The Peroxisome Proliferator-Activated Receptor delta Agonist, GW501516, Inhibits Angiogenesis through Dephosphorylation of Endothelial Nitric Oxide Synthase

OBJECTIVE: Peroxisome proliferator-activated receptor delta (PPAR-delta) is an ubiquitously expressed nuclear receptor that has been implicated in adipose tissue formation, brain development, and atherosclerosis. Despite mouse studies demonstrating that PPAR-delta activation has favorable anti-atherogenic properties by improving systemic lipid profiles, the relationship between PPAR-delta agonist and angiogenesis is unknown. We hypothesized that PPAR-delta ligands modulate the angiogenesis. METHODS: To test this hypothesis we treated primary cultures of bovine aortic endothelial cells with PPAR-delta specific ligand, GW501516 (50-800 nM) for 6 h. RESULTS: GW501516 dose-dependently decreased nitric oxide production without alteration in endothelial nitric oxide synthase (eNOS) expression. Analysis with phospho-specific antibodies against eNOS demonstrated that GW501516 significantly decreased the phosphorylation of eNOS at Serine1179 (eNOS-Ser1179). Concurrently, GW501516 also decreased the Akt phosphorylation. GW501516 did not affect endothelial cell proliferation or induce apoptosis. However, GW501516 inhibited endothelial cell migration, and tube formation in a high nanomolar concentration. The inhibition of endothelial cell tube formation by GW501516 was prevented by addition of the nitric oxide donor, DETA NONOate (5 microM). GW501516 was also found to inhibit angiogenesis in vivo in the chicken chorioallantoic membrane assay. CONCLUSION: These results provide that high nanomolar range of GW501516 inhibits angiogenesis by a mechanism involving dephosphorylation of eNOS-Ser1179.

A Congenital Cutis Laxa Fatality Caused by Early Onset Pulmonary Emphysema

Cutis laxa is a rare disorder of the elastic tissue characterized by loosely hanging and folded skin giving a premature senile appearance, often with internal organ involvement. Recently, we experienced a case of cutis laxa in a neonate. The patient who presented with dyspnea and loose skin at birth was delivered by Cesarean section in our hospital. He was the third baby of his mother and his siblings had no problem including skin. Physical examination on admission revealed a dyspneic neonate with skin showing loose folds, wrinkles and sagging over the face, neck, trunk and thighs. He had no family history of skin disease suggestive of cutis laxa. Histopathologic study of the skin specimen showed widespread breakdown and decreased number of elastic fibers with granular degeneration, shortening, and fragmentation. He had been dependent on ventilatory support throughout his hospital course and finally succumbed to intractable pulmonary emphysema at the age of 220 days.

Normative Data on Serum Levels of IGF-I, IGFBP-3 in Healthy Korean Children: Effect of Age, Sex, Height, Body Mass Index, and Pubertal Maturation on the Serum Levels / 대한소아내분비학회지

PURPOSE: This study was undertaken to obtain the normative data on serum levels of IGF-I and IGFBP-3 in healthy Korean children and to evaluate the effects of age, sex, height, body mass index and pubertal maturation on the serum levels of IGF-I and IGFBP-3. METHODS: This study included 301 healthy Korean subjects in pediatric age group. Serum levels of IGF-I and IGFBP-3 were measured twice using IRMA kit in each individual. The correlations between the serum levels of IGF-I or IGFBP-3 and age, auxological data or children's Tanner stages were evaluated. RESULTS: Serum levels of IGF-I and IGFBP-3 increased in proportion to age progression, and their rates of increase were remarkable shortly before and during the puberty. The correlations between serum levels of IGF-1 and age, sex, height standard deviation scores, BMI, or pubertal maturation were significant(P<0.05). However, the serum levels of IGFBP-3 was correlated only with height standard deviation scores(P<0.05). There was a significant positive correlation between serum levels of IGF-1 and those of IGFBP-3(P<0.001). CONCLUSION: Although IGF-I and IGFBP-3 assays can be utilized for the evaluation of endogenous growth hormone status, the effects of age, sex, BMI, height and pubertal development on the levels of IGF-I and IGFBP-3 must be considered. Therefore, these results would be helpful as a normative data for the growth evaluation of children in Korea.

Pancreatic Islets Transplantation through Spleenic Pulp and Peritoneum Using Hollow Fiber in Streptozotocin-induced Diabetic Nude Mouse / 대한소아내분비학회지

PURPOSE: Recently islets transplantation has been become a hot issue in insulin dependant diabetes mellitus. This study is aimed to review the technical method of islet isolation, pruification, and microencapsulation in animal model and to study the actual ability of transplated islets on controlling hyperglycemia. Finally, we want to know whether hollow fiber model for immunoislation in islet transplantation is effective in diabetic nude mouse. Method: We use 5-6 weeks old Spregue-Dawley rats as donor. After midline incision, collagenase was infused to proximal common bile duct and pancreas was extracted. With HBSS treatment and discontinuous density gradient centrifugation, islets were isolated. From 500-1,000 numbers of islets were transplanted to 6 strepozotocin-induced nude mice via upper pole of spleen and serial blood glucose level of nude mice were checked from conjunctival veins. Also, we examined transplanted-islets in spleen histologically with light and electron microscopy. Finally, after impregnation of 500 to 1,000 numbers of islets to 2-4 hollow fibers(Amicon R, H1P30-43 type, M.W:30,000) for immunoisolation, we inserted hollow fiber into peritoneum of 3 streptozotocin-induced nude mice and checked blood glucose level serially. Results: 1) Isolation of islets from rats was done successfully and we could calculate the number of islets under microscopy. 2) In 3 diabetic nude mice without islet transplantation(control group), all of them revealed hyperglycemia above 200mg/dL after 5days from strptozotocin injection. After then, blood glucose level was ranged from 300 to 500mg/dL persistently and all of them were died after 120 days. 3) We could observe the transplabted-islets in spleen with microscopy. Blood glucose level began to be controlled after 5 days from transplantation in 3 diabetic nude mice and all of 6 diabetic nude mouses revealed normoglycemia after 25 days from transplantation. 4) Islets transplantation with holler fibers into peritoneum of diabetic nude mice was not satisfactory. Although no technical difficulty was occured, persistent hyperglycemia was observed and all of 3 diabetic nude mice were died. CONCLUSION: Though islet transplantation through spleen was sucessful in diabetic nude mouse, further study is needed to clear the cause of failure of hollow fiber model in islets transplantation.

Two Cases of Citrullinemia Presented with Strokes

Urea cycle disorders are characterized by encephalopathy, respiratory alkalosis, and hyperammonemia. A urea cycle disorder should be considered a diagnostic possibility in any patient regardless of age with occult encephalopathy. The most common central nervous system pathology of urea cycle disorder is cerebral edema. The cerebral edema is caused by astrocyte swelling secondary to hyperammonemia and intracellular glutamine accumulation. Strokes in children occur in conjunction with cardiac disease, hematologic disorders, mitochondrial encephalopathy, trauma, intracranial infections and migraines. Recently, several inborn errors in metabolism have been recognized as possible causes of stroke. To our knowledge, there have been several reports on ornithine transcarbamylase deficiency with stroke. However, the case of citrullinemia presenting with a stroke-like episode has not been described previously. We report two infantile cases of citrullinemia with initial presentation of stroke. The differential diagnosis of unexplained strokes should include inborn errors of urea cycle metabolism during childhood.

Clinical Features and Natural Course of Hashimoto's Thyroiditis / 대한소아내분비학회지

PURPOSE:Although Hashimoto's thyroiditis is the most common cause of goiter in children and adolescents, it is not clear what proportion of patients become hypothyroid and which tests are the best predictors of this state. To determine whether these kinds of variations occur in the course of Hashimoto's thyroiditis and whether the size of the thyroid gland or immunologic markers correlate with the course or outcome of Hashimoto's thyroiditis are main objects of our study. METHODS:A total number of 48 patients who were diagnosed as having Hashimoto's thyroiditis at the Department of Pediatrics, Asan Medical Center during the period of January, 1992 to December, 1997 were included in this study. Retrospectively, we reviewed medical records as to their clinical and labaratory data. RESULTS:Thyroid function status at initial diagnosis of Hashimoto's thyroiditis were euthyroidism(33.3%), compensatory hypothyroidism(33.3%), overt hypothyroidism (27.1%), hyperthyroidism(8.3%) in order. Positivity of antithyroglobulin antibodies and antimicrosomal antibodies were 77.1% and 66.7% respectively. In 33 patients, 12(36.4 %) were on remission status after 3 years from initial diagnosis. Antithyroglobulin antibody titer was significantly decreased after 2-year follow up in remission group. Initial antithyroglobulin antibody titer and thyroid function status were not related to remission status after 3-year from diagnosis. CONCLUSION: About 36% of patients with Hashimoto's thyroiditis can be in remission after 3-year from diagnosis. Decrease of antithyroglobulin antibody titer is related to remission status. Further study is necessary to know what can be the predicting factors for early remission, for example, initial thyroid function status, initial antithyroid antibody titier, circulating immune complex, age, sex and size of thyroid.

A Case of Type 1 Gaucher Disease Treated with Enzyme Replacement

Type 1 Gaucher disease is one of the most common genetic lysosomal storage disease caused by the deficiency of glucocerobrosidase. Deficiency of this enzyme results in accumulation of glucoceramide in the macrophage and leads to hepatosplenomegaly, pancytopenia, bone damage and sometimes can be fatal. Recently, enzyme replacement has been considered as a major therapeutic strategy and about 2,000 patients have been treated successfully by macrophage- targeted human placental glucocerebrosidase worldwide. Our patient was a 16-month-old female child who visited our clinic with complaints of petechiae and splenomegaly. Complete blood count showed pancytopenia. Bone marrow study revealed Gaucher cells. Glucocerebrosidase activity was remarkably reduced. We infused macrophage-targeted (mannose-terminated) glucocerebrosidase into the patient for 18 months (30U/kg every 2 weeks for 2 months, 10U/kg every other day for 6 months, 5U/kg every other day for 6 months, and 20U/kg every 2 weeks for 4 months). After treatment, substantial increase in hemoglobin and thrombocyte counts was observed. In addition, hepatic and splenic volumes were strikingly decreased on volumetric CT scan. She felt better after treatment and catch-up growth has been achieved. In conclusion, enzyme replacement therapy should be considered as a major therapeutic option in type 1 Gaucher disease.

A Clinical and Histological Study of Allergic Colitis in Infant

PURPOSE: This study was done to evaluate the clinical and pathologic aspects of allergic colitis. METHODS: This study evaluated 19 infants who presented with fresh blood mixed stools. Limited colonoscopy and biopsy were performed. Among the 19 infants, 13 infants were diagnosed as allergic colitis by histological findings. We analyzed the clinical and histological characteristics of 13 infants. RESULTS: Male and female were 8 and 5 respectively. The mean age of the infants was 3 months (4 days to 12 months). Major symptoms were rectal bleeding (13), mucoid stool (6), diarrhea (5), vomiting (2). Feedings before diagnosis were breast milk (3), formula milk (4), formula and breast milk (5), and weaning diet (1). In labortory data, anemia (2) and eosinophilia (12) were found in some infants. Endoscopic findings were focal erythema (7), nodularity (1), erythema and nodularity (4), hemorrhage (1). Histopathologic finding was eosinophilic infiltration in lamina propria with preserved mucosal architecture in all. In addition, cryptitis (13), lymphoid follicular hyperplasia (7), crypt abscess (1) were also observed. All the infants improved with cessation of rectal bleeding and diarrhea within three days after dietary change. CONCLUSION: Allergic colitis should be considered as one of the major cause of rectal bleeding in healthy appearing infants. Limited colonoscopy and biopsy should be considered in establishing a definitive diagnosis.

Change in Pre-, Postoperative Endocrine Function and Growth Pattern in Patients with Craniopharyngioma / 대한소아내분비학회지

PURPOSE:Craniopharyngioma is one of the most important intracranial tumors in pediatric age which causes multiple pituitary hormone deficiencies. We have studied clinical characteristics in patients with craniopharyngioma, focusing on changes of endocrine function, change of growth pattern, and change of body mass index before and after surgery. In addition, we wanted to know the effect of growth hormone therapy on growth velocity and body mass index, and to identify contributing factors for spontaneous growth in spite of growth hormone deficiency. METHODS:A total number of 17 patients who were diagnosed as having craniopharyngioma at the Department of Pediatrics, Asan Medical Center during the period of January, 1991 to December, 1997 were included in this study. Retrospectively, we reviwed medical records as to their endocrine function tests and auxoloogical data before, after surgery. RESULTS: 1)The number of patients of male and female were 9 and 8 respectively. Mean age was 7.3+/-4.3 years. 2)Preoperatively, 3 patients were thyroid hormone deficient, 3 patients were corticosteroid deficient, and 3 patients suffered from diabetes inspidus. 3)Postoperatively, GH and TSH deficiency were found in 100%, ACTH in 88.2%, ADH in 82.3%, and LH/FSH in 60%, 53% respectively. 4) Mean growth velocity in 14 GH deficient patients without growth hormone treatment for 2 years were 3.5+/-2.4cm/year during the 1st year and 3.1+/-1.7cm/year during the 2nd year. Although height standard deviation score(Ht. SDS) was decreasing trend as -0.24+/-2.19 at diagnosis, -0.94+/-1.73 at 1 year later, and -0.76+/-1.76 at 2 years later, it was not statistically significant. To our suprise, 4 out of 14 patients achieved greater growth velocity than nomal in spite of growth hormone deficiency during the 1st year after operation. 5) Although the mean body mass index of 14 GH deficient patients without GH treatment was increasing trend as 17.9+/-3.5 at diagnosis, 19.0+/-4.5 at 1 year later, and 19.9+/-4.8 at 2 year later, it was not statistically significant. 6) The mean Ht. SDS increased significantly in 7 patients treated with growth hormone(P<0.05) for 2 years, but change of body mass index was not significant. 7) Comparision of postoperative serum prolactin levels and changes of body mass index between spontaneous growth and stunted growth group did not reveal significant difference. CONCLUSION: Since most patients with craniopharyngioma become multiple pituitary hormone deficient after operation, it is important to predict and detect pituitary dysfunction to manage it effectively. Although patients with postoperative GH deficiency responded well to GH treatment, further study is needed to clarify what are the main contributing or prognostic factors for spontaneous growth without growth hormone treatment.

Etiological Classifications of Children with Chief Complaint of Short Stature / 대한소아내분비학회지

Purpose : As the recombinant human growth hormone has been widely available, a lots of parents having short statured children are interested in promoting growth of them whatever the etiologies of short stature they have. However, the growth hormone therapy for growth-promoting effect is only justified in well-established indications such as growth hormone deficiency, fumer syndrome, and chronic renal insufficiency. This study was undertaken to classify the children with chief complaint of short stature by its cause and giving the basic epidemiologic data for it so that the size of population in which growth hormone is indicated can be estimated. Methods : According to Ranke's etiologic classification, we categorized the 579 children who visited our pediatric endocrinology clinic with chief complaint of short stature during the period of March 1994 to August 1996. In this prospective study, history regarding growth was taken, physical examination and laboratory tests including bone age, thyroid function, blood chemistry were carried out. The auxological data were analyzed. Additional chromosomal study or growth hormone provocative tests were performed when needed. Results : Out of 579 patients, 360(62.2%) were classified as normal and 127(21.9%) were classified as normal variants which consist of familial [74(12.8%)], constitutional [48(8.5%)], and mixed familial & constitutional short stature[5(0.9%)]. Pathologic short stature was found in only 80(13.8%). Those are growth hormone deficiency(28), Tumer syndrome(16), intrauterine growth retardation(14) in order. Other etiologies list varieties of dysmorphism, skeletal dysplasia, chromosomal disorders. Conclusions : This results suggest the vast majority of children with chief complaint of short stature are normal or normal variants. Only 7.8% of children who visited our clinic were indicated for growth hormone therapy.