Peripheral blood mononuclear cells from severe asthmatic children release lower amounts of IL-12 and IL-4 after LPS stimulation.

INTRODUCTION: Asthma is an inflammatory disorder of the airways associated with bronchial hyperresponsiveness, airway obstruction, and increased mucus production, with a predominance of type 2 immune response (Th2). According to the hygiene hypothesis, exposure to environmental bacterial lipopolysaccharide (LPS) may induce a type 1 immune response (Th1), modulating the development of asthma. OBJECTIVE: In this study we investigated cytokine production by peripheral blood mononuclear cells (PBMC) from children and adolescents with severe asthma, in response to LPS stimulation in vitro. MATERIALS AND METHODS: 26 children were selected: 13 severe asthmatics and 13 healthy controls, aged between 5 and 18 years. They were evaluated through routine medical history, physical examination and lung function test to diagnose severe asthma. Allergy status was confirmed by skin prick test and specific IgE assay. We collected blood samples to analyse in vitro LPS-induced cytokines release by PBMC. RESULTS: PBMC from severe asthmatic children produced lower levels of IL-12p70 in basal conditions and after 12 and 24h stimulation with LPS compared to healthy controls. PBMC from severe asthmatic children produced lower levels of IL-4 after 24h LPS stimulation compared to healthy controls. PBMC from severe asthmatic children produced more levels IL-17 and IL-10 after stimulus with LPS compared to healthy controls. The release of IFN-γ, IL-5 and TNF-α by PBMC from severe asthmatic children was similar to healthy controls. CONCLUSION: Our results demonstrate that LPS directly influence the cytokine profile of PBMC in children with severe asthma. These observations may be potentially helpful in developing new treatment strategies.

The outcome of Japanese anorexia nervosa patients treated with an inpatient therapy in an internal medicine unit.

OBJECTIVE: To investigate the outcome of Japanese anorexia nervosa (AN) patients who were treated with the standard Japanese inpatient therapy. METHOD: Of the 88 female AN patients treated with our inpatient therapy between January 1997 and December 2002, 67 (76.1%) who agreed to cooperate in this study were assessed by the Global Clinical Score (GCS) at admission and follow-up, 6.3±1.8 years after discharge. Their clinical characteristics at admission and discharge were also examined. RESULTS: Four (6.0%) patients had died before follow-up. BMI was significantly increased during inpatient therapy. At follow-up, excellent, much improved, symptomatic, and poor outcomes on GCS were 57.1%, 14.3%, 14.3% and 14.3%, respectively. Younger age at admission and larger BMI at discharge were significantly associated with a better outcome. DISCUSSION: This study shows the potential for the use of this method for the treatment of AN patients in countries without specialized eating disorder units.

Predictors of menstrual resumption by patients with anorexia nervosa.

OBJECTIVE: To investigate which factors predict the resumption of menstruation by patients with anorexia nervosa (AN). METHODS: Participants were AN patients who, even after weight recovery by inpatient treatment, had prolonged amenorrhea (N=11), AN patients who resumed menstruation after weight recovery (N=9), and age-matched healthy controls (N=12). Anthropometric data and the serum levels of leptin, insulin-like growth factor I (IGF-1), cortisol, luteinizing hormone (LH), estradiol (E2), and other hormones were measured at the beginning of the inpatient treatment and after weight recovery. RESULTS: Of the baseline anthropometric and hormonal factors, logistic regression analysis extracted a high serum cortisol level as a predictor of the inhibition of the resumption of menstruation. After weight recovery, the E2 and leptin levels were significantly higher for eumenorrheic patients than for amenorrheic patients. CONCLUSION: The baseline serum cortisol level was a predictor of the prolonged inhibition of menstrual recovery.

Somatic and psychological factors related to the body mass index of patients with anorexia nervosa.

OBJECTIVE: The aim of this study was to examine somatic and psychological factors related to the body mass index (BMI) of anorexia nervosa (AN) patients. METHOD: The analysis was of 24 hospitalized AN patients from the day after admission to the 4th day. The somatic factors analyzed were duration of AN, daily food intake, eating regulatory substances in blood (acylated ghrelin, desacyl ghrelin, leptin), serum cortisol, insulin and estimated creatinine clearance (CCr). The psychological factors analyzed were depression, anxiety, Eating Disorder Inventory (EDI), and hunger/fullness feeling. Measurement of BMI and collection of blood samples were done on the morning after hospitalization. Statistical analysis was by multiple linear regression analysis. RESULTS: BMI showed a reverse correlation with desacyl ghrelin (beta=-0.486, p=0.015) and maturity fears (beta=-0.375, p=0.046), but was not associated with any other factor by multiple regression analysis. CONCLUSION: The results suggest that desacyl ghrelin and maturity fears play important roles in the prolonged malnutrition state seen in AN patients.

Antibody response to pneumococcal capsular polysaccharide vaccine in Down syndrome patients.

The majority of children with Down syndrome (DS) tend to have frequent bacterial infections including recurrent respiratory infections. Our objective was to evaluate the production of antibodies to pneumococcal polysaccharide antigens after active immunization in DS subjects. IgG antibodies to pneumococcal serotypes (1, 3, 6B, 9V, and 14) were measured before and 6 weeks after immunization with a 23-valent pneumococcal vaccine (Pneumo23, Pasteur-Merrieux) in 6- to 13-year-old DS children (N = 17) and in aged-matched normal controls (N = 30). An adequate response was defined as a 4-fold increase over baseline or a post-immunization level of specific pneumococcal serotype antibody > or = 1.3 microg/mL. After immunization, all DS children had an increase in post-immunization levels against all serotypes analyzed. A 4-fold or more increase was observed in all DS children concerning serotypes 1 and 14, in 90% of subjects for serotypes 3 and 9V, and in 65% for serotype 6B. Regarding this increase, 8 of the 17 DS children had an adequate response to all serotypes analyzed, 8/17 patients to 4 serotypes and 1/17 to 3 serotypes. However, when we compared post-immunization levels between DS children and controls, we observed lower levels in the former group (P < 0.05) for all serotypes except serotype 3. We conclude that pneumococcal polysaccharide immunization could be beneficial for these DS children.

Accessory cell function in tumor-bearing mice and effects of Corynebacterium parvum.

Primary in vivo production of antibody to sheep red blood cells (SRBC) was consistently suppressed in EL 4 tumor-bearing C57BL/6 mice, but the secondary response was not suppressed. This suppressed primary in vivo production of antibody was partially restored by systemic administration of Corynebacterium parvum. For investigation of the mechanism of the immunosuppression in tumor-bearing mice and the effects of C. parvum, the accessory cell function of adherent cells from tumor-bearing mice and C. parvum-treated tumor-bearing mice in in vitro cultures was studied. Peritoneal and splenic cells from tumor-bearing mice were less efficient in promoting in vitro production of antibody to SRBC by macrophage-depleted normal nonadherent cells than the adherent cells from normal mice. C. parvum treatment restored the accessory cell function of splenic adherent cells from tumor-bearing mice but not that of peritoneal cells. Furthermore, adherent cells from tumor-bearing mice did not show suppressive activity against the in vitro plaque-forming cell response.

Factors related to renal dysfunction in patients with anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) patients were surveyed to determine which disease factors were related to AN influenced renal dysfunction. METHODS: Data were from forty-five AN patients hospitalized in our department between 1995 and 2002. The patients were classified into three groups based on the type of anorexia: restricting (n=18), self-induced vomiting (n=13), and laxative abuse (n=14). Twenty-four hour-creatinine clearance (Ccr) was calculated within two weeks of hospitalization for comparison among the three groups. RESULTS: The Ccr level of the laxative abuse group was significantly lower than that of the restricting group (65.8+/-31.4 ml/min vs restricting type: 104+/-23.3 ml/min, p=0.002). The laxative abuse group had a significantly longer duration of illness than the restricting group (p<0.0001). Multiple regression analysis revealed the duration of illness to be a risk factor for renal function deterioration in AN patients (r=0.580, p<0.001). DISCUSSION: Renal function should be carefully followed during the treatment of AN patients with a long duration of illness, especially those with long-term laxative abuse.

Psychopathological features of patients with prolonged anorexia nervosa as assessed by the Minnesota Multiphasic Personality Inventory.

OBJECTIVE: The duration of illness is quite long in some anorexia nervosa (AN) patients. In the present study, we investigated the psychopathological features of patients with prolonged AN as assessed by the Minnesota Multiphasic Personality Inventory-1 (MMPI-1). METHODS: Fifty-five AN patients completed the MMPI-1 on admission to Kyushu University Hospital from 1999 to 2002. The patients were divided into three groups on the basis of their illness duration: a short-term group, less than 5 years of illness duration (n=31); a middle-term group, from 5 to 10 years (n=14); and a prolonged group, 10 years or more (n=10). RESULTS: The prolonged group scored significantly higher on the MPPI-1 scales of hysteria (Hy), low back pain (Lb) and family conflict than the short-term group. DISCUSSION: AN patients whose illness duration was prolonged characteristically had more hysteria with family conflict. This should be considered in their treatment.

Effects of genetic diabetes and zinc nutriture on in vivo cell-mediated immunity in the mouse.

To examine whether an abnormal zinc status contributes significantly to the impaired in vivo cell-mediated immunity of the genetically diabetic C57BL/KsJ db/db mouse, we measured specific cytotoxicity of spleen cells from db/db and heterozygous (db/m) and homozygous (m/m) control mice fed either zinc-deficient (2 mg/kg) or zinc-adequate (20 mg/kg) semipurified diets. Low serum and femur zinc concentrations were seen after 4 wk in all mice fed the zinc-deficient diet, but impaired cytotoxicity was not seen until later in control mice fed that diet. In contrast, db/db mice fed zinc-adequate diets had diminished spleen weights and markedly impaired cytotoxicity by 4 wk. These mice had normal serum and only mildly decreased femur zinc concentrations. We, therefore, found no evidence to suggest that the mildly altered zinc status of db/db mice fed zinc-adequate diets is a major factor contributing to their markedly impaired in vivo cell-mediated immunity.

Alterations in lymphocyte subsets and pituitary-adrenal gland-related hormones during fasting.

We investigated changes in the immunoendocrine system during fasting. Ten hospitalized patients aged 14-46 y with psychosomatic disorders fasted for 7 or 10 d. Blood samples were collected before and on days 3 and 7 of the 7-d fasts. When fasting continued to 10 d, an additional sample was taken on day 10. We measured blood cellularity (white blood cells and total lymphocytes), the total number and percentage of lymphocyte subsets (CD2, CD3, CD4, CD8, and CD19), natural killer (NK) cell activity, cytokines (interleukin 1 beta, interleukin 2, interleukin 6, granulocyte-macrophage colony stimulating factor, tumor necrosis factor alpha, and interferon gamma), and soluble interleukin 2 receptors. Corticotropin, cortisol, and dehydroepiandrosterone sulfate (DHEAS) concentrations were also determined. Although the total number of lymphocytes decreased during fasting, NK cell activity increased significantly. Plasma cortisol and DHEAS concentrations also increased significantly whereas changes in corticotropin concentrations were not significant. The total number and percentage of CD4 cells decreased significantly during fasting but no other lymphocyte subsets changed significantly. The percentage of CD4 cells was negatively correlated with cortisol concentrations during fasting. No detectable changes occurred in cytokines or soluble interleukin 2 receptors during the study. All measured immunoendocrine values that changed during fasting returned to prefasting values during the refeeding period. These findings indicate that fasting affects immune variables such as T cell subsets and NK cell activity at least in part through changes in adrenal gland-related hormones.

Influence of short-term repeated fasting on the longevity of female (NZB x NZW)F1 mice.

Caloric restriction in rodents is well known to retard the rate of aging, increase mean and maximum life-spans, and inhibit the occurrence of many age-associated diseases. However, little is known about the influence of short-term repeated fasting on longevity. In this study, female (NZB x NZW)F1 mice were used to test the physiological effect of short-term repeated fasting (4 consecutive days, every 2 weeks). The results showed that fasting mice survived significantly longer than the full-fed mice, in spite of the fasting group having a heavier body weight than the control group. Mean survival times for fasting and control mice were 64.0+/-15.3 and 47.9+/-9.4 weeks, respectively. Short-term repeated fasting manipulation was also effective on the prolongation of life-span in autoimmune-prone mice.

Psychosomatic treatment of phantom limb pain with post-traumatic stress disorder: a case report.

The successful treatment of severe left lower limb phantom pain is reported. Hypnosis and antidepressant drugs were the basis for the treatment which controlled the phantom limb pain and an associated post-traumatic stress disorder.

Prostaglandin E(2) has antinociceptive effect through EP(1) receptor in the ventromedial hypothalamus in rats.

The effects of microinjection of prostaglandin E(2) (PGE(2)) (50 fg-50 ng/0.2 microl) into the ventromedial hypothalamus (VMH) on nociception were studied using a hot-plate test in rats. Microinjection of PGE(2) (5-500 pg and 50 ng/0.2 microl) into the VMH significantly prolonged the paw-withdrawal latency on a hot plate 5 and 10 min after injection, respectively. Maximal prolongation was obtained 5 min after the injection of PGE(2) at 5 pg. Subsequently, to determine whether the PGE(2) receptor subtype EP(1) is involved in the PGE(2)-induced antinociceptive effect in the VMH, we observed the changes in nociception after intraVMH microinjection of SC19220, an EP(1) receptor antagonist, and 17-phenyl-omega-trinor PGE(2), an EP(1) receptor agonist. Simultaneous injection of SC19220 (150 ng) with PGE(2) (500 pg) into the VMH blocked the PGE(2)-induced prolongation of the paw-withdrawal latency. Moreover, an intraVMH microinjection of 17-phenyl-omega-trinor PGE(2) (500 pg) prolonged it. These results indicate that PGE(2) in the VMH has antinociceptive effect through its actions on EP(1) receptors in rats.

Delayed type skin response to myelin basic protein in chronic relapsing experimental allergic encephalomyelitis.

The skin response to myelin basic protein (MBP) was studied in chronic relapsing experimental allergic encephalomyelitis (EAE) using strain 13 guinea pigs. The delayed type skin response showed a monophasic curve; it gradually increased after immunization, reached maximum levels around 80 days post-immunization, and decreased thereafter. Relapses were more frequent while it was at high levels although it did not correlate directly in individuals with the clinical stage. The skin response was also high in MBP-immunized animals which had recovered from acute EAE. Our results suggest that delayed type hypersensitivity to MBP is involved but is not sufficient by itself to cause relapsing EAE.

Restraint stress elevates the plasma interleukin-6 levels in germ-free mice.

Several recent reports demonstrated that restraint stress elevates plasma IL-6 levels; however, the precise mechanism whereby stress stimuli trigger the production of IL-6 remains to be clarified. In this study, in order to elucidate whether or not the intestinal microflora contribute to the stress-induced IL-6 elevation, the plasma IL-6 response of germ-free (GF) mice, which are indeed devoid of indigenous microflora, was compared to that of specific pathogen-free (SPF) mice. The plasma IL-6 level increased after 1 h of restraint stress and thereafter gradually decreased in GF mice as well as in SPF mice. In addition, such a stress-induced IL-6 elevation was also found in the mice reconstituted with SPF feces. The expression levels of IL-6 mRNA in the liver increased after 1 h of stress in both GF and SPF mice based on the findings of a semiquantitative RT-PCR method, although no such increase was observed in the spleen and kidney of both groups of mice. These results thus indicate that restraint stress is capable of elevating the plasma IL-6 levels independently of the intestinal microflora and the liver is one of the main sources responsible for the increased plasma IL-6 during stress.

Restraint stress-induced elevation of endogenous glucocorticoid suppresses migration of granulocytes and macrophages to an inflammatory locus.

It has been reported that restraint stress gives rise to various immunosuppressive events. In the present study, we focused our interest on an early stage of the host-defense system in which granulocytes, macrophages and natural killer (NK) cells are involved. We observed that an elevation of endogenous glucocorticoid levels in mice induced by 24 h-restraint stress (acute stress) did not significantly reduce the NK activity of the spleen cells but profoundly suppressed the migration of macrophages and granulocytes into peritoneal cavities of the mice at 24 h after an intraperitoneal injection of proteose peptone. The reduced number of the migrated granulocytes and macrophages corresponded to a down-regulated gene expression of such chemotactic factors as MCP-1/JE in the peritoneal exudate cells of the stress-loaded mice. The stress-loaded mice recovered from such a suppressive state upon treatment with the glucocorticoid antagonist, RU-486, or upon adrenalectomy, suggesting that the elevated level of endogenous glucocorticoid is responsible for these suppressive effects of acute stress.

The restraint stress-induced reduction in lymphocyte cell number in lymphoid organs correlates with the suppression of in vivo antibody production.

In this study, we examined the effects of restraint stress on some immune parameters such as the in vivo antibody levels, cytokine production, and lymphocyte cell number in the spleen or mesenteric lymph node (MLN). BALB/c mice were thus injected intraperitoneally 2-times with OVA absorbed into alum on days 0 and 21. Before the first injection, the animals were either restrained for 12 h (stress group) or returned to their home cage (control group). Exposure to stress resulted in a reduction in the serum levels of anti-OVA IgE, IgG1, and IgG2a. In addition, stress also caused a decrease in the IL-4 and IFN-gamma levels in the spleen or mesenteric lymph node cell culture supernatants. Furthermore, exposure to stress resulted in a decrease in the splenic and mesenteric lymphocyte cell number when examined immediately after the cessation of stress. This decrease persisted for at least 12 h after the termination of stress and thereafter disappeared 24 h after stress. The stress-induced reductions in antibody and cytokine production occurred only when antigen was given either immediately or 6 h after stress, but not when antigen was given 24 h post stress. These results thus suggest that the restraint stress-induced change in lymphocyte cell number in the spleen or MLN closely correlates with the altered antibody and cytokine levels.

Restraint stress-induced immunosuppression by inhibiting leukocyte migration and Th1 cytokine expression during the intraperitoneal infection of Listeria monocytogenes.

In this study, a murine model of Listeria monocytogenes infection was used to investigate effects of restraint stress (RST) on host defense. We observed that the L. monocytogenes infection as well as RST induced an elevation of endogenous corticosterone (CORT) levels and RST synergistically enhanced endogenous CORT levels during the listerial infection. RST suppressed the migration of leukocytes including macrophages, neutrophils, NK cells and lymphocytes into the peritoneal cavities after the intraperitoneal inoculation of L. monocytogenes. RST also suppressed the increase of the surface MHC class II antigen expression in both peritoneal macrophages and B cells during the listerial infection. Interestingly, gene expression of iNOS, MCP-1 (JE) and Th1-type cytokines including IFN-gamma and IL-12 was down-regulated but Th2-type cytokine (IL-4 and IL-6) gene expression in the PEC was rather up-regulated on day 7 after infection, indicating that Th2-type immune response is more resistant to the elevated endogenous CORT levels than Th1-type response. Treatment of mice with RU486, a glucocorticoid receptor antagonist, restored the immune responses suppressed by RST to their normal levels in the infected mice, suggesting that the RST-induced elevation of endogenous corticosterone levels is mainly responsible for the induction of the immunosuppressive events during L. monocytogenes infection.

Dehydroepiandrosterone attenuates the spontaneous elevation of serum IgE level in NC/Nga mice.

Dehydroepiandrosterone (DHEA) and its sulfate derivatives are known to affect host immune function; however if such hormones influence the development of atopic dermatitis has not yet been clarified. In this study, we examined the effects of DHEA on the allergic process using NC/Nga mouse, a model animal of human atopic dermatitis. The administration of DHEA profoundly suppressed the spontaneous elevation of both serum IgE and interleukin-6 levels in NC/Nga mice during the observation period. These results indicate that DHEA promotes a shift in Thl/Th2 balance toward Th1-dominant immunity, and thus may be one of the effective alternatives in treating atopic dermatitis.