Alteration of lymphocyte function in nzb/nzw mice

NZB/NZW F₁ female mice received levamisole in an attempt to increase suppressor T cell function. Responses varied with dosage of drug and age of mice. When treatment with 25 μg/gm doses (intermittent or daily) was begun at 12 weeks of age, nephritis was accelerated in spite of transient reduction of anti-DNA antibodies. When treatment was begun at 4 weeks, or when doses of 250 μg/gm were given, no clinical effects were observed. In the mice with accelerated disease, delayed hypersensitivity and antibody responses to sheep erythrocytes increased; antibody responses to pneumococcal poiysaccharide were unaffected. It is possible that some increased immune responses associated with levamisole are undesirable in murine lupus.     

Prostaglandin E treatment of NZB/NZW mice.

NZB/NZW F1 hybrid mice were treated with pharmacologic doses of prostaglandin E1 (PGE1) (200 microng subcutaneously either once or twice daily) from 6 through 52 weeks of age. PGE1-treated mice were protected against development anemia, clinical nephritis, and death. At 52 weeks 18 of 19 treated mice were alive, wherase only 2 of 19 untretreated control mice were alive. None of the 10 mice treated with PGE1 twice daily exhibited significant (greater than 2+) proteinuria at 1 year of age. PGE1 treatment did not prevent development of antibodies to nuclear antigens. The data also suggest that survival of NZB/NZW mice is prolonged when treatment with PGE1 is begun at 24 weeks, an age at which mice already show evidence of nephritis. Thus all 6 mice treated with PGE1 (200 microng sc twice daily) from 24 weeks were alive at 52 weeks, whereas only 2 of 6 untreated control mice were alive. The mechanisms whereby PGE1 treatment influences the course of disease in NZB/NZW mice are not known.     

The effect of trimethoprim and sulfamethoxazole on Toxoplasma gondii in vitro and in vivo.

Trimethoprim (TMP) and sulfamethoxazole (SMZ) were studied alone and in combination to determine their effect in vitro on intracellular Toxoplasma gondii and in vivo against murine toxoplasmosis. In the in vitro experiments, whereas 1 and 2 microgram/ml TMP had no demonstrable effect on intracellular T. gondii, 10-20 microgram/ml TMP resulted in death of the intracellular organisms; concentrations as high as 100 microgram/ml SMZ had no demonstrable effect against the intracellular organisms. When used in combination, a significant synergistic effect was noted with 2 microgram/ml TMP-50 microgram/ml SMZ. Studies on the kinetics of inhibition and/or killing of Toxoplasma revealed that 18 hours of treatment with 2 microgram/ml TMP-50 microgram/ml SMZ resulted in irreversible inhibition of the intracellular organisms. When used in vivo against a 50,000 LD100 dose of Toxoplasma, TMP fed by gavage or mixed in the diet had no effect in murine toxoplasmosis at doses as high as 200 mg/kg a day. SMZ administered by gavage had no effect at doses up to 200 mg/kg a day; but at 300 and 400 mg/kg SMZ, protection was 47% and 83%, respectively. Treatment of infected mice was continued for 14 consecutive days, whether the drugs were administered alone or in combination. The combination 200 mg/kg TMP-200 mg/kg SMZ, when administered by gavage, protected 87% of mice. Survival after 14 days of SMZ mixed in the diet was 0% at 100 mg/kg, 47% at 200 mg/kg, and 100% at 300 mg/kg. Survival with the combination was 40% for 200 mg/kg TMP-100 mg/kg SMZ and 100% for 100 mg/kg TMP-200 mg/kg SMZ. The half-life of TMP in serum of Swiss Webster mice was calculated to be 24 min. The results obtained in vivo were inferior to those obtainable with the combination of pyrimethamine plus sulfadiazine. The problems of interpretation of results obtained in the murine model using TMP-SMZ and in their extrapolation to the treatment of the infection in man are discussed.     

Effect of triiodothyronine on glucose utilization in diaphragm of obese (ob/ob) mice

Genetically obese-hyperglycemic (ob/ob) mice are hypothyroid, hyperinsulinemic, and insulin resistant. Because muscle plays an important role in glucose homeostasis, the role of triiodothyronine (T3) in regulation of insulin-sensitive glucose utilization by muscles of obese mice was examined. Four doses of T3, 5.0, 12.5, 25.0, and 50.0 micrograms/100 g body weight were injected, i.p., into obese and nonobese mice daily from 3 weeks until 6 weeks of age. Food consumption and body weight were decreased at lower doses of T3 and increased at higher doses of T3 in both obese and nonobese mice. By 6 weeks of age all doses of T3 treatment increased oxygen consumption in both genotypes. At 6 weeks of age, the diaphragms from the saline-injected nonobese mice had greater in-vitro insulin-stimulated glucose utilization than muscles from the saline-injected obese mice. Both anaerobic and aerobic glucose oxidation were increased by T3 treatment, but the obese had greater increases than those observed in muscles from nonobese mice. Muscles from obese mice increased insulin-stimulated glucose utilization by T3 treatment to that of the nonobese level, whereas there was no change in insulin-stimulated glucose utilization of nonobese mice. Muscle glycogen synthesis in obese and nonobese mice was decreased with very high T3 doses. A higher dose of T3 was required to increase glucose utilization in the obese muscles than in the nonobese muscles. The results suggest that a functional hypothyroidism or T3 resistance may be an early part of this particular obesity syndrome.     

Antibody responses of human infants to three doses of group A Neisseria meningitidis polysaccharide vaccine administered at two, four, and six months of age.

Infants were immunized with group A Neisseria meningitidis polysaccharide vaccine at two, four, and six months of age. Two lots of group A vaccine that differed in molecular weight were used; lot no. 1980A was of significantly larger molecular size than lot no. A-7. No significant adverse reactions occurred. The geometric mean concentration of serum antibody to group A N. meningitidis one month after the third dose of lot no. 1980A was 0.89 microgram/ml, nearly twice the concentration induced by lot no. A-7 (0.48 microgram/ml). When the infants were 12 months of age, concentrations of antibody in both groups had declined to similar levels, which were still greater than the mean concentration of antibody in unimmunized children. By 18 months of age, the antibody levels of immunized and unimmunized infants were the same. The three-dose schedule resulted in significantly lower concentrations of antibody than previously studied schedules of two doses given three to four months apart.     

Prostaglandin E1 treatment of NZB/NZW mice

NZB/NZW F₁ hybrid mice were treated with pharmacologic doses of prostaglandin E₁ (PGE₁) (200 μg subcutaneously either once or twice daily) from 6 through 52 weeks of age. PGE₁-treated mice were protected against development of anemia, clinical nephritis, and death. At 52 weeks, 18 of 19 treated mice were alive, whereas only 2 of 19 untreated control mice were alive. None of the 10 mice treated with PGE₁ twice daily exhibited significant (>2+) proteinuria at 1 year of age. PGE₁ treatment did not prevent development of antibodies to nuclear antigens. The data also suggest that survival of NZB/NZW mice is prolonged when treatment with PGE₁ is begun at 24 weeks, an age at which mice already show evidence of nephritis. Thus all 6 mice treated with PGE₁ (200 μg sc twice daily) from 24 weeks were alive at 52 weeks, whereas only 2 of 6 untreated control mice were alive. The mechanisms whereby PGE₁ treatment influences the course of disease in NZB/NZW mice are not known.     

Estrogenic stimulation of hypothalamic-limbic system metabolism in ageing diabetic C57BL/KsJ mice.

The therapeutic influences of estrogen treatment on age- and diabetes-related declines in regional brain glucose utilization (RBGU) rates were evaluated in 8- to 20-week-old female C57BL/KsJ normal (+/?) and diabetic (db/db) mice. Following either oil vehicle (oil: 0.1 ml) or estradiol (E: 1 microgram/3.5 days) treatments starting at 3 weeks of age, RBGU rates were subsequently determined at 8, 12, 16 and 20 weeks of age. A gradual decline in the basal rate of brain glucose utilization was observed in all control (oil- and E-treated) groups between 8 and 20 weeks. Expression of the hyperglycemic-obese diabetes syndrome in db/db mice resulted in a significant reduction in RBGU rates between 8 and 20 weeks relative to control values. In estrogen-sensitive hypothalamic, septal and amygdaloid regions, E therapy modulated RBGU rates in db/db mice relative to oil-treated diabetics, but did not significantly alter utilization rates in +/? mice. In cortical samples, E therapy had no significant influence on glucose utilization rates in either control or diabetic groups. A noticeable pattern of maturation-associated decline in CNS glucose utilization rates in all brain regions resulted in comparable regional metabolic indices being exhibited by all groups at 20 weeks of age, with the exception of the diabetes-associated exacerbation of RBGU rates in the oil-treated db/db group. These data demonstrate that the normal development-related decline in regional brain carbohydrate metabolism is accelerated by the diabetes syndrome, and that E therapy can modulate the syndrome-associated suppression of glucose utilization in steroid-sensitive CNS loci. These data suggest that the depressive influences of the diabetes syndrome on brain carbohydrate utilization rates may be therapeutically modified in recognized CNS regions possessing steroid-sequestering, metabolically responsive neurons.     

Accelerated appearance of neoplasms in female NZB/NZW mice treated with high-dose cyclophosphamide.

Prolonged immunosuppressive therapy with cyclophosphamide increases the prevalence of neoplasms in NZB/NZW mice, an animal model of systemic lupus erythematosus. The current study was designed to compare the oncogenic properties of high dose cyclophosphamide with a low dose therapeutic regimen. Female NZB/NZW mice received life-long therapy with "high dose" cyclophosphamide, 16 mg/kg/day, or "low-dose" cyclophosphamide, 5.7 mg/kg/day; control mice received saline. High dose therapy clearly accelerated appearance of neoplasms. Seventeen of 19 mice treated with high-dose cyclophosphamide developed neoplasms at the mean age of 61 weeks. Fifty-seven percent of these tumors were mammary carcinomas. Neoplasms appeared in all mice treated with low dose; mean longevity in this treatment group was 80 weeks (compared to high dose treated mice, P less than 0.001). Carcinomas, pulmonary adenomas, and lymphomas were the most common tumors in mice receiving low dose therapy. Positive tests for ANA were suppressed in high dose treated mice. AntiDNA antibody levels and glomerulonephritis were decreased significantly in both groups of cyclophosphamide-treated mice compared to controls. It was concluded that the high daily dose of immunosuppressive drug was related to early oncogenesis in autoimmune NZB/NZW mice.     

Improvement of glucose tolerance in Zucker diabetic fatty rats by long-term treatment with the dipeptidyl peptidase inhibitor P32/98: comparison with and combination with rosiglitazone

AIM: The aim of this study was to investigate the effect of long-term treatment with the dipeptidyl peptidase inhibitor P32/98 and its combination with rosiglitazone on blood glucose control and islet of Langerhans histology in male Zucker diabetic fatty (ZDF) rats, when treatment begins before or after the development of overt diabetes. METHODS: ZDF rats were treated with P32/98 from the age of 9, 12 or 15 weeks. Rosiglitazone maleate was given to a separate group from the age of 13 weeks. P32/98 was given to all of these rosiglitazone-treated rats from 16 weeks of age. Rosiglitazone maleate was also given from 16 weeks of age to half the rats that were given P32/98 from 9 weeks of age. The compounds were given by oral gavage until the rats were 14 weeks old and then in the diet. The experiment was terminated at the age of 20-21 weeks. Blood glucose, plasma insulin and oral glucose tolerance were measured at intervals; islet histology was assessed terminally. RESULTS: P32/98 improved glucose tolerance after both single and multiple doses when treatment started at 9 weeks of age, also after the third week of treatment when treatment began at 12 or 15 weeks of age. P32/98 reduced daytime blood glucose when treatment began at 12 weeks. Treatment with rosiglitazone increased food intake and body weight, and after 2 weeks, reduced daytime blood glucose, water intake and the area under the glucose tolerance curve. A single dose of P32/98 markedly improved glucose tolerance in rosiglitazone-treated rats. When treatment had begun at 9 weeks of age, P32/98 stimulated insulin secretion in some glucose tolerance tests. Neither P32/98 nor rosiglitazone affected pancreatic insulin content, nor did they have clear effects on islet histology. CONCLUSION: P32/98 elicited a sustained improvement in glucose tolerance in both prediabetic and diabetic ZDF rats. The effects of P32/98 on glucose and insulin were similar to those of rosiglitazone, and in contrast to rosiglitazone, P32/98 did not increase food intake or body weight. However, neither compound was especially effective at improving diabetes in ZDF rats when treatment began at 9, 12 or 15 (P32/98) or 13 (rosiglitazone) weeks of age.     

Timing affects the efficacy of LDL immunization on atherosclerotic lesions in apo E (-/-) mice

BACKGROUND: Immunization of animals with LDL reduces atherosclerosis. However, whether the timing of immunization affects its efficacy is not known. In this study, we evaluated the influence of timing of immunization on the athero-protective effects of LDL immunization in apo E (-/-) mice. METHODS AND RESULTS: Hypercholesterolemic apo E (-/-) mice were immunized with native LDL (nLDL) at age of 6-7 weeks old or at 20 weeks old. Compared to adjuvant group, mice that were immunized at the age of 6-7 weeks developed significantly smaller aortic sinus plaques with reduced gelatinolytic activity and increased collagen content. This was associated with an increase of oxidized LDL (oxLDL) antibody titer and a marked decrease in splenic IL-4 mRNA expression. Immunization at 20 weeks of age also increased oxLDL antibody titer but did not reduce plaque size, gelatinolytic activity or collagen content but resulted in a modest decrease in macrophage infiltration. Late immunization did not alter splenic IL-4 mRNA expression. CONCLUSIONS: Our findings demonstrate that, only early nLDL immunization modulates humoral and cellular immune responses and affects plaques size and composition in apo E (-/-) mice, indicating the critical importance of timing of immunization for its antiatherogenic efficacy.     

Antibody responses to hepatitis A virus vaccine in HIV-infected children with evidence of immunologic reconstitution while receiving highly active antiretroviral therapy

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients have weak responses to vaccines and may require revised immunization regimens. We investigated the safety and immunogenicity of 2 doses of hepatitis A virus (HAV) vaccine followed by a booster dose in HIV-infected children receiving stable highly active antiretroviral therapy. METHODS: A total of 235 children with CD4+ T cell percentages > or = 20% received 2 vaccine doses 24 weeks apart, and 117 received a third vaccine dose after 104 weeks. Anti-HAV antibody titers were measured at baseline and at 32, 104, and 112 weeks after the first vaccination. Subjects with antibody titers > or = 20 mIU/mL were defined as being seropositive. High and low antibody responses were defined as titers > or = 250 and <250 mIU/mL, respectively. RESULTS: Of 151 subjects who were HAV seronegative at baseline, 97% seroconverted after 2 vaccine doses, and 47% had low antibody responses. At 104 weeks, 90% of subjects had antibody titers > or = 20 mIU/mL, and those with low antibody responses were more likely to lose protective antibody titers. A third vaccine dose generated significantly higher antibody titers than those observed after the second vaccine dose. Undetectable HIV RNA at baseline was associated with higher anti-HAV antibody titers after the second vaccine dose. Antibody titers after the second and third vaccine doses were weakly correlated with CD4+ T cell percentages at the time when each vaccine dose was administered. In the 45 subjects who were HAV seropositive at baseline, responses to 2 and 3 vaccine doses were higher than those in subjects who were HAV seronegative at baseline, but the responses showed similar correlations. There were no serious adverse events associated with the vaccine. CONCLUSIONS: HIV-infected children with CD4+ T cell percentages > or = 20% responded better to the HAV vaccine if they had undetectable HIV RNA. The standard 2-dose immunization regimen generated low antibody titers with limited persistence. A third vaccine dose was safe and increased the antibody titers, suggesting that an increase in immunizations may be warranted in this population.     

Antioxidants suppress mortality in the female NZB x NZW F1 mouse model of systemic lupus erythematosus (SLE)

Inflammation produces reactive oxygen intermediates (ROI) that cause vascular damage and activate T lymphocytes. Conversely, antioxidants not only protect tissue from oxidative damage but also suppress immune reactivity. The objective of this study was to examine immunomodulatory effects of the non-enzymatic antioxidants, N-acetylcysteine (NAC) and cysteamine (CYST), on autoimmune disease, glomerulonephritis, and mortality in the female B/W mouse model of human systemic lupus erythematosus (SLE). The development of murine lupus was assessed during the lifespan of female B/W mice given NAC or CYST. Morbidity and mortality were assessed daily. At 6 week intervals mice were examined for weight change, albuminuria, serum BUN, antibodies to DNA, and IgG immunoglobulin levels. Serum prolactin, estrogen and progesterone were measured at 18 weeks of age. In a parallel study, NAC- and CYST-treated and control B/W mice were examined at 24 weeks of age for interval renal histopathology, lymphocyte adhesion molecule expression, and antibody titers and in vitro cytokine production in response to immunization with DNP-KLH. CYST significantly suppressed development of albuminuria and azotemia at 36 and 42 weeks of age compared to control and NAC-treated mice. NAC significantly suppressed anti-DNA antibody levels at 24 weeks. In contrast CYST significantly increased anti-DNA antibody levels at 18 weeks of age (P < 0.001 CYST vs control and NAC-treated mice). Kidneys of CYST-treated mice also had accelerated inflammatory histologic changes despite their lower incidence of albuminuria and azotemia. Mean (+/- s.e.m.) survival of control mice was 33 +/- 2 weeks compared to 38 +/- 2 weeks in NAC-treated mice (P < 0.05 vs control), and 48 +/- 2 weeks in the CYST-treated group (P < 0.01 vs control mice). The antioxidants, NAC and CYST, significantly improved mortality in the female B/W mouse model of SLE. NAC suppressed autoantibody formation and modestly prolonged survival. CYST, despite its augmentation of anti-DNA levels and renal inflammatory changes, inhibited the development of renal insufficiency and markedly improved survival. These findings suggest that ROIs play a role in the pathogenesis of lupus nephritis and that antioxidants reduce the damage causing renal insufficiency. Antioxidants may be a beneficial adjunctive therapy in the treatment of human SLE.     

Monoclonal antibody therapy for prevention of acute coxsackievirus B3 myocarditis in mice

The efficacy of monoclonal antibodies against T cell subsets in the therapy of experimental myocarditis caused by coxsackievirus B3 (CB3) was investigated. Two-week-old male C3H/He mice were inoculated with CB3 virus. Treatment was begun in the viremic stage (starting on the day of inoculation) in experiment 1 and in the later aviremic stage (starting on day 10) in experiment 2. Rat anti-mouse monoclonal antibodies, Lyt 1 (helper/inducer T) at 1 microgram/mouse (group 2 in experiment 1; group 6 in experiment 2), Lyt 2 (suppressor/cytotoxic T) at 1 microgram/mouse (group 3 in experiment 1; group 7 in experiment 2), and Lyt 1 at 1 microgram plus Lyt 2 at 1 microgram/mouse (group 4 in experiment 1; group 8 in experiment 2), were administered subcutaneously daily for 2 weeks. The treatment groups were compared with infected controls (group 1 in experiment 1; group 5 in experiment 2). In experiment 1, the survival rate in group 4 was higher (p less than 0.01) than in group 1. In experiment 2, mice treated with Lyt 1 plus Lyt 2 (group 8) survived significantly longer (p less than 0.05) than did controls (group 5). In experiment 1, myocardial virus titers on days 5 and 6 did not show any significant differences among the four groups. Serum-neutralizing antibody titers between group 1 and group 4 in experiment 1 or between group 5 and group 8 in experiment 2 did not differ significantly. Histologic examination showed extensive myocardial necrosis and cellular infiltration in untreated groups: there was less infiltration in group 4 and in group 8 and less severe necrosis in group 8.(ABSTRACT TRUNCATED AT 250 WORDS)     

Restorative effects of levamisole on cell-mediated immune responses following chemotherapy with aniline mustard in mice bearing ADJ-PC5 plasmacytoma.

Restorative effects of levamisole on general and tumor-associated cell-mediated immune responses were investigated following aniline mustard (AM) chemotherapy of BALB/c mice bearing ADJ-PC5 plasmacytoma. Total eradication of tumor following AM chemotherapy resulted in severe depression of lymphoproliferative (LP) responses which recovered after a prolonged period of 4-6 weeks. During this time, spleen cells from these treated mice were shown to be generally depressed to T- and B-cell mitogens. Levamisole, an anthelmintic drug capable of enhancing depressed immune responses in mice and in man, was employed following AM chemotherapy in an attempt to restore immunocompetency. Administration of levamisole following AM had a significant effect on the ability of mice to resist rechallenge with ADJ-PC5 tumor and in tumor cell neutralization. The enhanced resistance to tumor cell challenge appeared to be associated with a faster recovery of the general T-cell immunocompetence as demonstrated in the LP assays among the mice receiving chemotherapy followed by adjuvant therapy. Levamisole, when administered alone to tumor-bearing mice, did not appear to possess a direct antitumor effect. In addition, levamisole did not potentiate cellular immunity to higher than normal levels in nonimmunodepressed mice. These results demonstrate the efficacy of levamisole as a restorative agent of the general and tumor-associated immunocompetency in the immunodepressed host.     

Ribavirin treatment in murine autoimmune disease. I. Therapeutic efficacy and effect on the immune response.

NZB/W F1 female mice were treated from 20 weeks of age with ribavirin (a broad spectrum antiviral drug), cyclophosphamide, or saline. Treatment with ribavirin (250 mg/kg twice weekly) prolonged survival from 9.8 to 18.5 months, reduced anti-DNA antibodies, and prevented proteinuria. Ability of ribavirin to prolong survival was dose related when given on a twice weekly schedule. However, daily ribavirin (25 mg/kg/day) was as effective as higher intermittent doses. Optimal ribavirin therapy was equal to cyclophosphamide treatment with regard to prolongation of survival. Ribavirin treatment did not significantly alter the body weight, hematocrit, WBC count, serum immunoglobulins, or Coombs reactivity. No alterations in either cellular or humoral immune responses were noted in NZB/W F1 or BALB/c mice treated for prolonged periods with ribavirin. The impressive therapeutic response to a broad spectrum antiviral agent seen in mice already manifesting immune complex nephritis provides a new therapeutic approach to the treatment of autoimmunity.     

Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine.

The safety, immunogenicity, and impact on carriage of a nonvalent pneumococcal vaccine given at ages 6, 10, and 14 weeks were examined in a double-blind, randomized, placebo-controlled trial in 500 infants in Soweto, South Africa. No serious local or systemic side effects were recorded. Significant antibody responses to all pneumococcal serotypes were observed 4 weeks after the third dose. Haemophilus influenzae type b polyribosylribitol phosphate (geometric mean titer, 11.62 microg/mL) and diphtheria (1.39 IU/mL) antibodies were significantly higher in children receiving pneumococcal conjugate, compared with placebo recipients (4.58 microgram/mL and 0.98 IU/mL, respectively). Nasopharyngeal carriage of vaccine serotypes decreased in vaccinees at age 9 months (18% vs. 36%), whereas carriage of nonvaccine serotypes increased (36% vs. 25%). Carriage of penicillin-resistant pneumococci (21% vs. 41%) and cotrimoxazole-resistant pneumococci (23% vs. 35%) were significantly reduced 9 months after vaccination, compared with controls.     

Immune-modulation by polyclonal IgM treatment reduces atherosclerosis in hypercholesterolemic apoE-/- mice

ObjectiveGamma-globulin treatment reduces experimental atherosclerosis by modulating immune function; however the effect of IgM on atherosclerosis is not known. We investigated the effect of serum-derived, non-immune polyclonal IgM (Poly-IgM) on atherosclerosis in mice with advanced disease and also assessed its immune-modulatory effects.Methods and resultsAortic atherosclerosis was assessed in apoE?/? mice fed atherogenic diet starting at 6 weeks of age. In addition, mice were also subjected to perivascular cuff injury to the carotid artery at 25 weeks of age to induce accelerated atherosclerosis. At the time of injury, the mice were treated weekly with a commercially available Poly-IgM (0.4 mg/mouse) or PBS for 4 weeks and euthanized at 29 weeks of age. Poly-IgM reduced aortic atherosclerosis, and reduced lesion size in the aortic sinus and injured carotid artery, without significant changes in serum cholesterol levels. Poly-IgM treatment was associated with increased anti-oxLDL IgG titers and a reduction in the % splenic CD4⁺ T cells compared to controls. The splenic CD4⁺ T cell cultured from the Poly-IgM treated mice had reduced proliferation in vitro compared with controls.ConclusionPoly-IgM treatment reduced aortic and accelerated carotid atherosclerosis in apoE?/? mice in association with increased anti-oxLDL IgG titers, and reduced number and proliferative function of splenic CD4⁺ T cells. Our study identifies a novel athero-protective and immunomodulatory role for non-immune polyclonal IgM.     

Changes in hypothalamic monoamine oxidase activity in relation to season, ovariectomy, and 17 beta-estradiol administration in intact and ovariectomized catfish, Clarias batrachus (L.)

Cyclic changes in hypothalamic monoamine oxidase (MAO) activity were noted during the annual ovarian cycle of Clarias batrachus, with a high level in the preparatory phase and a low level in the spawning phase. Administration of 17 beta-estradiol (E2) daily for 3 days induced both season- and dose-dependent responses in enzyme activity. In the preparatory phase, 0.05, 0.1, and 0.5 microgram/g doses of E2 enhanced enzyme activity in a dose-dependent manner, with significant changes being observed in the latter two dose groups. Administration of 1.0 and 10.0 micrograms/g doses decreased enzyme activity, with a significant difference elicited by the latter dose. In the spawning phase, enzyme activity was significantly elevated by 0.05 and 0.1 microgram/g doses. MAO activity decreased insignificantly in the 0.5 and 1.0 microgram/g groups and significantly in the 10.0 micrograms/g E2 group. Enzyme activity decreased significantly 2, 3, and 4 weeks after ovariectomy (prespawning phase), in a time-dependent manner, and increased after 5 weeks (not significantly different from the sham control value) and 6 weeks. Administration of E2 to 3-week ovariectomized fish elicited dose-dependent effects on MAO activity. E2 injections at 0.05 and 0.1 microgram/g doses not only restored the ovariectomy-induced decrease, but also elevated enzyme activity significantly compared with the sham + vehicle control. The higher doses (0.5 and 1.0 microgram/g) were ineffective in restoring enzyme activity, which decreased significantly in the 1.0 microgram/g group compared with ovariectomy and sham control values.(ABSTRACT TRUNCATED AT 250 WORDS)     

左旋咪唑防御日本血吸虫尾蚴感染的实验研究

目的　探讨左旋咪唑预防日本血吸虫尾蚴感染的作用。方法　盐酸左旋咪唑和左旋咪唑碱口服剂量为 2 6 .2 5 m g/kg,分别于小鼠感染前 2天口服 ,连服 7d;涂肤剂为 1.0 %、2 .0 %、3.0 %、5 .0 %和 7.0 % ,分别于感染前 2、1天和当天涂肤。停药后 4周解剖 ,检获虫体。结果　盐酸左旋咪唑水溶液和左旋咪唑碱水溶液分别口服 ,两者的减虫率都为 0 ;5 .0 %的盐酸左旋咪唑于感染当天涂肤、7.0 %盐酸左旋咪唑于感染前 1天涂肤 ,减虫率均为 10 0 .0 % ;2 .0 %、3.0 %和 5 .0 %的左旋咪唑碱于感染前 1天涂药 ,减虫率即可达到 10 0 .0 %。结论　左旋咪唑涂剂能防御日本血吸虫尾蚴的感染 ,左旋咪唑碱效果优于盐酸左旋咪唑。口服无效。     

Toxicity,pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study

OBJECTIVE: To evaluate the safety and pharmacokinetics of multiple infusions of a humanized anti-interleukin-6 (IL-6) receptor antibody, MRA, in patients with rheumatoid arthritis (RA). METHODS: In an open label trial, 15 patients with active RA were intravenously administered 3 doses (2, 4, or 8 mg/kg) of MRA biweekly for 6 weeks, and pharmacokinetics were assessed. Patients continued on MRA treatment for 24 weeks, and were then assessed for safety and efficacy. RESULTS: The treatment was well tolerated at all doses with no severe adverse event. Increased total serum cholesterol was detected as an MRA related reaction in 10/15 (66%) patients. There was no statistically significant difference in the frequency of adverse events among the 3 dose groups. There were no new observations of antinuclear antibody or anti-DNA antibody, and no anti-MRA antibody was detected. The T1/2 increased with repeated doses and as the dose increased. T1/2 after the 3rd dose of 8 mg/kg reached 241.8 +/- 71.4 h. In 12/15 (80%) patients whose serum MRA was detectable during the treatment period, objective inflammatory indicators such as C-reactive protein, erythrocyte sedimentation rate, and serum amyloid A were completely normalized at 6 weeks, although there was no statistically significant difference in efficacy among the 3 dose groups. Nine of 15 patients achieved ACR 20 at 6 weeks. At 24 weeks, 13 patients achieved ACR 20 and 5 achieved ACR 50. CONCLUSION: Repetitive treatment with MRA was safe and normalized acute phase response in patients with RA. Optimal dosing schedule was not defined in this small study, but maintenance of serum MRA concentration seemed important to achieve efficacy.