Effect of anti-IL-1ß antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo-controlled trial.

AIMS: Evaluate anti-interleukin-1ß (IL-1ß) antibody, canakinumab, in patients with type 2 diabetes and impaired glucose tolerance (IGT) in whom hyperglycaemia may trigger IL-1ß-associated inflammation leading to suppressed insulin secretion and ß-cell dysfunction. METHODS: This 4-week, parallel-group study randomized 190 patients with type 2 diabetes 2 : 1, canakinumab versus placebo, into the following treatment arms: metformin monotherapy, metformin + sulfonylurea, metformin + sulfonylurea + thiazolidinedione or insulin ± metformin. IGT population (n = 54) was randomized 1 : 1, canakinumab versus placebo. Primary efficacy assessment was change from baseline in insulin secretion rate (ISR) relative to glucose 0-2 h. RESULTS: Mean changes from baseline to week 4 in ISR relative to glucose at 0-2 h or other time points were not statistically significant for canakinumab versus placebo across groups. ISR (relative to glucose) at 0-0.5 h (first-phase insulin secretion) numerically favoured canakinumab versus placebo in insulin-treated patients {difference in mean change from baseline [point estimate (PE)] 3.81 pmol/min/m(2)/mmol/l; p = 0.0525} and in the IGT group (PE 3.92 pmol/min/m(2)/mmol/l; p = 0.1729). Mean change from baseline in fasting plasma glucose favoured canakinumab in the type 2 diabetes/metformin group and the IGT group; however, differences were not statistically significant. Mean change from baseline in peak insulin level and insulin AUC 0-4 h were statistically significantly higher in the canakinumab group in IGT patients. Canakinumab was well tolerated and consistent with known safety experience. CONCLUSIONS: The trend towards improving ISR relative to glucose 0-0.5 h in patients treated with insulin supports the hypothesis that insulin secretion can be improved by blocking IL-1ß.

Feminizing adrenal adenoma in a boy. Case report and literature review.

Feminizing adrenal tumors in young boys are rare; such patients initially show bilateral gynecomastia, and may have signs of virilization. We present a patient with bilateral gynecomastia, left adrenal adenoma, and elevated estrogen levels but normal levels of 17-ketosteroids.

Hypertrophic osteoarthropathy in association with pulmonary metastasis from osteogenic sacroma.

Hypertrophic osteoarthropathy in children is rare, especially when it is associated with lung metastsis. The patient reported herein had metastic osteogenic sarcoma and failed to respond to chemotherapy or thoractomy. There are several theories as to the pathogenesis of osteoarthropathy, but none is totally convincing. Vagotomy or transection of intercostal nerves has been advocated to relieve the symptoms of osteoarthropathy.

Growth during and after a trial of growth hormone releasing hormone 1-29 in children with idiopathic short stature or growth hormone neurosecretory dysfunction.

The growth promoting effects of once nightly subcutaneous injections of growth hormone releasing hormone (GHRH) 1-29 (30 microg/kg) for 6 months were studied in 16 slowly growing prepubertal children with idiopathic short stature (ISS; Group 1) and 8 similar children with growth hormone neurosecretory dysfunction (GHND; Group 2). Each child underwent endogenous growth hormone evaluation using both pharmacological and physiological testing; each had stimulated values > 10 microg/l and were subsequently placed into one of two groups based on pooled 12-hour overnight GH of < or > or = 3 microg/l. Each patient was followed every three months for one year. There were no significant differences in the two groups throughout the study with the exception of the endogenous GH levels. Both groups responded to GHRH therapy with similar significant increases in their rates of growth. Although a subset of patients (6 of 21) continued to grow at a rate significantly greater than the pre-therapy rate of growth, overall rates of growth were not significantly different from the pre-therapy growth rates 6 months following the discontinuation of GHRH treatment. We conclude that GHRH 1-29, given in the doses provided, leads to similar changes in growth rates in short, slowly growing children who are GH sufficient and those with GHND. Despite prior reports to the contrary, GHND patients do not experience a sustained increased in growth rate upon discontinuation of GHRH.

Neonatal genital reconstruction.

It is evident from studies of boys who suffered a surgical catastrophe at a young age and were then assigned a female sex role that cultural and environmental influence are a potent determinant of a child's gender identity. It is imperative that parents have their child's sex assignment firmly fixed in their minds as early as possible. Early surgical correction of a child with ambiguous genitalia to conform to the sex of assignment will serve greatly to reinforce appropriate behavior in the parent. Such surgical intervention for diagnostic and reconstructive purposes is both desirable and safe in the first weeks of life.

Impact of interleukin-1ß antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial.

AIMS/HYPOTHESIS: This study was conducted to determine the optimal monthly subcutaneous dose of canakinumab (a human monoclonal anti-human IL-1ß antibody) needed to improve glucose control in metformin-treated patients with type 2 diabetes mellitus (T2DM). METHODS: This was a parallel-group, randomized, double-blind, multicentre, placebo-controlled study designed to assess the effect on HbA(1c) and the safety/tolerability of four monthly doses of canakinumab (5, 15, 50, or 150 mg) as an add-on to metformin over 4 months. RESULTS: Patients (n=551; mean age 54.1 years; mean baseline HbA(1c) 7.4%) were randomized and treated in a double-blind fashion to canakinumab 5 mg (n=93), 15 mg (n=95), 50 mg (n=92), 150 mg (n=92) or placebo (n=179) monthly. There was no dose response detected between active canakinumab doses, but all doses numerically lowered HbA(1c) (primary endpoint) from baseline between 0.19% and 0.31% (placebo-unadjusted), with maximal effect noted in the 50mg dose of canakinumab (-0.18% difference vs placebo; multiplicity-adjusted, P=0.13902) as reported earlier (Ridker et al., 2012). No other glycaemic control parameters (FPG, fasting insulin, plasma glucose AUC(0-4h), 2-h PPG, peak glucose, C-peptide AUC(0-4h), peak C-peptide, insulin AUC(0-4h), peak insulin, ISR(0-2h), HOMA-ß and HOMA-IR) showed any meaningful changes by canakinumab therapy. Canakinumab treatment was safe and well tolerated. There were no relevant differences in adverse events between the canakinumab and placebo groups. CONCLUSIONS/INTERPRETATION: A 4-month course of monthly canakinumab (50 mg) produced a numerical reduction of HbA(1c) in T2DM patients on metformin, potentially by improving beta-cell function. The safety and tolerability profile of canakinumab was consistent with prior trials. TRIAL REGISTRATION: Registry: http://www.ClinicalTrials.gov, Registration No.: NCT00900146.

[Insulin growth factor-I-based dosing of growth hormone therapy in children: a randomized, controlled study].

Weight-based dosing of growth hormone (GH) is the standard of therapy in short children although insulin-like growth factor-I (IGF-I) is a major mediator of GH actions on growth. Objective: to test whether the IGF-I levels achieved during GH therapy are determinants of the growth responses to GH therapy. This was a two-year open-label, randomized IGF-I concentration-controlled trial. Prepubertal short children [n = 172; mean age 7.53 years; mean height SD score (HT-SDS - 2.64] with low IGF-I levels (mean IGF-I SDS - 3.56) were randomized to receive one of two GH dose-titration arms in which GH dosage was titrated to achieve an IGF-I SDS at the mean [IGF(low) group, n = 70) or the upper limit of the normal range [+2 SDS, IGF(high) group, n = 68] or to a comparison group of conventional GH dose of 40 mg/kg/day (n = 34). The multicenter study was performed in the outpatient centers. The primary outcome measure was to determine changes in HT-SDS during 2-year therapy. One hundred and forty-seven patients completed the trial. Target IGF-I levels were achieved in the dose-titration arms within 6-9 months. The changes in HT-SDS were +1.0, +1.1, and +1.6 for conventional, IGF(low), and IGF(high), respectively, with IGF(high) showing significantly greater linear growth response (p < 0.001), compared with the two other groups). The IGF-I(high) arm required higher doses ( > 2.5 times) than the IGF-I(low) arm, and these GH doses were highly variable (20-346 mg/kg/day). Multivariate analyses suggest that the rise in IGF-I SDS significantly impacted height outcome along with the GH dose and the pretreatment peak-stimulated GH level. IGF-I-based GH dosing is clinically feasible and allows maintaining serum IGF-I concentrations within the desired target range. Titrating the GH dose to achieve higher IGF-I target results in improved growth responses, although at higher average GH doses.

Children with growth hormone deficiency. Intermittent treatment with somatropin and oxandrolone.

The effectiveness of a combination of somatropin (0.1 IU/kg in three doses per week) and oxandrolone (0.1 mg/kg/day) in the treatment of human growth hormone deficiency was evaluated. Twelve children with hypopituitarism were placed into two separate groups. Each group was treated for five 6-month periods, and anthropologic measurements and bone-age determinations were obtained at the end of each period. Both groups of children grew approximately 20 cm during the 30 months of treatment. Somatropin increased the growth rate significantly both when given alone and when given in combination with oxandrolone. Although the addition of oxandrolone may have diminished the waning effect often seen during somatropin therapy, the acceleration in bone age indicates the need for further long-term studies before oxandrolone can be recommended as an adjunct to treatment with somatropin.

Eikenella corrodens as a cause of thyroid abscess.

Acute suppurative thyroiditis in children is rarely reported. It is generally associated with upper respiratory tract infections and is manifest as an acute febrile illness with swelling of the thyroid gland. Diagnosis is established by aspiration of the affected area, and cultures for both aerobic and anaerobic bacteria should be carried out. Therapy is based on drainage of the abscess and treatment with specific antimicrobial drugs, as determined by culture results. We describe a 3 1/2-year-old girl with a thyroid abscess from whom Eikenella corrodens, in addition to mixed flora, was recovered. No disturbance in thyroid function was observed. We review the pathogenesis of acute bacterial infections of the thyroid gland and the literature regarding the specific cause of these infections.

Comparison of growth and somatomedin C responses following growth hormone treatment in children with small-for-date short stature, significant idiopathic short stature and hypopituitarism.

Somatomedin-C (Sm-C) and growth hormone (GH) levels were determined before, during and after human growth hormone (hGH) treatment in 18 children with small-for-date short stature ( SDSS ), 7 children with significant idiopathic short stature ( SISS ) and 14 children with hypopituitarism. Data on the acute effects of hGH on Sm-C were compared to growth responses after 6 to 9 months therapy. Eleven of the 25 non-hypopituitary patients with normal basal and stimulated serum GH levels and normal basal Sm-C levels increased their rates of growth more than 3.0 cm/year. This compared with 11 of the 14 children with hypopituitarism who increased their rates of growth by at least 3.0 cm/year when treated with GH. Neither the basal somatomedin levels nor the GH-stimulated somatomedin levels correlated well with subsequent growth in the non-hypopituitary patients. These studies indicate that GH therapy may be effective in treating short stature in children without demonstrable GH deficiency.

Skeletal changes following growth hormone treatment in a child with combined hypopituitarism and a skeletal dysplasia.

A child with combined hypopituitarism and an undefined skeletal dysplasia is described. The hypopituitarism was manifested by post-natal growth failure, excessive sc fat, micropenis, and poor growth hormone response to provocative tests. Disproportionately short limbs, especially distally, and skeletal radiographs showing generalized brachydactyly, cone epiphyses of the phalanges and ossification defects in the proximal femoral metaphyses characterized the skeletal dysplasia. In contrast to the normal structure of the endochondral growth plate seen in hypopituitarism, the growth plate in this child was structurally abnormal; there was no differentiation of chondrocytes into hypertrophic and degenerative cells. Treatment with hGH for 8 months was associated with the appearance of chondrocyte differentiation, the restoration of growth plate structure to almost normal and a substantial increase in growth rate. There was no change in his disproportion or improvement in his radiographic abnormalities. These observations suggest that hGH may influence growth plate structure in certain instances and that this may be associated with increased linear growth.

Congenital nephrosis in association with hypothyroidism and hypoadrenocorticism.

Adrenal abnormalities are rarely recognized in association with the nephrotic syndrome. This report describes the hospital course of an 11-week-old child with congenital nephrotic syndrome secondary to diffuse mesangial sclerosis, in addition to hypothyroidism and hypoadrenocorticism.

Determination of leucine flux in vivo by gas chromatography-mass spectrometry utilizing stable isotopes for trace and internal standard.

A simple and reliable method is described for the determination of leucine flux in vivo using two stable isotopes of leucine and gas chromatography-mass spectrometry (GC-MS). [6,6,6-2H3]Leucine is administered as a primed-dose constant infusion in vivo and DL-[2H7]-leucine is added to plasma as an internal standard. Plasma leucine concentration and moles per cent enrichment of [2H3]leucine can be determined simultaneously by GC-MS and selected ion monitoring. Leucine flux calculated from the [6,6,6-2H3]leucine data was nearly identical to that obtained with L-[U-14C]leucine in dogs. This method is readily applicable to the study of leucine metabolism in humans of all ages and laboratory animals.

Effects of long-term growth hormone releasing hormone 1-29 in significantly short children.

Seven children with significant idiopathic short stature (SISS) whose heights were significantly below the third percentile (SD score for height -2.5 to -3.5) and who had normal levels of growth hormone (GH) were treated with growth hormone releasing hormone (GH-RH) in a dose of 30 micrograms/kg/day. Therapy was discontinued if patients failed to increase their rates of growth by more than 2.0 cm/year over their pre-therapy growth rate. Treatment was discontinued in two of the patients after 12 months but was continued in the other five for 24 months. These data demonstrate that some patients with SISS grow well during the first 2 years of treatment with GH-RH.

A randomized trial of a somatostatin analog for preserving beta cell function in children with insulin dependent diabetes mellitus.

In an attempt to rest the beta cells of newly diagnosed children with type I diabetes mellitus (IDDM) and thus possibly preserve beta cell function, ten children were given Octreotide, a somatostatin analog, for the first 21 days after diagnosis. Ten age-matched diabetic children served as controls. Although there were no differences in either insulin requirements or in hemoglobin A1 levels, there were significant increases in the glucagon-stimulated C-peptide levels of the experimental group at six and 12 months after diagnosis, compared to control patients.

Prolactinoma associated with transient growth hormone deficiency but persistent growth retardation.

A 14.8 year old boy was evaluated for galactorrhea of two months duration and growth deceleration for greater than three years. He was 3.7 standard deviations (SD) below the mean for age in height and euthyroid with uncompromised vision, bilateral galactorrhea, and pubertal arrest. MRI demonstrated a 10 x 8 mm left pituitary mass. Bone age was 11.5 years. Serum prolactin (PRL) decreased by more than 85% after 5 weeks of treatment with bromocriptine (Br). After five months, the prolactinoma (PRLoma) measured 5 x 4 mm. Hypothalamic-pituitary function indicated growth hormone (GH) deficiency and hypogonadotropic hypogonadism as assessed by ITT-TRH-GnRH-clonidine. After nine months of Br, despite return of adequate gonadotropin and GH secretion as assessed by repeat ITT-TRH-GnRH-clonidine, pooled 12 hour nocturnal spontaneous GH secretion, and clinical progression of puberty, there was no linear "catch-up growth" (growth rate = 4.4 cm/yr and height 4.2 SD below the mean for age). Growth rate increased following supplemental GH administration without untoward effect. We conclude that there may be discordance/lag between reduction in secretion and size of PRLomas and growth despite resolution of other anterior pituitary dysfunction. Other possibilities are discussed.

The influence of oral contraceptives on hormonal and metabolic homeostasis in young adolescents.

In order to evaluate the effects of oral contraceptives on metabolic and endocrine function in teenagers, Norinyl 1/50 was begun in 46 12-17-year-old girls after a 16-hour-fasting blood sample was obtained for glucose, insulin, glucagon, growth hormone, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, prolactin, gluconeogenic substrates, total lipids, and cholesterol. Sampling was repeated at 6 and 12 months of therapy. Of the 46 patients enrolled in the study, 23 returned for follow-up after 6 months, and 13 completed the study. Blood sampling after 6 and 12 months of therapy demonstrated no significant changes (p greater than 0.05). Our results suggest that there were no changes in the metabolic or endocrine functions studied at 6 and 12 months on a medium-dose contraceptive agent.

PIP: In order to evaluate the effects of oral contraceptives on metabolic and endocrine function in teenagers, Norinyl 1/50 was begun in 46 12-17-year-old girls after a 16-hour-fasting flood sample was obtained for glucose, insulin, glucagon, growth hormone, lutenizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, prolactin, gluconeogenic substrates, total lipids, and cholesterol. Sampling was repeated at 6 and 12 months of therapy. Of the 46 patients enrolled in the study, 23 returned for follow-up after 6 months, and 13 completed the study. Blood sampling after 6 and 12 months of therapy demonstrated no significant changes (p 0.05). Our results suggest that there were no changes in the metabolic or endocrine functions studied at 6 and 12 months on a medium-dose contraceptive agent. Study participants had requested an oral contraceptive and informed consent was obtained from all participants and their parents or guardians. The 36 black and 10 white patients ranged in age from 12.17 to 17.08 years with a mean of 15.0 years. Sexual development was Tanner stage 4 or 5. Mean gynecologic age was 2.83 years.

"Low-dose" growth hormone therapy during peritoneal dialysis or following renal transplantation.

The minimal effective dose of growth hormone (GH) to promote growth in children on dialysis or following renal transplantation remains unsettled. In order to study the issue, "low-dose" GH was administered to children with end-stage renal disease (ESRD) receiving chronic automated peritoneal dialysis (APD, n = 6, 4 males, 2 females) or following renal transplantation (T, n = 9, 8 males, 1 female). No APD patient was GH deficient, while 1 T patient (no. 2) had data consistent with GH deficiency, although he was obese (body mass index = 34 kg/m2). The mean dose of GH after 6 and 12 months of treatment was 0.16 +/- 0.02 and 0.22 +/- 0.07 versus 0.16 +/- 0.03 and 0.27 +/- 0.21 mg/kg per week for APD and T patients, respectively. When analyzing all patients, there were no significant differences before or after 6 and 12 months of GH therapy within or between the two groups, in terms of height velocity, bone age, renal function (in the T group) and height Z-scores (Z-Ht). However, the height velocity Z-score (Z-HV) increased significantly at 6 and 12 months compared with baseline in the APD patients only (P < 0.05). When the 2 T patients with the most impaired renal function were excluded from the analysis, Z-HV also increased significantly in the T patients after 12 months of GH (P < 0.02). We conclude that following "low-dose" GH therapy, children with ESRD treated with APD or T have similar increases in HV, allowing maintenance of Z-Ht but not "catch-up" growth.