Val Abbassi

Poly I:C Induces Development of Diabetes Mellitus in BB Rat

Polyinosinic polycytidilic acid (poly I:C), an inducer of α-interferon, accelerates the development of diabetes in diabetes-prone (DP) BioBreeding (BB) rats. This study investigates the effect of administering poly I:C to a diabetes-resistant (DR) strain of BB rats. We compared the incidence of diabetes, the degree of insulitis, the number of NK cells, helper-inducer cells, cytotoxic-suppressor cells, Ia+ T cells, RT6.1+ T cells, and NK cell bioactivity in DR rats treated with saline and with a 5 micrograms/g body wt (poly-5) dose and a 10 micrograms/g body wt (poly-10) dose of poly I:C. The incidence of diabetes was also compared with that of DP rats receiving poly-5. We found that both doses of poly I:C significantly induce the development of diabetes in the DR BB rat. However, treatment of DR rats with the higher dose induces a greater rate of development of diabetes and earlier onset of diabetes than the lower poly-5 dose. The rate of diabetes development and the mean age of onset were similar in poly-10–treated DR and poly-5–treated DP rats. A significant degree of insulitis occurred in all the poly I:C–treated DR rats, even those not developing diabetes. Peripheral blood NK cell number was greater in poly I:C than in saline-treated rats, after 2 wk of treatment and when killed. The percentage of OX19+ peripheral blood mononuclear cells expressing RT6.1 allotype or Ia antigen were similar in poly I:C– and saline-treated rats. of diabetes in poly-10–treated DR rats and poly-5–treated DP rats is consistent with a similar mechanism of poly I:C action in the DR and DP BB rats. Although the specific mechanism is not defined, NK cell numbers are elevated with poly I:C treatment. Alterations in RT6.1+ and la+ T cells do not appear to play a role.

Humoral and Cell-Mediated Immunity in Growth Hormone-Deficient Children: Effect of Therapy with Human Growth Hormone

ABSTRACT: To delineate the role of growth hormone (GH) in the development and function of the immune system, immunological parameters including quantitative immunoglobulins, T and B lymphocytes, phytohemagglutinin lymphoproliferative response and delayed hypersensitivity skin tests were studied in nine GH-deficient children prior to GH therapy and at 2 months and 9 to 12 months following therapy. The phytohemagglutinin response (74.1 ± 37.6, mean ± SD), and the T rosette (58.3% ± 9.4), B rosette (21.1% ± 6.1), IgG (810 ± 241 mg/dl), (IgA 140 ± 85), and IgM (176 ± 70) levels in GH-deficient children were comparable to age adjusted values in normal children. Following GH therapy the phytohemagglutinin response increased significantly at 9 to 12 months posttherapy, 123.2 ± 51.9 versus 74.1 ± 37.6, p < 0.05. T and B rosettes, immunoglobulin concentrations, and hypersensitivity skin tests were not affected by GH therapy. Al-though an effect of GH was not demonstrable by these studies, a positive role of GH cannot be entirely excluded since total GH deficiency did not exist in all children.

Poly I:C Induction of α-Interferon in the Diabetes-Prone BB and Normal Wistar Rats: Dose-Response Relationships

Although the administration of a fixed dose of the α-interferon (α-IFN) inducer, polyinosinic polycytidilic acid (poly I:C), accelerates the development of diabetes in DP-BB rats, no reports have characterized the dose-response relationship of poly I:C with serum alpha-IFN levels and the development of diabetes. This study examines the dose-response relationships of poly I:C with the induction of serum α-IFN and the development of diabetes in DP-BB and normal Wistar rats. Also tested in this study is the hypothesis that the lack of development of diabetes in poly I:C-treated normal Wistar rats is attributable to a deficient α-IFN response. Using poly I:C doses of 0.5, 1.5, 5, and 10 μ/g body weight, a direct dose-response relationship was observed in DP-BB rats with the serum α-IFN response. Moreover, all doses of poly I:C accelerated the onset of diabetes in BB rats. Serum α-IFN levels inversely correlated with time of onset of diabetes (P < 0.01). Also, BB rats with higher levels of serum α-IFN were associated with earlier onset of diabetes (P < 0.001). Poly I:C-induced serum α-IFN levels were significantly lower in diabetic than in nondiabetic BB rats. In normal Wistar rats, although all doses of poly I:C significantly increased serum α-IFN levels, diabetes was not induced. The results of this study indicate that poly I:C administration elevates serum α-IFN and accelerates the development of diabetes in BB rats at even very low doses. This finding in conjunction with the correlation of serum α-IFN with the onset of diabetes is consistent with a pathogenetic role of α-IFN. The absence of a diabetogenic effect of poly I:C in Wistar rats suggests that α-IFN alone cannot induce diabetes in this animal.

Evaluation of sodium L-thyroxine (T4) requirement in replacement therapy of hypothyroidism.

Sodium-L-thyroxine (T4) was utilized in the treatment of 15 pediatric patients with hypothyroidism. Adequacy of replacement therapy was confirmed by clinical evaluation in conjunction with determination of serum thyroxine, tri-odothyronine, and thyrotropin concentrations. Daily dose of thyroxine capable of including clinical and biochemical euthyroidism ranged from 2.5 to 5 mug/kg of body weight with a mean of 3.5 +/- 0.3 mug in the 4- to 17-year-old age group. Two infants with congenital hypothyroidism diagnosese observations imply that physiologic requirements of thyroxine are distinctly lower than previously recommended dosages. Further studies to establish more precise therapeutic guidelines are needed.

Benign Elevation of Serum Alkaline Phosphatase, Transient and Persistent Variety

Markedly increased serum concentration of alkaline phosphatase (AP) was discovered in seven children. Investigation showed the finding to be benign in each case. Family survey and follow- up studies revealed a familial pattern in four children and a transient, idiopathic origin in the other three. Awareness of these benign forms of hyperphosphatasemia will aid the physician in the interpretation of elevated AP.

The role of NK cell activity in the pathogenesis of poly I:C accelerated and spontaneous diabetes in the diabetes prone BB rat

The development of insulin dependent diabetes mellitus (IDDM) and diabetes in the diabetes prone (DP) BB rat animal model of IDDM is thought to be due to an autoimmune process. Natural killer (NK) cells have been implicated but not proven to play a pathogenetic role in BB rats due to the increased NK cell number and activity found in these animals. We have recently reported that poly I:C, an inducer of cytokines and a potent enhancer of NK cell function, accelerates the development of diabetes in DP BB rats and induces diabetes in diabetes resistant (DR) BB rats. Since we have further demonstrated that poly I:C administration to BB rats increases NK cell number and levels of inducers of NK cell activity, interferon-alpha and IL-6 which is described therein, we tested the hypothesis that NK cell activity plays an important role in poly I:C accelerated disease. The role of NK cells in poly I:C accelerated diabetes and spontaneous diabetes was examined by determining whether selective depletion of NK cells using a rat NK cell specific antibody (anti-NKR-P1 antibody) alters the development of diabetes. The treatment of BB rats with anti-NKR-P1 antibody resulted in a significantly lower mean NK cell activity of splenic mononuclear cells than that found in control animals. However, the development of diabetes and degree of insulitis was not significantly different between treatment groups. BB rats administered anti-NKR-P1 antibody with poly I:C had a lower mean splenocyte NK cell activity and lower mean NK cell number within the peripheral blood and inflamed islets than rats administered poly I:C alone. However, anti-NKR-P1 antibody administration did not alter the accelerated development of diabetes or the degree of insulitis in poly I:C treated animals. These data document that NK cells do not play a major role in the pathogenesis of poly I:C accelerated diabetes or spontaneous diabetes in the DP BB rat.

Use of Fructosamine Test in Diabetic Children

Objective The goal of this study was to assess the effect of glucose and the contribution of the aldimine component on the measurement of fructosamine, the relationship of serum fructosamine with glycosylated plasma proteins, as measured by a new high-performance liquid chromatography methodology (Glyc PP-HPLC) and by an affinity chromatography (Glyc PP), and the ability of serum fructosamine to assess acute, short-term (1–2 wk), and long-term (2–3 mo) glycemic control. Research Design and Methods The measurement of fructosamine was unaltered by the addition of up to 27.5 mM glucose or by the elimination of the aldimine component of serum specimens by dialysis. Fructosamine was generated in vitro by incubating serum aliquots. This generation was dependent on time, glucose concentration, and temperature. Results Fructosamine (n = 27) correlated well with Glyc PP (r = 0.76, P < 0.01) and significantly less with Glyc PP-HPLC (r = 0.46, P < 0.01). Although oral glucose ingestion increased serum glucose acutely by 200% fructosamine was unchanged at each time interval. Improving glycemic control decreased the mean serum fructosamine concentration from 3.68 (baseline) to 3.28 mM (P < 0.01) at 1 wk and to 3.13 mM (P < 0.01) at 2 wk. HbA1c correlated with fructosamine (r = 0.59) and Glyc PP-HPLC (r = 0.47) but correlated best with Glyc PP (r = 0.83). Conclusions These results indicate the fructosamine assay is unaltered by serum glucose, solely measures the ketoamine component, correlates well with glycosylated plasma proteins measured by aminophenylboronic acid column chromatography, is unaffected by acute changes of serum glucose, and may be used to monitor changes in glycemic control over a 1-wk interval.

The Differing Presentation of Insulin-Dependent Diabetes Mellitus in Infants and Children:

agnosed with IDDM in the past, less than 1 % were reported in children under the age of 3 years.2~3 However, IDDM in infants (defined as age less than 2 years) appears to be increasing.’ Some recent studies from England and France find that as many as 13% of all pediatric patients diagnosed with diabetes are less than 4 years old .5,1 It is often stated that a majority of infants and toddlers with IDDM come to medical attention

426 IS GH SECRETORY STATUS A DETERMINANT OF THE PITUITARY TSH RESPONSE TO TRH

A suppressive GH effect on the pituitary TSH responsiveness to TRH and instances of clinical hypothyroldism developing in children receiving GH therapy have been described. To further clarify the mechanism, 17 children with GH deficiency were studied. Eleven children suffered from isolated GH deficiency (IGHD). Six children, in addition, had TSH deficiency attributable to TRH deficiency. Baseline thyroid studies including T4, RT3U, FT4 and TSH were determined in all and a TRH test (7 ug/kg IV) was performed prior to initiation of GH therapy, 2 weeks post-therapy and subsequently at 3 month intervals. In children with IGHD baseline thyroid studies were normal, and TSH response to TRH was comparable to controls. GH therapy up to 12 months did not alter thyroid function nor the TSH responsiveness to TRH.(Table)Children with GH and TSH deficiencies had variable baseline thyroid levels and hyper-responsiveness to TRH. The data indicates that in IGHD pituitary TRH responsiveness is intact and that GH therapy does not influence this responsiveness. Routine T4 substitution in children on GH therapy therefore, is unwarranted.