Phthalates suppress type I interferon in human plasmacytoid dendritic cells via epigenetic regulation.

BACKGROUND: Exposure to environmental endocrine-disrupting chemicals (EDCs) is associated with allergy, chronic inflammation, and immunodeficiency. Phthalates, the common EDCs used in plastic industry, may act as adjuvants to disrupt immune system and enhance allergy. Plasmacytoid DCs (pDCs) are predominant cells secreting type I interferon (IFN) against infection and are professional antigen-presenting cells in regulating adaptive immunity. However, the effects of phthalates on the function of pDCs are unknown. METHODS: Circulating pDCs were isolated from healthy subjects, were pretreated with diethylhexyl phthalate (DEHP) and butyl benzyl phthalate (BBP), and were stimulated with Toll-like receptor (TLR)-9 agonist CpG. IFN-α/IFN-ß levels, surface markers, and T-cell stimulatory function were investigated using ELISA, flow cytometry, and pDC/T-cell coculture assay. Mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting, and chromatin immunoprecipitation. RESULTS: Diethylhexyl phthalate and butyl benzyl phthalate suppressed CpG-induced IFN-α/IFN-ß expression in pDCs, and the effect was reversed by aryl hydrocarbon receptor (AHR) antagonist. Diethylhexyl phthalate suppressed CpG-activated mitogen-activated protein kinase (MAPK)-MEK1/2-ERK-ELK1 and NFκB signaling pathways. Diethylhexyl phthalate suppressed CpG-induced interferon regulatory factor (IRF)-7 expression by suppressing histone H3K4 trimethylation at IRF7 gene promoter region through inhibiting translocation of H3K4-specific trimethyltransferase WDR5 from cytoplasm into nucleus. Butyl benzyl phthalate or diethylhexyl phthalate-treated pDCs suppressed IFN-γ but enhanced IL-13 production by CD4+ T cells. CONCLUSION: Phthalates may interfere with immunity against infection and promote the deviation of Th2 response to increase allergy by acting on human pDCs via suppressing IFN-α/IFN-ß expression and modulating the ability to stimulate T-cell responses.

Heterogeneous responses to the long-term treatment of active acromegaly with octreotide.

To study GH response to the long-acting somatostatin analogue, we treated 11 actively acromegalic patients with octreotide (Sandostatin), 100 micrograms, sc, tid, for six months. Their endocrinological outcomes and clinical improvements varied. The 11-h GH secretory profiles on pretreatment day confirmed the hypersecretion of GH in all patients. Three hours after the first dose of octreotide, serum GH declined rapidly to levels below 5 ng/ml in all but two patients who failed to normalize their serum GH. In spite of the subsequent doses, there was no further suppression in serum GH. Drug resistance with GH rebound developed in some patients after three months of continued treatment. The paradoxical serum GH rises in response to oral glucose or iv TRH detected before the treatment in all patients attenuated or disappeared after the 6-month octreotide therapy; an exceptional case was one of the above-mentioned two patients, whose serum GH was stimulated more than before by glucose and TRH at the end of therapy. Serum insulin-like growth factor I (IGF-I) levels of all patients showed a significant reduction after 6-month treatment, but their mean values remained abnormally high. There were no intolerable adverse side effects; some patients, however, experienced pain at the injection site, passage of loose stool, and incidence of new gall stone or intrahepatic lesions on octreotide therapy. We concluded that octreotide was a useful long-term adjunctive therapeutic agent for patients with active acromegaly, but that a high degree of response heterogeneity including total refractoriness would be expected.

Linear growth response to recombinant human growth hormone in children with growth hormone deficiency.

BACKGROUND: This study was to evaluate the efficacy, safety and immunogenicity of recombinant human growth hormone (rhGH) in treatment of children with growth hormone deficiency (GHD). METHODS: We selected 15 children with GHD for a 12-month clinical trial and separated them into three groups with each 5 patients receiving one of the 3 tested rhGH (Saizen by Serono, Aubonne, Switzerland; Genotropin by KabiVitrum, Stockholm, Sweden and Humatrope by Eli Lilly, Indianapolis, USA). RESULTS: In Saizen group, 3 boys and 2 girls with a mean chronological age (CA) of 10.6 +/- 1.7 yrs and bone age (BA) of 6.7 +/- 1.2 yrs, at dose of 0.2 IU/kg sc tiw, gained an average BA of 2.1 +/- 1.3 yrs. The mean height velocity (HV) increased from 3.7 +/- 1.2 to 11.1 +/- 3.3 cm/yr. The height standard deviation score (SDS) increased from -4.2 +/- 3.1 to -3.1 +/- 2.9. In Genotropin group, 2 boys and 3 girls with a mean CA of 9.2 +/- 2.3 yrs and BA of 5.6 +/- 2.1 yrs, at dose of 0.1 IU/kg sc qd, gained an average BA of 0.8 +/- 0.2 yr. The mean HV increased from 3.4 +/- 0.7 to 11.3 +/- 2.0 cm/yr. The height SDS increased from -4.0 +/- 0.5 to -2.7 +/- 0.7. In Humatrope group, 4 boys and 1 girl with a mean CA of 10.3 +/- 3.5 yrs and BA of 5.8 +/- 2.9 yrs, at dose of 0.1 IU/kg sc qd, gained at average BA of 0.8 +/- 0.7 yr. The mean HV increased from 4.0 +/- 1.3 to 9.4 +/- 1.9 cm2yr, and the height SDS increased from -2.9 +/- 0.7 to -2.2 +/- 1.0. Very low titers of anti-rhGH antibodies were noted only in two patients, one in Saizen group (titer = 1:10) and the other in Genotropin group (titer = 1:6). Their HV was not affected (Saizen: 13.3 cm/yr, Genotropin: 11.2 cm/yr). One patient evolved subclinical hypothyroidism whereas no side effect at all was noted in the rest of patients. CONCLUSIONS: Three tested GH (Saizen, Genotropin, Humatrope) produced by recombinant DNA technology appear to make no significant difference in this clinical trial, and rhGH therapy is an effective and safe treatment for prepubertal GHD children.

Recombinant human growth hormone (Genotropin) in treatment of children with growth hormone deficiency: the first year observation.

Five prepubertal children with previously untreated growth hormone deficiency were enrolled in this trial and treated with authentic recombinant human growth hormone hGH, 0.1 IU/Kg/day, subcutaneously, for one year. All of the children markedly increased their growth rate; the height velocity increased from 3.4 +/- 0.7 cm/yr to 11.3 +/- 2.0 cm/yr during one year's treatment. The height-standard deviation score for chronological age increased from -4.03 +/- 0.52 to -2.70 +/- 0.68. The bone age increased from 5.6 +/- 1.5 year before treatment to 6.4 +/- 1.6 years after one-year treatment. Only one child acquired low titer anti-hGH antibodies during the course of treatment (1:2 to 1:6). No untoward symptoms were complained of by these children and no biochemical abnormalities occurred except transient subclinical hypothyroidism in one child during the treatment course.

Recombinant DNA produced somatropin in the treatment of prepubertal growth hormone deficient children.

The safety and efficacy of recombinant DNA produced human growth hormone in the treatment of growth failure in prepubertal children with idiopathic or organic deficiency of pituitary GH has been assessed. Five patients entered this clinical trial. They had never been treated with hGH, anabolic steroids or any medicine that affected GH and all of them were healthy without any chronic disease; except patient 1, who took a surgical operation for cerebellar astrocytoma at the age of 3. Each patient was treated with subcutaneous injection of recombinant somatropin (SAIZEN) at a dosage of 0.2 IU/Kg +/- 10% three times per week in the evening for 1 year. Typical catch up growth was observed. The height increased by between 6.3 and 15.1 cm and their mean growth velocity of 3.7 cm/yr prior to therapy increased to 11.1 cm/yr during one year of treatment. The annual change in bone age during the treatment with SAIZEN was 2.0 +/- 0.6 years in four patients, except patient 2 who showed different bone age (right hand 3.5 years, left hand 6.0 years). Anti-hGH antibodies were observed in patient 1, but the binding capacity was low (1:10), and no clinical symptoms or growth attenuation occurred. No side effects or laboratory abnormalities were noted throughout the clinical trial. In conclusion, recombinant somatropin has a growth promoting effect and low immunogenicity, and it is shown to be safe and effective during the first year of therapy in children with GH deficiency.

The action of gliclazide on insulin secretion and insulin sensitivity in non-obese non-insulin dependent diabetic patients.

We evaluated the effects of gliclazide on the secretion and action of insulin in 18 non-obese (BMI 24.09 +/- 0.47 Kg/m2, range 20.89-27.52 Kg/m2) non-insulin dependent diabetic patients (mean age 56.9 +/- 1.8 years, range 39-67 years) by the oral glucose tolerance test (OGTT) and insulin suppression test (IST). Most of them were diagnosed recently and thus untreated previously. All subjects were treated with gliclazide or placebo for 3 months in a double blind cross-over design. After gliclazide therapy, fasting and 2 hour post-OGTT plasma glucose significantly decreased (136 vs. 185 mg/dl, P less than 0.005 291 vs. 358 mg/dl, P less than 0.005), 2 hours post-OGTT plasma insulin was significantly increased (79 vs. 59 uU/ml, P less than 0.05) while fasting plasma insulin remained unchanged (21 vs. 19 uU/ml, P greater than 0.1). HbAlc decreased significantly with gliclazide therapy (6.6 vs. 7.6%, P less than 0.005). In addition, oral glucose tolerance, as measured by the mean incremental areas under the plasma glucose curve, were improved significantly (1430.6 +/- 682.4 vs. 16192.5 +/- 608.5 mg.min/dl, P less than 0.005). The mean incremental areas under the plasma insulin curve during OGTT also increased (4482.0 +/- 637.1 vs. 3167.5 +/- 511.9 uU.min/ml, P less than 0.05) after gliclazide therapy. Mean steady state plasma glucose levels (SSPG) showed no remarkable difference during drug and placebo administration (188 vs. 190 mg/dl). Throughout the trial there was no significant change of body weight, nor any side effect as judged from blood counts, urinalysis, and the results of SMA-23 and EKG.(ABSTRACT TRUNCATED AT 250 WORDS)

A simple method for maintaining Xanthomonas campestris pv. citri.

A typical colony of each of strains XW17, XW45, XW47, XW82, XW86, XW118, and XW138 of Xanthomonas campestris pv. citri was streaked onto nutrient agar, GY agar, minimal agar, and semi-enriched minimal agar plates, respectively. The agar plates, after incubated at 30 degrees C for 2-4 days, were inverted and stored at 4 degrees C in darkness. All of the X. campestris pv. citri strains retained their viability for at least 26 weeks on the semi-enriched minimal agar plates; whereas, cultures of these bacterial strains survived for only 2-10 weeks on the nutrient agar, 2-5 weeks on the GY agar plates and 12-26 weeks on the minimal agar plates. The bacterial strains which survived after 22-26 weeks on the semi-enriched minimal agar and minimal agar plates, respectively, also retained their ability to produce typical colonies and virulence. Thus, this semi-enriched minimal agar plate method is a simple and efficient way for maintaining the X. campestris pv. citri strains for a relatively long period.