Mice lacking ornithine-delta-aminotransferase have paradoxical neonatal hypoornithinaemia and retinal degeneration.

Deficiency of ornithine-delta-aminotransferase (OAT) in humans causes hyperornithinaemia and gyrate atrophy (GA), a blinding chorioretinal degeneration. Surprisingly, OAT-deficient mice produced by gene targeting exhibit neonatal hypoornithinaemia and lethality, rescuable by short-term arginine supplementation. Post-weaning, these mice develop hyperornithinaemia similar to human GA patients. Subsequent studies in one human GA infant also showed transient hypoornithinaemia. Thus, the OAT reaction plays opposite roles in neonatal and adult mammals. Over several months, OAT-deficient mice develop a retinal degeneration with involvement of photoreceptors and pigment epithelium. OAT-deficient mice appear to be an excellent model of human GA.

Evaluation of on-farm biological treatment processes for wastewaters from vegetable peeling.

This study highlights the need for the development of simple, efficient, and cost-effective farm-scale applications to treat wastewater arising from vegetable-peeling operations. The aim was to evaluate two full-scale biological wastewater treatment systems, a sequencing batch reactor (SBR) and a biofilter, and a chemical wastewater treatment system on farms carrying out peeling of vegetables. The types, design criteria and parameters of the processes, as well as properties of the untreated and treated wastewaters were presented and evaluated. Seven-day biochemical oxygen demand (BOD7) entering the SBR was 3100 +/- 529 mg l(-1) (mean +/- standard deviation). The results showed that the SBR was very stable and effective in the treatment of carrot-processing wastewaters, the BOD7 for effluent being about 10 mg l(-1). The biofilter examined did not operate well because the pH too low: the reduction for BOD7 was 63% and, for COD, 58%. When wastewater from potato processing was treated with aluminium sulphate and conveyed to an artificial pond, removal of BOD7 was 67% and that of COD 69%. This method is only suitable for pre- or post-treatment of these wastewaters. Control of the treatment processes appeared to be essential for their proper functioning.

Response to growth hormone treatment and final height in Noonan syndrome in a large cohort of patients in the KIGS database.

BACKGROUND: Noonan syndrome (NS) is an autosomal dominant inherited disease, characterized by a distinctive facial appearance, congenital heart defects, and short stature. Treatment with growth hormone (GH) is an option to enhance height, but long-term effects are still unclear. PATIENTS AND METHODS: A cohort of 402 patients (269 males, 133 females), mean age 9.7 years at start with GH, was studied within the KIGS International growth database with respect to long-term response to GH therapy and final height after GH therapy. RESULTS: At the start of GH therapy median height was -2.61 SDS (Tanner 1966 standards). Seventy-three patients who were followed longitudinally for 3 years had an increment in height SDS (Ht SDS) over the first 3 successive years of 0.54, 0.13 and 0.13, respectively. Twenty-four patients had reached their final height after 4-12 years of GH treatment. Their Ht SDS increased from a median of -3.28 to a median of -2.41 at final height. CONCLUSION: This group of patients with NS showed an early response to GH treatment, with an attenuation of this effect thereafter. At final height the median increment of final height was 0.61 SDS according to Tanner standards and 0.97 SDS according to Noonan standards. No serious side effects were reported.

Gyrate atrophy of the choroid and retina with hyperornithinemia. Deficient formation of guanidinoacetic acid from arginine.

Patients with gyrate atrophy of the choroid and retina have 10- to 20-fold increased ornithine concentrations in body fluids and significantly reduced activity of ornithine aminotransferase in lymphocytes and cultured fibroblasts. We administered intravenous arginine to six patients and six controls to study in vivo inhibition by high ornithine concentrations of arginine-glycine transamidinase, the rate-limiting enzyme in creatine synthesis. Serum arginine concentrations curves after administration were similar for the two groups. The increment in serum ornithine was more than three times as great in patients as in controls. The mean half-times in plasma ornithine were 360 and 97 min, respectively. In the patients, the metabolic clearance of ornithine from the extracellular fluid was significantly delayed. Urinary guanidinoacetate excretion rose markedly in all controls, the excretion rate being higher in females. The patients always excreted less than the controls, the differences within the sexes being highly significant. Differences in creatine excretion after administration were less marked. We conclude that in gyrate atrophy patients, formation of guanidinoacetate, creatine, and possibly phosphocreatine is inhibited at the transaminidation step by the high concentrations of ornithine. Deficiency of the high-energy phosphates may underlie the pathogenesis of the eye and muscle atrophies.

Gyrate atrophy of the choroid and retina with hyperornithinemia: characterization of mutant liver L-ornithine:2-oxoacid aminotransferase kinetics.

Deficient activity of L-ornithine:2-oxoacid aminotransferase is associated with gyrate atrophy of the choroid and retina with hyperornithinemia, an autosomal recessive disease leading to blindness. Liver tissue from two patients contained trace activity of the enzyme. The Michaelis (Km) value of the mutant enzyme for ornithine was 200 mM, 50-fold higher than normal, but increasing the concentrations of alpha-oxoglutarate and pyridoxal 5'-phosphate to 10 times those giving maximal activity of the normal enzyme had no effect on the mutant enzyme. Substrate inhibition of the mutant could not be demonstrated at 1,000 mM ornithine concentration, whereas ornithine concentrations above 70 mM inhibited the normal enzyme. The data suggest that the abnormal L-ornithine:2-oxoacid aminotransferase in the two patients studied has an altered binding site for ornithine.

Inhibition of arginine-glycine amidinotransferase by ornithine. A possible mechanism for the muscular and chorioretinal atrophies in gyrate atrophy of the choroid and retina with hyperornithinemia.

The inhibitory effect of ornithine on L-arginine:glycine amidinotransferase (EC 2.1.4.1) was studied in crude rat kidney homogenates. The enzyme activity was linear with time up to 45 min and with protein up to 200 microgram. The apparent Km and V of amidinotransferase were 9.21 mM and 1.53 mu mol/g protein per min, respectively. The enzyme was competitively inhibited by ornithine, with a Ki of 0.253 mM. Kidney arginase was inhibited only slightly and non-competitively. The inhibition of amidinotransferase by ornithine may thus be important in creatine biosynthesis. In gyrate atrophy of the choroid and retina with hyperornithinemia, a human autosomal recessive disease caused by decreased ornithine aminotransferase activity, plasma ornithine concentrations are elevated 10-20-fold (0.65-1.35 mM during fasting). In consequence endogenous creatine production probably is severely decreased because of inhibition of the rate-limiting transamidination step by ornithine. The deficiency of creatine and further of readily available energy in the form of phosphocreatine is suggested to be involved in the pathogenesis of the choroidal, retinal and type II muscle fiver atrophies in gyrate atrophy.

Use of percutaneous estrogen gel for induction of puberty in girls with Turner syndrome.

The aim of pubertal induction by estrogen in hypogonadic girls is to achieve physical and psychological development similar to that in natural puberty. We investigated the use of percutaneous estradiol gel for induction of puberty in girls with Turner syndrome (TS).Twenty-three girls with TS and hypogonadism were included in the study. The initial percutaneous dose of 0.1 mg ended as 1.5 mg in the fifth year. The efficacy of the treatment was monitored by measuring height, weight, skeletal age, pubertal status, and serum hormone levels and gynecological ultrasonographic examinations throughout the study. Mean serum estradiol concentrations increased from 22.2 pmol/liter at baseline to 162.2 pmol/liter, and mean FSH levels decreased from 77.4 IU/liter at baseline to 19.2 IU/liter after 5 yr. There were no significant differences between GH users and nonusers with regard to height sd score, weight sd score, bone age acceleration, or adult height. The development of secondary sexual characteristics and uterine growth progressed gradually during the study. All girls reached at least stage B4P4. With percutaneous estradiol gel, the development of secondary sexual characteristics and uterine growth proceeded gradually, mimicking natural puberty. Estradiol gel was safe, easy to use, and well accepted by the subjects and provides an excellent way to individualize pubertal induction.

Recombinant human growth hormone improves growth in children receiving glucocorticoid treatment after liver transplantation.

Linear growth is often impaired after successful liver transplantation. The cause is multifactorial; poor graft function and long term glucocorticoid treatment are the main factors responsible. The efficacy and safety of recombinant human GH (rhGH) treatment were assessed in eight growth-retarded children (five boys and three girls) with liver transplants. Immunosuppression comprised azathioprine, cyclosporin, and methylprednisolone. rhGH was administered in a dose of 1 IU/kg x week, given by daily sc injections. The median age at the start of treatment was 9.7 yr (range, 5.9-14.9 yr). All but one of the patients remained prepubertal during treatment. The median growth rate increased from 3.2 to 7.l cm/yr (P = 0.025) and height SD score increased from -3.9 to -3.1 (P = 0.036) during the first year of rhGH treatment. Serum insulin-like growth factor I and insulin-like growth factor-binding protein-3 levels increased significantly during treatment. Graft function was normal in all except one patient, and no rejections or other serious side-effects were documented. In conclusion, rhGH treatment is effective in short, non-GH-deficient, liver-transplanted children receiving long term glucocorticoid treatment. Due to potential risk of allograft rejection, close monitoring of liver function and immunosuppression is required.

Gyrate atrophy of the choroid and retina with hyperornithinemia: tubular aggregates and type 2 fiber atrophy in muscle.

We studied 21 patients with gyrate atrophy of the choroid and retina and hyperornithinemia. Although the patients were not weak, type 2 muscle fibers were almost universally atrophic and had tubular aggregates. Gyrate atrophy is the first disease in which females are shown to have tubular aggregates; the sexes were affected equally. In gyrate atrophy the number of type 2 fibers decreases with age. The muscle and eye changes are probably related to abnormal creatine synthesis, caused, in gyrate atrophy, by the increased body pool of ornithine; muscle abnormalities may also be present in other tapetoretinal dystrophies.

Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia.

OBJECTIVE: To analyze in vivo brain creatine (Cr) content in gyrate atrophy of the choroid and retina with hyperornithinemia (GA). BACKGROUND: GA is caused by inherited deficiency of ornithine-delta-aminotransferase activity. Patients lose their vision by middle age and develop selective atrophy of type II skeletal muscle fibers. As demonstrated by MRS, the patients' skeletal muscles have diminished stores of high-energy Cr phosphate. Minor structural and electrophysiologic abnormalities in the brain of these patients also imply that the CNS may be affected. METHODS: The authors acquired proton MR spectra of the basal ganglia of 22 healthy control subjects and 20 GA patients. Nine patients received supplementary Cr or its precursors, and one child was on an arginine-restricted diet to normalize plasma ornithine concentration. The ratios of N-acetylaspartate (NAA) to Cr, NAA to choline (Cho), and Cho to Cr, and the ratios of NAA, Cho, and Cr to tissue water were calculated. RESULTS: NAA/Cr (Cho/Cr) in the untreated and treated patients and control subjects were (mean +/- SD) 3.3+/-0.4, 2.0+/-0.4, and 1.5+/-0.7 (1.9+/-0.3, 1.3+/-0.4, and 0.9+/-0.2), indicating that Cr content in untreated GA patients was proportionally and markedly diminished, and partially corrected by therapy (p < 0.0001). NAA/Cho was similar in all three groups. Cr/water in the untreated patients was only 46%, and increased to 75% of the control ratios in the treated patients (p < 0.0001). CONCLUSIONS: Hyperornithinemia-associated Cr deficiency in GA also affects the CNS, further supporting the possibility that Cr deficiency also has a pathogenetic role in the retina. The deficiency was partially corrected by Cr supplementation and an arginine-restricted diet.

Differences in linear growth and cortisol production between liver and renal transplant recipients on similar immunosuppression.

Linear growth is more often impaired after liver than after renal transplantation (Tx) in childhood. As similar triple immunosuppression was used in our liver and renal transplant recipients, we were able to compare growth and endocrine function between 19 prepubertal liver and 35 renal transplant recipients. There were no significant differences in median age, weight-for-height index, or height standard deviation score at Tx. Seventy-eight percent of the liver Tx patients, but only 7% of the renal Tx patients, were below the normal range for height 3 years after Tx. Graft function was good in both liver and renal transplant recipients 3 years after Tx. There was no significant difference in growth hormone secretion, serum insulin-like growth factor (IGF)-I, and IGF-binding protein-3 levels, or in methylprednisolone and cyclosporine doses. However, the blood cyclosporine levels were significantly higher in the liver transplant recipients (P = 0.001 1 year and P = 0.005 2 years after Tx). Cortisol production was significantly lower in the liver transplant recipients (P = 0.002 1 year and P = 0.049 2 years after Tx), which suggests greater steroid-mediated suppression of adrenal function. Growth inhibition is more often observed in liver than in renal transplant recipients on similar triple immunosuppression, and may not be related to deficient function of the growth hormone-IGF-I axis. Similar cyclosporine doses result in higher plasma levels of the drug and similar methylprednisolone doses result in more inhibited adrenal cortisol production in liver transplant recipients. In children with organ transplants, cyclosporine and methylprednisolone should be administered on an individual basis.

Craniofacial and dental characteristics of Silver-Russell syndrome.

We found significant differences in a craniometric, cephalometric, and dental study of 19 Silver-Russell syndrome patients (13 without growth hormone treatment) with appropriate controls. Although head circumference was normal for age, head length was increased, while cranial and facial widths and facial heights were reduced. Posterior facial height, posterior cranial base length, cranial base height, and mandibular body size were significantly smaller than in healthy children of the same height. Articulatory speech disorders were common. Enamel defects pointed to an early prenatal insult. Delayed dental age and small mandibular and cranial base dimensions support the possibility of physiological growth hormone deficiency in many Silver-Russell syndrome children; however, facial soft tissue structures were strikingly different from those observed in classical growth hormone deficiency.

Growth failure and growth hormone deficiency in children after bone marrow transplantation for leukemia.

Eleven patients between the ages of 6 and 18 years who had been treated for acute leukemia were investigated for growth and growth hormone (GH) secretion. All had undergone bone marrow transplantation (BMT) between 0.7 and 5.1 (median 2.0) years previously. Preparation of patients for BMT had included high-dose cyclophosphamide and total body irradiation. In the eight patients at risk of growth failure, the relative height decreased 0.5-2.5 SD units (median 1.0) during the follow-up period. Eight patients secreted subnormal amounts of GH as studied by measuring spontaneous pulsatile GH secretion overnight. The maximal nocturnal GH peak varied between 3.3 and 28.3 micrograms/l (median 9.3). The mean nocturnal GH concentration varied from 1.2 to 8.3 micrograms/l (median 2.3) and depended on the length of the follow-up period. We conclude that deficient GH secretion is one reason for poor growth after BMT. A good growth response to GH substitution would support the role of GH deficiency in the observed growth retardation after BMT.

Psychosocial development and premorbid skeletal growth in Legg-Calvé-Perthes disease: a study of nineteen patients.

We studied psychosocial development and skeletal growth in 19 newly diagnosed patients with Legg-Calvé-Perthes disease (LCPD). Eleven patients had problems in visuospatial skills and five of 12 school-aged children had learning difficulties. The growth velocity of the patients was evaluated from 4 years before until 2 years after the diagnosis was made. Eight patients had a catch-up growth with +1.2 (0.9-1.7) delta SDS score (SDS: mean and ranges) before the diagnosis. Four patients with short stature and retarded bone age slightly diminished their growth velocity. Overnight serum growth hormone (GH) concentration and insulin-like growth factor I (IGF-I) levels were examined in the first nine consecutive patients. One patient had a high and another had a low mean GH concentration level, whereas all patients had IGF-I levels within normal limits. These results suggest that different kinds of growth disturbances may be associated with LCPD.