Immunoregulation with levamisole in children with frequently relapsing steroid responsive nephrotic syndrome

The immunological and clinical effects of levamisole were studied in 10 children with frequently relapsing steroid responsive nephrotic syndrome (SRNS). The efficacy of the drug was tested during remission of the disease with all patients on alternate day steroid therapy. The lymphocyte proliferative response to phytohemagglutinin (PHA), concanavalin-A (Con-A) and pokeweed mitogen (PWM) were normal. The Con-A induced suppressor T-lymphocyte activity of 7 patients was low before treatment with levamisole 8 +/- 3.7% and increased to normal values during therapy 34 +/- 6%; p less than 0.001 (control 32 +/- 5%). In these 7 children prednisolone dosage could be decreased significantly or discontinued altogether (44.1 +/- 5.3%). Patients without immunoregulatory abnormalities did not respond to levamisole. In 3 out of 4 children tested the percentage of OKT8+ cells rose during levamisole therapy from 19.7 +/- 2.1 to 37 +/- 2.3 (p less than 0.001), thus correcting the elevated pre-treatment OKT4+/OKT8+ ratio from 3.1 +/- 0.2 to 1.5 +/- 0.2; p less than 0.001 (control 1.47 +/- 0.2). These data support the hypothesis that abnormal immunoregulation may play a role in the pathogenesis of SRNS. Treatment with levamisole can be useful in some patients with the frequently relapsing form of the disease.     

Phenotypes of Peripheral Blood Lymphocytes during Acute Hepatitis A

ABSTRACT. We investigated peripheral blood lymphocyte phenotypes of 74 patients at weekly intervals during the course of acute hepatitis A. In the second week after onset of jaundice, a significant elevation of total lymphocytes was observed (4096 × 10⁶± 1003 × 10⁶/l vs. controls 3038 × 10⁶± 1208 × 10⁶/l, p < 0.005). However, no change in the relative percentages of B-cells (CD20+), T-cells (CD3+ or CD2+), or T-cell subpopulations (CD4+ helper cells and CD8+ suppressor cells) could be demonstrated during the course of the disease. Activated T-cells (CD3+DR+) were elevated during the first week (204 × 10⁶± 134 × 10⁶/l vs. normal 91 × 10⁶± 54 × 10⁶/l, p <0.005) and during the second week (202 × 10⁶± 82 × 10⁶/l, p < 0.0005) after onset of disease and returned to normal values until the third week. Cells expressing phenotypes of lymphocytes capable of exerting non-MHC-restricted cellular cytotoxicity, i.e. Natural Killer cell activity (CD57+, CD16+, and CD56+) were significantly elevated in percentage in the first week of disease, as compared to controls (CD57: 14.5 ± 7.0% vs. 9.3 ± 5.8%, p <0.05; CD16: 13.4 ± 7.3 vs. 9.5 ± 5.1%, p < 0.05; CD56: 10.5 ± 3.5% vs. 8.0 ± 1.5%, p < 0.005). Also the absolute numbers of these lymphocyte subpopulations were found to be elevated during the first and second week. The increase in NK cells in the initial phase of acute hepatitis A suggests an important role of these cells in the first line of defence in this disease.     

Both allergen-specific CD4 and CD8 Type 2 T cells decreased in asthmatic children with immunotherapy

Allergen-specific immunotherapy (IT) has been used for the treatment of atopic diseases since the turn of this century. The precise working mechanisms, however, remain to be clarified. The aim of this study was to investigate the role of particular subsets of allergen-specific T cells in the non-atopic individuals, untreated asthmatic children and the asthmatic children receiving immunotherapy. We collected peripheral blood from 16 untreated asthmatic children and 17 asthmatic children receiving immunotherapy over one and half years. All the patients were sensitive to mite allergen. Peripheral blood mononuclear cells (PBMC) were isolated and, in vitro , stimulated with crude mite extract to enrich the mite-specific T-cell population. After 14 days, the enriched mite-specific T cells were stimulated with phorbol-12-myristate-13-acetate (PMA) and ionomycin for intracellular detection of cytokines such as IFN-γ, IL-4 in CD4⁺ and CD8⁺ T lymphocytes. The data here demonstrated that the levels of mite-specific IgG4 and IgA increased significantly in asthmatic children after immunotherapy. In addition, both IL-4 expressing CD4⁺ and CD8⁺ T cells were significantly lower in asthmatic children after immunotherapy compared with those of before treatment and the normal control (p < 0.05). In contrast, the frequency of IFN-γ expressing CD4⁺ and CD8⁺ T cells did not significantly differ between untreated and SIT-treated groups. All these data suggested that decreased Type 2 CD4⁺ and CD8⁺ T cells might be closely correlated with the regulatory mechanisms of immunotherapy.     

Randomized trial comparing intravenous immunoglobulin with methylprednisolone pulse therapy in acute idiopathic thrombocytopenic purpura

Forty-three children with newly diagnosed idiopathic thrombocytopenic purpura (ITP), platelet count (PC) below 20 × 10⁹ 1⁻¹, and either continued bleeding or failure to show a spontaneous rise in the PC after a 3 day observation period were randomized to treatment with either intravenous immunoglobulin (IVIG) infusions I gkg⁻¹ (n = 23) or intravenous methylprednisolone pulse therapy (MPPT) 30mgkg¹ (n = 20) on two consecutive days. After 72h, IVIG had induced greater platelet responses (mean PC 188 × 10⁹ versus 77 × 10⁹1⁻¹ 2p < 0.001) and raised the PC to a haemostatically safe level above 50 × 10⁹1⁻¹ more frequently (91 versus 50%, one-sided e×act p = 0.003). Children responding poorly were then given the alternative treatment in addition. After 6 days, a normal PC of over 150 × 10⁹1⁻¹ had been obtained more frequently in the group given first-line IVIG (70 versus 50%, p = 0.16). The relapse rates during 6 months of follow-up were not significantly different (26 versus 40%, p = 0.26). Cross-over treatment in 11 children with relapse confirmed the superior response to IVIG. The treatment given was restricted to the two initial infusions more often in the IVIG group (70 versus 35%, p = 0.05). These results indicate that IVIG may be preferable to MPPT as the initial treatment for ITP.     

Treatment of Idiopathic Nephrotic Syndrome with Levamisole

Thirty children with frequently relapsing idiopathic nephrotic syndrome (INS) were treated with levamisole (2.5 mg/kg BW) twice a week for a mean period of 9.9 months. A beneficial effect was observed in 16 children in whom corticosteroids could be significantly decreased without relapse. Levamisole was ineffective in 14 patients. There was no difference between the two groups in the duration of INS, the number of relapses and the duration of treatment with levamisole. The mean age at onset of INS was higher in the group of patients where levamisole was effective (5.8 years versus 2.8 years). In 7 patients who responded to levamisole neutrophils decreased below 4×10⁹/l. Transient granulocytopenia was observed in 3. It is concluded that levamisole may be effective in frequently relapsing INS with minimal side effects     

Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity

Erythropoietin (rHuEPO) therapy has been shown to be beneficial in preventing and treating anaemia of prematurity and to decrease the need for blood transfusions. There is, however, only scanty data on the effect of rHuEPO therapy on iron metabolism. We studied 29 preterm infants (age 34 ± 14 days) who were randomly assigned to receive either rHuEPO 900 U kg^-1 week^-1 with 6 mg kg^-1 day^-1 of iron for 4 weeks ( n= 15) or no therapy. The following parameters were evaluated and compared between and within groups at the beginning, during and at the end of the study: Haematocrit (SI), reticulocytes (10⁹μgl^-1), serum ferritin (μg1^-1) and iron (μmol 1^-1). The results were as follows. At the baseline, erythropoietin levels were similar in both groups: 7.2 ± 5.6 versus 6.2 ± 3.2 mU ml^-1 (NS). In the treated infants the haematocrit remained stable during the study and was significantly higher than in the control group by the end of the study: 0.34 ± 0.03 versus 0.28 ± 0.05 ( p = O.001). rHuEPO therapy increased the reticulocyte count from 130 ± 70 to 430 ± 200 ( p = 0.0002). However, rHuEPO therapy depleted both serum ferritin and it-on levels from 321 ± 191 to 76 ± 58 $uMgl^-1 ( p = 0.04) and from 18 ± 5 to 13 ± 4 μmoll^-1 ( p = 0.03), respectively. We conclude that rHuEPO therapy prevented anaemia and its sequelae; however, serum ferritin and iron levels were depleted. We suggest that the effect of rHuEPO may be further increased by higher iron supplementation.     

Phenotypic changes of T-lymphocyte subsets induced by interleukin-12 and interleukin-15 in umbilical cord vs. adult peripheral blood mononuclear cells

The decreased incidence of graft-vs.-host disease found following umbilical cord blood (CB) transplantation, and the increased susceptibility of newborns to infections, have been attributed, in part, to functional and phenotypic immaturity of neonatal T cells. We investigated the phenotypic changes of CB T cells induced by two immunoregulary cytokines, interleukin (IL)-12 and IL-15, alone or in combination. Adult peripheral blood (APB) mononuclear cells (MNCs) were also tested for comparison. Prior to culture, the percentages of CD3⁺ CD8⁺, CD3⁺ CD25⁺, and CD3⁺ CD56⁺ cells were significantly lower in CB MNCs than in APB MNCs. IL-15, but not IL-12, significantly increased CD3⁺ CD8⁺ expression among the CB MNCs after 1 week of culture. Combining IL-12 and IL-15, however, resulted in decreased CB CD3⁺ CD8⁺ expression compared with IL-15 alone. The percentage of CD3⁺ CD25⁺ cells in CB MNCs spontaneously increased in the absence of cytokines, while that of CD3⁺ CD56⁺ cells in CB MNCs could not be enhanced with cytokines. In contrast, the percentages of CD3⁺ CD25⁺ and CD3⁺ CD56⁺ cells among the APB MNCs could be increased with IL-12, IL-15, and further with IL-12 and IL-15 combined. Thus, different patterns of T-cell subset changes were demonstrated between CB MNCs and APB MNCs in response to IL-12 and/or IL-15. These data may serve as a foundation for using cytokine therapy in newborns and children receiving CB transplants.     

T Cell Activation and T Cell Receptor Variable Region Gene Usage in Measles

T cell activation and T cell receptor variable (V) regions were studied with monoclonal antibodies in peripheral blood lymphocytes from 22 patients with measles. Increased (> 5%) activated T cells (HLA-DR⁺ CD3⁺ cells) were noted in 14 of the 22 patients. Elevations of Vβ5⁺ and Vβ8 + T cells were observed in two and four patients, respectively, and appeared to be associated with T cell activation. The duration of fever was significantly prolonged in those with increased (> 10%) activated T cells (p < 0.01). These results suggest that T cell activation and the preferential expansion of Vβ8⁺ and Vβ5⁺ T cells are associated with the pathogenic process of measles.     

Follow-up of antibodies to growth hormone in 210 growth hormone-deficient children treated with different commercial preparations

The aim of the study was to evaluate the immunogenicity of different commercial recombinant-growth hormone preparations. The presence of antibodies to growth hormone was tested in 210 growth hormone-deficient children at 6-month intervals during treatment for 6-66 months. The patients were treated with three preparations (groups A, B and C of 70 cases each) having the authentic growth hormone sequence. Groups A and B received hormone synthesized by the recombinant DNA technique in E. coli, while the group C preparation was produced in a mammalian cell line. The preparations showed poor immunogenicity and antibodies were found as follows: 1.4% in patients of group A (1 case: binding capacity 0.2mg/l and Ka 3.5 10⁷ 1 M^-1), 2.8% in patients of group B (2 cases; case 1 binding capacity 0.7mg/l and Ka 1.5 10⁷1M^-1; case 2 binding capacity 0.04mg/1 and Ka of 1.8 10⁸ and 6.5 10⁶ 1 M^-1), and 8.5% in group C (6 cases; binding capacity from 0.4 to less than 0.02 mg/ 1, Ka from 1.6 10⁷ to 3.8 10⁸ 1 M^-1). Only two patients of group C presented the antibodies in two subsequent examinations; in the other patients the positivity was found once. In all patients positive samples were found at intervals of 6-24 months after the start of therapy. In all antibody-positive patients growth velocity presented no decrease at the time of antibody detection and was never different to that of negative patients. We conclude that the three commercial preparations examined showed poor immunogenicity without clinical relevance.     

Physical effects of growth hormone treatment in children with Prader-Willi syndrome

A randomized, controlled study of 54 children (age, 4-16 years) with Prader-Willi syndrome was conducted to assess the potential beneficial effects of growth hormone (GH) treatment. After observation for 6 months, the children were randomized to receive GH at a dose of 3 IU/m²/day (1 mg/m²/day) ( n = 35) or no intervention ( n = 19). The effects of GH treatment on linear growth, body composition, muscle strength, pulmonary function and resting energy expenditure were assessed. The levels of GH secreted in resonse to clonidine stimulation were universally low, and mean (± SD) insulin-like growth factor I SDS was -1.2 ± 0.8 pretreatment. In children treated for 1 year, mean height velocity SDS significantly increased from -1.0 ± 2.5 to 4.6 ± 2.9 ( p < 0.0001), mean percentage body fat decreased from 46.3 ± 8.4% to 38.4 ± 10.7% ( p < 0.001), mean lean body mass increased from 20.5 ± 6.3 kg to 25.6 ± 4.3 kg ( p <0.01) and respiratory muscle function and physical strength imporved. Mean respiratory quotients significantly decreased from 0.81 to 0.77 ( p < 0.001); however, resting energy expenditure did not change. Therefore, GH therapy appears to reduce some of the physical disabilities experienced by children with Prader-Willi syndrome.     

Renal magnesium handling in infants and children

Renal handling of magnesium (Mg) has been incompletely studied during infancy and childhood due to the difficulty, until recently, of measuring the diffusible fraction of plasma Mg. In the present investigation this methodology has been used to assess Mg homeostasis in 45 healthy infants, aged 1 to 12 months, and in 63 healthy children, aged 1 to 15 years. When compared to children, infants had significantly higher plasma values (mean ± SD) for both total (0.76 ± 0.08 versus 0.70 ± 0.06 mmol 1 ¹; p <0.001) and ultrafilterable Mg (0.51 ±0.07 versus 0.49±0.04mmol l^-1; p <0.05). No significant correlations were present between values of plasma Mg and plasma concentrations of calcium, creatinine, total protein or albumin. The ratio U _Mg/ U _Cr, calculated in the second morning urine (median, 3rd-97th centiles), was also significantly higher during infancy (0.023, 0.009-0.07 versus 0.015,0.006-0.04;p < 0.001). On the contrary, fractional excretion of Mg (median, 3rd-97th centiles) was identical in both age groups and did not correlate significantly with age (infants: 3.2, 1.0-7.8%, children 3.4, 1.6-8.1%; p = NS). During a Mg infusion, carried out in six children, we could establish an approximative value for renal Mg threshold (plasma ultrafilterable Mg = 0.50 mmoll^-1) close to that found in adults. These results indicate that no functional immaturity is present during infancy for renal tubular reabsorption of Mg and that the high U _Mg/ U _Cr ratio observed in this age group is a phenomenon not dependent on a higher urinary Mg excretion but probably related to a lower urinary creatinine excretion per unit of lean body mass.     

Premature Thelarche–Natural History and Sex Hormone Secretion in 68 Girls

ABSTRACT. Data obtained during long-term follow-up of 68 girls with premature thelarche were analysed. In 85 % onset was before the age of 2 years, in 30.8 % being present at birth. In 44.1 % there was a regression after 3^2/12±2^8/12 12years (SD). Basal levels of plasma FSH and response to LH-RH were significantly higher than prepubertal controls (1.93± 1.56 vs. 0.8±0.1 mU/ml and peaks 12.3±5.4 vs. 7.9±1.0 mU/ml respectively; p <0.001). Twenty-seven of 52 patients tested had increased plasma estradiol and in 27 of 40 patients tested, urocytograms or vaginal smear showed estrogenization. Basal levels of LH and response to LH-RH were prepubertal. The girls with premature thelarche were significantly taller than normal controls of the same age ( p <0.001). These results suggest that premature thelarche is an incomplete form of precocious sexual development probably due to derangement in the maturation of the hypothalamo-pituitary-gonadal axis which results in a higher than normal secretion of FSH, as well as a defect in the peripheral sensitivity to the sex hormones.     

Immunotherapy with autologous dendritic cells and tumor antigens for children with refractory malignant solid tumors

Abstract:  Immature DCs were generated from the peripheral blood monocytes from five children with refractory solid tumors (Ewing sarcoma, synovial sarcoma, neuroblastoma) using GM-CSF and IL-4. These DCs were then pulsed with tumor-specific synthetic peptides or tumor lysates in the presence of the immunogenic protein KLH for 12 h. Pulsed DCs were administered subcutaneously every one or two weeks in an outpatient setting without any toxicity. In one patient with Ewing sarcoma, the residual tumor disappeared following autologous PBSCT and DC therapy, and a complete remission has been maintained for 77 months. In two patients with synovial sarcoma or with neuroblastoma, growth of the tumors was temporally suppressed for one and 10 months, respectively, followed by their exacerbation. A DTH response was detected against KLH in all five patients and against the tumor lysate in one patient. In the patients with a possible DC-mediated anti-tumor effect, the number of CD8⁺ HLA-DR⁺ lymphocytes and INF-γ⁺CD8⁺ lymphocytes increased and an elevation of the NK cell cytotoxic activity was observed during and/or after DC therapy. DC-based immunotherapy may therefore be a feasible, well-tolerated and promising approach in the treatment of children with refractory malignant tumors.     

Low sodium levels in serum are associated with subsequent febrile seizures

Fever plays an important role in causing disturbances in fluid and electrolyte balance. Hyponatraemia has been thought to enhance the susceptibility to seizures associated with febrile illnesses in childhood. We have studied serum electrolyte levels in children with simple and complicated febrile convulsions. Sodium levels were lower in those children with complicated convulsions in comparison with those having simple convulsions (136.07 ± 3.06 mmoll⁻¹, mean ± SD, n = 42, and 137.62 ±2.63mmoir¹, n = 71, respectively; p < 0.01, Student's Mest). The sodium concentrations were lowest in children with repeated seizures (134.20 ± 2.30 mmoll⁻¹, n= 15) compared with children having simple ( p < 0.01, ANOVA, Duncan's test) or other complicated types of febrile convulsions: focal seizures (137.08 ± 3.82 mmoir¹, n = 12, p < 0.01), seizures lasting longer than 15 minutes (138.00 ± 2.45 mmoll⁻¹, n = 5, p < 0.05) and children over 5 years (136.70 ±2.06 mmoll⁻¹, n = 10, p < 0.05). Serum potassium levels showed no statistically significant differences between the patient groups. Our results show that hyponatraemia may increase the risk for multiple convulsions during the same febrile illness.     

Absorption of macronutrients and nitrogen balance in children with dysentery fed an amylase-treated energy-dense porridge

The aim of this study was to determine the absorption of macronutrients and energy from an energy-dense diet liquefied with amylase from germinated wheat (ARF) in children suffering from acute dysentery. Thirty-male children aged 6–35 months presenting with acute dysentery were randomly assigned to receive either an ARF-treated porridge or a standard porridge liquefied with water to make its consistency similar to the ARF porridge. After 24-h stabilization a 72-h metabolic balance was performed. Sixteen children received an ARF-treated porridge and 14 received a standard porridge liquefied with water. The mean ± SD coefficients of absorption (%) of carbohydrate, fat. protein and energy (ARF porridge vs regular porridge) were 81.4 ± 11 vs 86.9 ± 7. 86.1 ± 10 vs 82.8 ± 15, 57.3 ± 12 vs 48.4 ± 24 and 81.4 ± 9 vs 83.1 ± 8, respectively. The stool loss of carbohydrate, protein, fat and energy was similar in the two groups. The net absorption of energy was substantially greater in the ARF-fed than regular porridge-fed children (by 28%, p = 0.01). The nitrogen balance was 6.9 ± 3.4mgkg^-1 d^-1 in the ARF porridge group and 1.1 ± 6.7mgkg^-1 d^-1 in the regular porridge group ( p = 0.01). These results show that, despite being hyperosmolar, an amylase-treated liquefied energy-dense porridge is absorbed as well as a regular porridge by malnourished children with severe dysentery. Consequently, its use substantially increased the absorption of a net amount of macronutrients and resulted in a better nitrogen balance. These results further support this innovative approach of feeding sick children in developing countries.     

Lymphocyte subsets and cytokines in adenoviral infection in children

To determine the distribution of major blood lymphocyte subsets we evaluated blood lymphocytes by flow cytometry in adenovirus-infected infants aged 30–730 d. In addition, interleukin-1-receptor antagonist, interleukin-10 and transforming growth factor-β1 were measured in serum by enzyme-linked immunosorbent assay. According to clinical parameters, mechanical ventilation and outcome, infections were classified as moderate ( n = 15), severe ( n = 11) and fatal ( n = 12). Controls were 13 healthy children. In severe and fatal infection, T cells (CD5⁺/CD19^-), NK effectors (CD16⁺), CD4⁺ T subset and B1 subset of B lymphocytes (CD5⁺/CD19⁺) were all significantly decreased. CD8⁺ cells were decreased in severe but not fatal cases. There was no difference in serum values of interleukin-10; however, fatal cases had high interleukin 1-receptor antagonist values. Interestingly, patients with moderate infection showed significantly increased values of transforming growth factor-β1. These results demonstrate that life-threatening adenoviral infection is associated with marked abnormalities in blood lymphocyte and cytokine profile.     

Short-course oral prednisone therapy in children presenting with acute immune thrombocytopenic purpura (ITP)

Immune thrombocytopenic purpura (ITP) is a disorder for which management remains controversial. The ongoing goal is to define the minimal therapy required for children with acute ITP. A pilot study of short-course oral prednisone (4 mg⁻¹ kg⁻¹ d⁻¹ for 4 d with no tapering) was undertaken in 25 consecutive children with acute ITP and platelet counts under 20 × 10⁹ 1⁻¹. Of the 25 children, 22 responded to the prednisone therapy by achieving a platelet count higher than 20 × 10⁹ 1⁻¹ within 1 week of commencing treatment. This regimen was found to be safe, inexpensive and effective in increasing the platelet count of children to a haemostatically safe level.     

Mucosal T cells recovered from mice after infection with respiratory syncytial virus display a memory/activation phenotype

Pgp-1 expression was studied as a marker of memory/activation on systemic and mucosal T cells of BALB/c and C57BL/6 mice after infection with respiratory syncytial virus (RSV), using two-color dual fluorescence flow cytometry employing anti-L3T4 (CD4), anti-Ly2 (CD8), and anti-Pgp-1 (CD44) monoclonal antibodies. Pgp-1 was expressed in relatively low densities on T cells of C57BL/6 mice, allowing differentiation of a dual population of Pgp-1¹⁰ and Pgp-1^hi T cells after antigenic stimulation in vivo. On the contrary, T cells of BALB/c mice were uniformely Pgp-1^hi, making this mouse strain less suitable for studies with this marker. In blood and spleen consistently more CD8⁺ than CD4⁺ T cells were Pgp-1^hi, while in BAL more CD4⁺ than CD8⁺ T cells were Pgp-1^hiAfter primary but not after secondary infection, CD4⁺ Pgp-1^hi T cells increased significantly in the blood and spleen. After secondary infection both CD4⁺ Pgp-1^hi and CD8⁺ Pgp-1^hi T cells increased in the BAL. It is hypothesized that after primary infection systemic RSV-specific T cells acquire an activation/memory phenotype as characterized by an enhanced expression of Pgp-1, resulting in a faster and stronger influx of these cells in the lungs after secondary infection.     

Prevention of Neonatal HBV Infection with the Combination of HBIG and HBV Vaccine and Its Long-Term Efficacy in Infants Born to HBeAg Positive HBV Carrier Mothers

Seventy-three infants born to HBeAg positive HBV carrier mothers were protected from neonatal HBV infection with our standard prevention schedule consisting of two doses of HBIC (0, 2 mo) and three doses of HBV vaccine (2, 3, 5 mo). In 62 infants who successfully responded to HBV vaccine with a titer of anti-HBs greater than 2³, anti-HBs titer was monitored for as long as 48 months (25.6 ±11.0 mo) and found to decrease as follows: 5.1 ± 1.7 at 12 mo., 4.5 ± 1.8 at 18 mo., 4.2 ± 1.8 at 24 mo., 4.0± 1.6 at 30 mo., 3.7 ± 1.7 at 36 mo., 32 ± 2.0 at 48 mo. During the follow-up period, eight HBV events (11.9%) were demonstrated: one case showed an increase of anti-HBs, three showed a reappearance of anti-HBc alone, three showed a reappearance of anti-HBc with increase of anti-HBs, and one became a chronic HBV carrier. All infants were further divided into three groups by their maximal response of anti-HBs to HBV vaccine: Group I (2⁶), Group II (2³-2⁵), and Group III (2²). Group I sustained a higher titer from 12 to 30 months of age and had less HBV events than (3-II and G-III. Our study suggests that acquisition of a high titer of anti-HBs is important in long-term prevention of HBV infection as well as in the neonatal period in infants born to HBeAg positive HBV carrier mothers.     

Insulin secretion and hepatic insulin clearance as determinants of hyperinsulinaemia in normotolerant grossly obese adolescents

Obesity is characterized by variable degrees of hyperinsulinaemia, which has been attributed to either β-cell hypersecretion or reduced hepatic insulin extraction, or both. To investigate this controversial issue, a 4-h frequently sampled i.v. glucose tolerance test (glucose dose 12.8 g m^-2) was performed in 13 normotolerant, grossly obese adolescents (10 F/3 M; 13 ± 1 y; body mass index 32 ± 0.9; pubertal stage 4–5; obesity duration 7.8 ± 3 y) and in a comparable group of 8 healthy, normal-weight subjects. Glucose, insulin and C-peptide time-course were analysed by the minimal model technique, which estimates β-cell secretion, insulin sensitivity ( S _i), glucose effectiveness ( S _G) and hepatic insulin extraction (HE). Despite similar fasting and after load glucose patterns ( S _G similar in the two groups), obese adolescents showed sustained peripheral hyperinsulinaemia (total insulin area under the concentration curve 67.2 ± 10.8 vs 19.1 ± 1.2 pmol l^-1 in 240 min; p < 0:002) and a 71% reduction in S _i (2.02 ± 0.33 vs 6.95 ± 1.03±10⁴ min^-1 (μU ml^-1); p < 0:001). Compared with control subjects, the total amounts of prehepatic insulin secretion and posthepatic insulin delivery were also increased significantly in obese adolescents by 30% and 46%, respectively; HE was reduced by 15% during the first 30 min of the test, but recovered within the normal range during the rest of the test. In conclusion, severely obese adolescents are insulin resistant and their hyperinsulinaemia is primarily caused by β-cell hypersecretion, whereas the reduction in insulin hepatic extraction is a transient metabolic phenomenon.