesis. The pathogenesis of RA has been shown to be mediated by Th1-type T cells, because Th1-related chemokine receptors are preferentially expressed on cells in synovial fluid and synovial tissue. Accordingly, antichemokine therapy may be important as a possible new approach to therapeutic intervention in RA.

Subcorneal pustular dermatosis-type IgA pemphigus induced by thiol drugs.

We report a case of subcorneal pustular dermatosis (SPD)-type IgA pemphigus arising in a 49 year-old woman with rheumatoid arthritis who had been treated with chrysotherapy. Scaly erythemic plaques containing vesicles and pustules occurred on her chest and abdomen during the course of anti-rheumatic treatments using prednisolone at 11 mg/day and thiol compounds (bucillamine and gold sodium thiomalate). Histological investigations revealed subcorneal pustules containing many neutrophils and a few acantholytic cells, and intercellular IgA deposits at the upper epidermis of the eruptions without any other immunoglobulins and complement component C3. Circulating IgA antibodies directed against intercellular spaces of the epidermis were found by prolonged incubation of normal skin specimens in medium containing 20% patient's serum in an explant culture, although standard indirect immunofluorescence for IgA antibodies was negative. The eruptions were treated successfully with prednisolone, 30 mg/day, dapsone, 50 mg/day, and discontinuance of the thiol compound. In addition to the coexistent rheumatoid arthritis, both thiol compounds might have been responsible for the development of the eruptions.

Recalcitrant trichophytic granuloma associated with NK-cell deficiency in a SLE patient treated with corticosteroid.

Although deep trichophytic infection often occurs in immunocompromised patients, the immune deficiency in such patients has not been clarified. A 28-year-old man who suffered from recalcitrant trichophytic granuloma and tinea universalis during treatment for SLE with corticosteroid is described here to define the immunological abnormalities. In addition to routine immunological tests, we evaluated the patient's innate and specific immune functions to dermatophytes, including T cell, natural killer (NK) cell and neutrophil functions and activation of the complement cascade. We measured the minimum inhibitory concentration (MIC) of itraconazole for the isolated fungus and its concentrations in the patient's serum and pus. Trichophyton (T.) rubrum was constantly isolated from the exudates of the patient's skin lesions, although the concentrations of itraconazole in his serum (198 ng/ml) and lesions (210 ng/ml) were sufficient to inhibit the growth of the isolated fungus in vitro. Specific cell-mediated immune responses, determined by T cell stimulation and IFN-gamma production, were evoked following stimulation with trichophytic antigens. The patient's innate immunity, assessed by activation of the complement cascade and neutrophil-mediated phagocytosis, was not impaired. The number of circulating NK cells was markedly decreased (0.2% of the peripheral blood mononuclear cells), and was associated with low NK cell activity against K-562 cells even though lymphopenia had improved. The deficiency of innate immunity mediated by NK cells might be responsible for a part of the persistence of trichophytic granuloma in our case. Dermatophytes usually affect the horny layer of the skin and do not invade the living layers because the host immune system uses various mechanisms to eliminate the fungi. Both specific T cell-mediated immunity and nonspecific immunological mechanisms provide host defense against fungal infections. An adaptive immune response is usually preceded by innate immune responses mediated by neutrophils, NK cells, and circulating proteins such as complement components and anti-microbial peptides. However, in patients with localized or systemic immunological defects, granulomatous cutaneous infection of dermatophytes mostly caused by trichophytic fungi may occur [1]. Trichophytic granuloma includes Majocchi's granuloma [2] and disseminated trichophytic granuloma [3]. Recently, we experienced a patient with trichophytic granuloma and tinea universalis caused by Trichophyton (T.) rubrum infection during treatment with corticosteroid for systemic lupus erythematosus (SLE). We describe the clinical details of this patient, focusing on his immunological defects which led to the persistence of the fungal infection.

Expressed emotion and psychoeducational intervention for relatives of patients with schizophrenia: a randomized controlled study in Japan.

The benefit of single-family treatment (SFT) in addition to short educational sessions (SES) consisting of multiple-family treatment was investigated. The study design was a randomized controlled study. Subjects were 30 patients suffering from schizophrenia with at least one of their family members showing high expressed emotion (EE) in the Camberwell Family Interview. After the SES, the patients were randomly allocated to two groups: those who received routine individual outpatient treatment and those who received additional SFT and routine treatment. The two groups were followed for 9 months after discharge, and the relapse risks were compared. The relapse risk was lower in the SES+SFT group than in the SES group (23.1% vs. 35.3%). However, the difference was not significant. When high-EE families were classified into those with many critical comments (high-CC) or a high score of emotional overinvolvement (high-EOI), the relapse risk was 0% in the patients living with a high-CC family not only in the SES+SFT group but also in SES group. In the patients living with a high-EOI family, the relapse risk was lower in the SES+SFT group than in the SES group (42.9% vs. 60.0%). These findings suggest that high-EE families should receive at least SES, and additional SFT should be given to families with specific needs.

Involvement of hepatocyte growth factor on hepatocarcinogenesis induced by peroxisome proliferators.

Hepatocyte growth factor (HGF) has been known to enhance the growth of normal hepatocytes, but also to inhibit the growth of neoplastic cells. This article examines the involvement of HGF in the hepatocarcinogenesis caused by peroxisome proliferators (PPs). Up to 78 wk after male F-344 rats were orally given (4-chloro-6-[2,3-xylidino]-2-pyrimidinylthio) acetic acid (Wy-14,643), the hepatocarcinomas and (pre)neoplastic nodules in the livers were observed. At that time, the content of HGF and the expression of HGF mRNA in the liver tumors were significantly decreased. These changes were observed also in the liver of rats treated with other PPs, such as dehydroepiandrosterone and di(2-ethylhexyl)phthalate, but were not observed in tumors induced by genotoxic carcinogens (diethylnitrosamine-phenobarbital). In in vivo experiments, the formation of preneoplastic lesions and the tumors caused by Wy-14,643 administration were markedly suppressed by i.v.-injection of HGF in a dose-dependent manner. In the colony assay using (pre)neoplastic cells from livers of Wy-14,643-treated rats, HGF inhibited the colony formation of (pre)neoplastic cells in a dose-dependent manner. These findings may indicate that decreases in hepatic HGF levels are common and specific events induced by PPs, but not by genotoxic carcinogens, and that those changes play an important role in the promotion of neoplastic or preneoplastic cell growth induced by PPs.

Wy-14,643, a peroxisome proliferator, inhibits compensative cell proliferation and hepatocyte growth factor mRNA expression in the rat liver.

Previously, we found that a peroxisome proliferator significantly reduced hepatic and plasma hepatocyte growth factor (HGF) levels in male F-344 rats, and that the growth of preneoplastic or neoplastic cells induced by this peroxisome proliferator was markedly inhibited by HGF. Here, we examined the effects of [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643), a peroxisome proliferator, on cell proliferation and HGF mRNA levels in the liver of rats after stimulation of compensative cell proliferation. After 2 weeks of treatment with Wy-14,643, hepatic DNA synthesis caused by partial hepatectomy was decreased by 50% compared with untreated controls. DNA synthesis was maintained at the same reduced level for up to 10 weeks. During this period, hepatic HGF mRNA level was also much lower in Wy-14,643-treated rats than untreated controls. Therefore Wy-14,643, a peroxisome proliferator, would inhibit the growth of normal hepatocytes, and then produce an advantageous circumstance for the selective growth of neoplastic or preneoplastic cells.

Induction of hepatic poly(ADP-ribose) polymerase by peroxisome proliferators, non-genotoxic hepatocarcinogens.

Two peroxisome proliferators, [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643) or di(2-ethylhexyl) phthalate (DEHP), were given orally to male F-344 rats for up to 78 or 97 weeks. At 1 week, the activity of poly(ADP-ribose) polymerase (pADPRP) was increased 2- and 1.8-fold in the liver of rats treated with Wy-14,643 and DEHP, respectively. The induction of the activity was maintained at 2.5- or 2-fold for up to 52 weeks. The immunoblot and Northern blot analyses revealed that the induction of pADPRP activity would be responsible for the increase in the amount of mRNA. In addition, in the liver tumor induced by Wy-14,643 and DEHP, the pADPRP mRNA level increased 3.6- or 3.7-fold. The magnitude of the increase in the mRNA level was higher than that in the non-tumor portion. These findings suggest that the induction of pADPRP may play an important role in the hepatocarcinogenesis induced by peroxisome proliferators.

Decreased hepatocyte growth factor level by Wy-14,643, non-genotoxic hepatocarcinogen in F-344 rats.

We examined the role of hepatocyte growth factor (HGF) in the hepatocarcinogenesis caused by [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643), a peroxisome proliferator. Wy-14,643 (100 mg/kg body wt or 0.1% (w/w) in diet) was given orally to male F-344 rats for up to 78 weeks. At 78 weeks the hepatocarcinomas or adenomas in the livers of Wy-14,643-treated rats were observed. Markedly decreased amounts of hepatic HGF mRNA were observed in rats fed Wy-14,643 for 78 weeks. The degree of reduction was higher in the tumour portions of the liver than in the normal portions. After 7 days of treatment with Wy-14,643 (100 mg/kg body wt), the expression of hepatic HGF mRNA was slightly decreased. Wy-14,643 treatment resulted in a time-dependent decrease in hepatic HGF mRNA levels to 63% of the control level after 14 days of treatment. In long-term treatment (18-40 weeks), hepatic HGF mRNA levels were reduced further, reaching 44% of the control level at the 40-week stage. As shown by ELISA, the amounts of hepatic and plasma HGF were significantly decreased by 60 and 50%, respectively, compared with controls. The degree of the reduction correlated with the level of hepatic HGF mRNA. In the lung and kidney, also HGF secretory organs, Wy-14,643 slightly reduced the amount of HGF mRNA. In the colony assay using preneoplastic or neoplastic cells from Wy-14,643-treated livers, 5-15 ng/ml of HGF, which induces proliferation in normal hepatocytes, inhibited the colony formation of neoplastic or preneoplastic cells. The inhibitory effect was dependent on HGF concentration. In the presence of 300 ng/ml HGF, the growth of colonies was suppressed to 36% of the control level. These findings indicate that reductions in hepatic HGF levels, induced by Wy-14,643, may play an important role in the promotion of neoplastic or preneoplastic cell growth.

[The correlation between interleukin-10 and interferon-gamma produced by peripheral blood mononuclear cells stimulated by house dust mite antigen in atopic dermatitis].

The production of interleukin (IL)-10 and interferon (IFN)-gamma by peripheral blood mononuclear cells (PBMC) stimulated by house dust mite (HDM)antigen and concanavaln A (Con A) was measured in patients with atopic dermatitis (AD). The HDM-stimulated PBMC from AD patients revealed to produce significantly higher levels of IL-10 (12 h: 918.4 +/- 206.5, 24 h: 1252.5 +/- 145.8, 72 h: 1332.7 +/- 123.9 pg/ml) than those from normal control subjects (12 h: 231.1 +/- 139.0, 24 h: 585.7 +/- 196.2, 72 h: 813.5 +/- 181.8 pg/ml). Con A-stimulated AD-PBMC also showed significantly higher levels of IL-10 production than those from normal controls, although they were lower than the productions induced by HDM antigen. By contrast, the levels of IFN-gamma from AD PBMC stimulated with HDM or Con A, were significantly lower than those from normal controls. IFN-gamm production might be down-regulated by IL-10 in AD-PBMC. The overproduction of IL-10 seems to show that helper T type 2 (Th2) cells are rather dominantly activated than Th1 cells and Th2 cells might contribute to produce the cytokines in response to HDM antigen in AD patients.

High-power CO(2) laser with a Gauss-core resonator for high-speed cutting of thin metal sheets.

A novel resonator, the Gauss-core resonator, based on a stable resonator configuration designed to yield a highly focusing beam operating in a large-volume TEM(00) mode, is presented. A 6.2 kW linearly polarized output beam with an M(2) factor of 1.7 is obtained experimentally for a high-power cw CO(2) laser. The capability of the Gauss-core resonator to process laser materials is also studied. We can cut 1-mm-thick mild (soft) steel with a maximum cutting speed of 58 m/min at 5.6 kW and 0.2-mm-thick steel 145 m/min at 2.8 kW.

Diversity of immunobiological functions of T-cell lines established from patients with adult T-cell leukaemia.

In order to understand the variety of HTLV-1-associated cutaneous diseases, we studied the cytological profile of HTLV-1-infected T-cell lines established from patients with adult T-cell leukaemia (ATL). Among four CD4+ cell lines, termed 16T(-), 35T(-), MH-1, and KS-2, the 16T(-) cells secreted elevated quantities of IL-4, IL-6 and IFN-gamma and expressed mRNA for each cytokine in the absence of exogenous stimulation. The 35T(-) cells secreted IL-6 and a small amount of IFN-gamma, but not IL-4. The MH-1 and KS-2 cells secreted only IL-6 in the absence of stimulation. In response to stimulation with phorbol-12-myristate-13 acetate (PMA), the 16T(-) cells produced more IL-4 and IFN-gamma, whereas the 35T(-) and MH-1 cells exhibited increased secretion of IFN-gamma, but still no IL-4 or IL-4 mRNA production. Although neither IL-4 nor IFN-gamma were found in the culture supernatant of KS-2 cells, the production of IL-4 mRNA was detected by RT-PCR. Culture supernatants from the 16T(-) and 35T(-) cells induced the expression of intercellular adhesion molecule-1 (ICAM-1) and HLA-DR by cultured keratinocytes. This response was inhibited by pretreatment of the supernatant with anti-IFN-gamma antibodies. These results indicate that some HTLV-1-infected T-cell lines constitutively secrete various cytokines, including biologically active IFN-gamma. The diversity of immunobiological functions of the T-cell lines may be related to the variety of clinical features present in ATL patients.

Comparative studies on the usefulness of phosphate versus glycerin enema in preparation for colon examinations.

Fifty of 100 persons who had undergone health screening received phosphate enema while the other 50 received glycerin enema prior to proctoscopy and barium enema, and their usefulness for preparation for colon examination was compared by a double-blind test. There was no significant difference in the degree of colonic cleansing achieved by proctoscopy and barium enema. In the subjects who received phosphate enema, the incidence of abdominal pain was less than that in those who received glycerin enema, while the effect of phosphate enema on defecation appeared later than that of glycerin enema, indicating prolonged stool retention in the subjects given phosphate enema. To study the safety of the two enemas, either phosphate enema, glycerin enema or physiological saline solution as a control was administered at 0.35 ml/animal in the rectum by 4-h closure of the anus in 10 male 7-week-old Wistar rats, and the rectal mucosa was observed for irritation macroscopically and histopathologically. Glycerin enema produced less irritation than phosphate enema diffusely in the entire area of the rectum, while phosphate enema produced more local irritation at the end of the rectum than glycerin enema. The differences in the extent of irritation and injury between phosphate and glycerin enemas were considered to be derived from differences in the pharmacologic actions of these drugs. If the extent of injury were included in the extent of irritation, the difference in irritation between phosphate and glycerin enemas would not be significant. As described above, no specific difference seem to exist in the usefulness of phosphate and glycerin enemas as preparation for colon examination.

Sulfation of polysaccharides generates potent and selective inhibitors of human immunodeficiency virus infection and replication in vitro.

The inhibitory effects of several polysaccharides, dextran, xylofuranan, and ribofuranan, and their sulfated counterparts on the infectivity and replication of human immunodeficiency virus (HIV) were examined by using an HTLV-I-carrying cell line, MT-4, in vitro. Dextran sulfate (Mw 34 X 10(3], xylofuranan sulfate, and ribofuranan sulfate completely prevented HIV-induced cytopathic effects (CPE) at concentrations greater than 10 micrograms/ml and dextran sulfate (Mw 7 X 10(3] at concentrations greater than 100 micrograms/ml. However, the non-sulfated compounds did not prevent them at any concentration tested. The anti-HIV effect of these polysaccharides was confirmed by measuring HIV-specific antigen expression in infected MT-4 cells. In cocultures with MOLT-4 and MOLT-4/HIVHTLV-IIIB cells, formation of multinucleated cells was completely inhibited in the presence of 100 micrograms/ml of these sulfated compounds. Dextran sulfate showed 20-30% growth inhibition of uninfected MT-4 cells at 1000 micrograms/ml but dextran sulfate, xylofuranan sulfate, and ribofuranan sulfate showed no effect on sulfated polysaccharides efficiently inhibited the reverse transcriptase activity of avian myeloblastosis virus and HIV.

Purification and characterization of an avian myeloblastosis and human immunodeficiency virus reverse transcriptase inhibitor, sulfated polysaccharides extracted from sea algae.

A new reverse transcriptase (RT) inhibitor was extracted and purified from the red alga Schizymenia pacifica. The chromatographic behavior and chemical properties of this sea algal extract (SAE) suggest that it is a sulfated polysaccharide having a molecular weight of approximately 2,000,000. SAE is composed of galactose (73%), sulfonate (20%), and 3,6-anhydrogalactose (0.65%). SAE is a member of the lambda-carrageenan family, based on its infrared spectrum and products of hydrolysis. SAE selectively inhibited human immunodeficiency virus (HIV) RT and replication in vitro. When MT-4 cells were treated with more than 10(4) inhibitory units (IU) of SAE per ml after HIV infection, significant inhibition of viral antigen synthesis was observed. Furthermore, more than 90% of cells were viable in the cultures exposed to 4 X 10(4) to 8 X 10(4) IU of SAE per ml, while almost all the MT-4 cells in the control culture had died by 10 days after HIV infection. The inhibitory effect of SAE on HIV replication was confirmed by plaque reduction assays. The 50% inhibitory dose of SAE was 9.5 x 10(3) IU/ml. Chondroitin sulfate A, dermatan sulfate, heparan sulfate, keratan polysulfate, and heparin also inhibited the RT of avian myeloblastosis virus. SAE immediately inhibited RT activity when added to an assay mixture after the start of the reaction.

A new anti-human immunodeficiency virus substance, glycyrrhizin sulfate; endowment of glycyrrhizin with reverse transcriptase-inhibitory activity by chemical modification.

Glycyrrhizin sulfate (GLS) was synthesized and investigated for antiviral effect on the human immunodeficiency virus (HIV) in vitro in comparison with the parental anti-HIV compound glycyrrhizin (GL). In MT-4 cells after HIV infection, the virus-induced cytopathic effect and the expression of viral antigens were inhibited by 0.25 mg/ml (0.184 mM) of GLS. Moreover, GLS completely inhibited HIV-induced plaque formation in MT-4 cells at a concentration of 1 mg/ml (736 microM), the 50% inhibitory dose being 0.055 mg/ml (40 microM). GLS was found to be an efficient inhibitor of reverse transcriptase. The effect of GLS was 4 times stronger than that of GL in molar terms.

Antiretroviral activity in a marine red alga: reverse transcriptase inhibition by an aqueous extract of Schizymenia pacifica.

An aqueous extract from the marine red alga, Schizymenia pacifica has been tested in a cell free system for its effect on reverse transcriptase from avian retrovirus (avian myeloblastosis virus), and mammalian retrovirus (Rauscher murine leukemia virus). The extract inhibited reverse transcriptase from both these retroviruses but showed almost no effect, if any, on the activity of cellular DNA polymerase alpha and RNA polymerase II in vitro. Consequently it is unlikely to have an adverse effect on the growth of cultured cell. The inhibitory activity of the extract was stable over a relatively wide pH range (pH 1-11) and was not lost after pronase digestion. Inhibitory activity of the extract was lost after boiling at 100 degrees C in 0.67 N HCl, and after treatment with 100 mM NaIO4. The active principle in the extract has an apparent molecular weight in excess of 100,000 daltons. This new reverse transcriptase inhibitor is probably a polysaccharide.

Isolation and characterization of I5B2, a new phosphorus containing inhibitor of angiotensin I converting enzyme produced by Actinomadura sp.

A new inhibitor of angiotensin I converting enzyme, I5B2, was isolated from the culture broth of Actinomadura sp. No. 937ZE-1. This compound contains N-methylvaline, tyrosine and 1-amino-2-(4-hydroxyphenyl)ethylphosphonic acid. The microorganism also produced another inhibitor, I5B1, which is identical with K-4 isolated from Actinomadura sp. as an antihypertensive agent.