An approach to model monitoring and surveillance data of wildlife diseases-exemplified by Classical Swine Fever in wild boar.

The analysis of epidemiological field data from monitoring and surveillance systems (MOSSs) in wild animals is of great importance in order to evaluate the performance of such systems. By parameter estimation from MOSS data, conclusions about disease dynamics in the observed population can be drawn. To strengthen the analysis, the implementation of a maximum likelihood estimation is the main aim of our work. The new approach presented here is based on an underlying simple SIR (susceptible-infected-recovered) model for a disease scenario in a wildlife population. The three corresponding classes are assumed to govern the intensities (number of animals in the classes) of non-homogeneous Poisson processes. A sampling rate was defined which describes the process of data collection (for MOSSs). Further, the performance of the diagnostics was implemented in the model by a diagnostic matrix containing misclassification rates. Both descriptions of these MOSS parts were included in the Poisson process approach. For simulation studies, the combined model demonstrates its ability to validly estimate epidemiological parameters, such as the basic reproduction rate R0. These parameters will help the evaluation of existing disease control systems. They will also enable comparison with other simulation models. The model has been tested with data from a Classical Swine Fever (CSF) outbreak in wild boars (Sus scrofa scrofa L.) from a region of Germany (1999-2002). The results show that the hunting strategy as a sole control tool is insufficient to decrease the threshold for susceptible animals to eradicate the disease, since the estimated R0 confirms an ongoing epidemic of CSF.

Impact of overweight on effectiveness of treatment with human growth hormone in growth hormone deficient children: analysis of German KIGS data.

BACKGROUND: We hypothesized that overweight children with growth hormone deficiency (GHD) demonstrate a lower response to growth hormone (GH) as a result of a misclassification since obesity is associated with lower GH peaks in stimulation tests. METHODS: Anthropometric data, response, and responsiveness to GH in the first year of treatment were compared in 1.712 prepubertal children with GHD from the German KIGS database according to BMI (underweight=group A, normal weight=group B, overweight=group C) (median age: group A, B, C: 7.3, 7.28, and 8.4 years). RESULTS: Maximum GH levels to tests (median: group A, B, C: 5.8, 5.8, and 4.0 µg/ml) were significantly lower in group C. IGF-I SDS levels were not different between the groups. Growth velocity in the first year of GH treatment was significantly lower in the underweight cohort (median: group A, B, C: 8.2, 8.8, and 9.0 cm/yr), while the gain in height was not different between groups. The difference between observed and predicted growth velocity expressed as Studentized residuals was not significantly different between groups. Separating the 164 overweight children into obese children (BMI>97th centile; n=71) and moderate overweight children (BMI>90th to 97th centile, n=93) demonstrated no significant difference in any parameter. CONCLUSIONS: Overweight prepubertal children with idiopathic GHD demonstrated similar levels of responsiveness to GH treatment compared to normal weight children. Furthermore, the IGF-I levels were low in overweight children. Therefore, a misclassification of GHD in overweight prepubertal children within the KIGS database seems unlikely. The first year growth prediction models can be applied to overweight and obese GHD children.

Is the response to growth hormone in short children born small for gestational age dependent on genetic or maternal factors?

BACKGROUND/AIMS: We investigated whether genetic or maternal/environmental risk factors for being born small for gestational age (SGA), e.g. Silver-Russell syndrome, congenital heart defects, infections of mothers or smoking during pregnancy, explain the variation in the first-year growth response to GH therapy. METHODS: Secondary analysis was made of growth response in 135 short prepubertal German children (66% males) enrolled in a SGA phase III trial. Initial mean patient age was 6.8 +/- 2.6 years; mean patient height SDS -3.8 +/- 1.2, and GH treatment dose was 0.066 mg/kg body weight per day. RESULTS: Growth velocity increased by 4.5 +/- 2.0 cm/year and height SDS by 1.0 +/- 0.5 SDS. Although patient number was limited and variation was high, both growth response (cm/year) and change in height SDS did not appear to differ between subgroups which also did not differ in terms of Studentized residuals set up in the KIGS growth prediction model for SGA. Likewise, in a step-forward multivariate analysis, the variables Silver-Russell syndrome, congenital heart defects, infections of mothers and smoking were not identified as independent factors influencing growth velocity. CONCLUSION: The retrospectively analyzed genetic and maternal/environmental risk factors for SGA do not appear to explain the observed patient variance in response to GH. Larger prospective studies are needed, however, to substantiate these preliminary findings.

Adult height after GH therapy in 188 Ullrich-Turner syndrome patients: results of the German IGLU Follow-up Study 2001.

OBJECTIVES: We aimed to evaluate the factors influencing true adult height (HT) after long-term (from 1987 to 2000) GH treatment in Ullrich-Turner syndrome (UTS) based on modalities conceived in the 1980s. DESIGN: Out of 347 near-adult (>16 Years) patients from 96 German centres, whose longitudinal growth was documented within KIGS (Pharmacia International Growth Database), 188 (45, X=59%; bone age >15 Years) were available for further anthropometric measurements. RESULTS: At a median GH dose of 0.88 (10th/90th percentiles: 0.47/1.06) IU/kg per week, a gain of 6.0 (-1.3/+13) cm above the projected adult height was recorded. Variables were recorded at GH start, after 1 Year GH, puberty onset, and last visit on GH therapy. At these visits, the median ages were 11.7, 12.7, 14.2, 16.6 and 18.7 Years; and median heights, 0.4, 1.1, 1.7, 1.7 and 1.3 SDS (UTS) respectively. Height gain (DeltaHT) after GH discontinuation was 1.5 cm. Total DeltaHT correlated (P<0.001) negatively with bone age and HT SDS at GH start, but positively with DeltaHT after the first Year, DeltaHT at puberty onset, and GH duration. Final HT correlated (P<0.001) positively with HT at GH start, first-Year DeltaHT, and HT at puberty onset. Body mass index increased slightly (P<0.05), with values at start and adult follow-up correlating highly (R=0.70, P<0.001). No major side effects of GH occurred. CONCLUSIONS: GH dosages conceived in the 1980s are safe but too low for most UTS patients. HT gain and height are determined by age and HT at GH start. Height gain during the first Year on GH is indicative of overall height gain. After spontaneous or induced puberty, little gain in height occurs.

Favorable final height outcome in girls with Ullrich-Turner syndrome treated with low-dose growth hormone together with oxandrolone despite starting treatment after 10 years of age.

The objective of this study was to find out whether moderate doses of growth hormone (GH) in combination with oxandrolone (Ox) and late initiation of puberty could improve adult height even in relatively old patients with Ullrich-Turner syndrome (UTS). Ninety-one patients with UTS were randomly assigned to receive either GH alone (Saizen, Ares-Serono, Geneva) 18 IU/m2/week (0.2 mg/kg/week) by daily s.c. injections (group GH) or a combination of GH and Ox 0.1 mg/kg/day p.o. (group GH + Ox). Prior to treatment mean age was 10.2 years (GH) and 10.5 years (GH + Ox), mean projected adult height (PAH) was 146.4 cm (GH) and 146.7 cm (GH + Ox). During year 2 the GH dose was increased in the GH group to 24 and later to 28 IU/m2/week (0.27 mg and later 0.31 mg/kg/week). In group GH + Ox, the Ox dose was reduced to 0.05 mg/kg/day after the first 12 months of therapy, and during the last treatment years the GH dose was raised to 24-28 IU/m2/week (0.27-0.31 mg/kg/week) due to declining growth promotion. Some of the patients of group GH were later given Ox in addition to GH because of waning growth velocity, whereas some of the patients of group GH + Ox were taken off Ox due to virilizing side-effects of the high Ox dose, thus making up a third group of patients: group GH + transient Ox. Puberty was induced at a mean age of 14.9 years. In group GH + Ox, cumulative growth during 5 years of therapy was twice the growth anticipated from standards of untreated patients with UTS. Forty-seven patients are now near or at final height: in group GH (n = 7), mean final height was 151.7 cm (PAH 148.1 cm, gain 3.6 cm); in group GH + Ox (n = 15), 155.1 cm (PAH 147.2 cm, gain 7.9 cm); and in group GH + transient Ox (n = 25), 152.8 cm (PAH 146.4 cm, gain 6.4 cm). These results should be regarded as an underestimate of true final height since some the patients are still growing. Moderate doses of GH plus Ox and late induction of puberty definitely improved final height even in patients with UTS treated relatively late.

Transsphenoidal surgery for pituitary gigantism and galactorrhea in a 3.5 year old child.

The management of pituitary macroadenomas which lead to gigantism may require multiple therapeutical approaches, including medical treatment, surgery, and radiation therapy. Transsphenoidal surgery (TSS) during early childhood that achieves total removal of a growth hormone (GH) secreting tumor is rarely reported. The surgeon is confronted with special problems regarding the infantile anatomy. In this case, a 3.5 year old child, the youngest successfully treated by TSS so far, suffered from a GH- and prolactin (PRL) secreting macroadenoma of the pituitary gland. The girl initially presented with an increasing growth rate, later with breast development, and finally, at the age of 2.8 years, with galactorrhea and secretion of blood from the nipples. Increased levels of GH [122 micrograms/l], insulin-like growth factor (IGF-1) [830 micrograms/l], insulin-like growth factor binding protein 3 (IGFBP-3) [8.6 mg/l] and PRL [590 micrograms/l] were found. MRI scans revealed a macroadenoma of 2.7 cm diameter. An eight-week trial of relatively low dose dopamine agonists led to a reduction of PRL, while the GH- and IGF-1 levels remained unchanged; the tumor showed only little shrinkage. Since there was chiasma compression, we opted for early TSS. A complete tumor removal was achieved despite the difficulties of a narrow approach. After TSS, low levels of GH, IGF-1, and PRL documented a complete tumor removal, but persistent diabetes insipidus and anterior lobe deficits resulted from surgery. In summary, if primary medical therapy alone is unable to adequately reduce hormone hypersecretion and tumor size in early childhood, TSS is recommended. Thus, radiation therapy may be reserved for surgical failure.

Leukemia in growth-hormone-treated patients: an update, 1992.

Since 1988 the number of growth hormone (GH)-treated patients has markedly increased worldwide. To date, leukemia has been observed in 31 patients during or following GH therapy and related malignancies in 2 further patients. Leukemia occurred in 10 patients in Japan, 10 in the USA, and 10 in Europe, and in 1 patient in Canada. In 29 patients GH therapy had been started in 1975 or later. The onset of leukemia was 1984 or later in 28 patients with a mean time between the start of GH therapy and leukemia onset of 5.0 (0.2-18.8) years. Patients had received both pituitary and recombinant GH in moderate doses. In 15 patients definite additional leukemia risk was evident: Fanconi anemia in 2, myelodysplastic syndrome in 1, Bloom's syndrome in 1, radiation for brain tumor (+chemotherapy) in 9, chemotherapy in 2. The leukemic patients without a strong additional risk do not represent a definitely higher leukemia incidence worldwide, except for Japan where the occurrence is higher than expected.

Growth response to recombinant human growth hormone of mammalian cell origin in prepubertal growth hormone-deficient children during the first two years of treatment.

In five clinical studies performed in Austria, France, the FRG, Italy, Switzerland, the UK and the USA, 304 growth hormone (GH)-deficient children were treated with recombinant human GH (rhGH) of mammalian cell origin. Two hundred and twenty-five patients were previously untreated (naive patients), and 79 were transferred from pituitary hGH after interruption of therapy for at least 6 months (transfer patients). Two treatment protocols, differing in both dose and frequency of injections, were used: (1) a dose of 0.6 IU/kg body weight per week was administered in 3 s.c. injections to 203 patients (178 naive, 25 transfer; group 1); and (2) a dose of 0.45 IU/kg body weight per week was administered in 7 s.c. injections to 101 patients (47 naive, 54 transfer; group 2). After 1 and 2 years of treatment, 143 and 109 naive, and 51 and 46 transfer patients, respectively, were still prepubertal, and their data were analyzed for efficacy. During the 1st year of treatment, both naive and transfer patients on daily injections (group 2) demonstrated better growth than those on 3 injections per week (group 1), with height velocities (HVs) of 10.6 +/- 2.7 cm/year (group 2) versus 8.6 +/- 2.0 cm/year (group 1) for naive patients (p < 0.001), and 9.9 +/- 1.9 cm/year (group 2) versus 7.2 +/- 2.7 cm/year (group 1) for transfer patients (p < 0.001). The corresponding changes in height standard deviation score (delta H SDS) for chronological age (CA) were +1.3 +/- 0.6 (group 2) versus +0.8 +/- 0.5 (group 1) for naive patients (p < 0.01), and +1.1 +/- 0.3 (group 2) versus +0.6 +/- 0.4 (group 1) for transfer patients (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human growth hormone and oxandrolone in treatment of short stature in girls with Turner syndrome.

91 girls with Turner syndrome (TS) with a mean chronological age (CA) and bone age (BA) of 10.3 +/- 2.3 and 8.9 +/- 1.9 years, respectively, were randomly assigned to subcutaneous treatment with recombinant human growth hormone (rhGH) alone (n = 47), 2.6 IU/m2 body surface area daily or combination treatment (n = 44) with the same dose of rhGH and oxandrolone 0.1 mg/kg body weight orally, for the first 12 months of this study. During the 1st year of therapy, there was a striking increase in height velocity (HV) in both groups, from 4.0 +/- 0.8 to 6.3 +/- 1.3 cm/year [HV standard (standards of untreated Turner patients) deviation score (SDS) for CA from 0.0 +/- 0.7 to 2.9 +/- 1.3] in the rhGH group and from 4.2 +/- 1.2 to 8.5 +2- 1.7 cm/year (HV SDS-CA from +0.3 +/- 1.0 to 5.6 +/- 1.6) in the combination group. The difference between the groups was statistically significant (p < 0.01). During the 2nd year of treatment, the rhGH dose was increased to 3.4 IU/m2 daily for the rhGH-alone group, whereas in the combination treatment group the oxandrolone dose was reduced to 0.05 mg/kg daily. HV was maintained at significantly higher levels than those prior to treatment, at 5.3 +/- 1.1 cm/year (HV SDS-CA: +2.1 +/- 1.3) and 6.2 +/- 1.5 cm/year (HV SDS-CA: +3.6 +/- 1.4) in the rhGH-alone and the combination group, respectively (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Replacement therapy in hypothalamus-pituitary insufficiency: management in the adolescent.

GH, formerly administered 2-3 times a week intramuscularly, is nowadays injected daily subcutaneously at a dosage of 14 IU/m2/day. In some patients, a 1.5- to 2.0-fold higher GH dosage is necessary for normal pubertal growth spurt. Though delayed initiation of puberty in additional gonadotropin deficiency may be favourable for final height, puberty should be induced in boys at bone age 12-13 years with low doses of testosterone enanthate, and in girls at bone age 12 years with low doses of ethinyl estradiol. Patients with additional ACTH deficiency should receive only a low-dose glucocorticoid replacement (but a steroid cover for physical stress situations). During GH therapy, thyroid function has to be evaluated regularly; often thyroxine replacement will be necessary.

Precocious pseudopuberty associated with multiple ovarian follicular cysts and low plasma oestradiol concentrations.

A 6 year 11 month old girl had pseudoprecocious puberty caused by multiple ovarian follicular cysts. In contrast to previously reported patients, oestrogen levels in blood and urine were not elevated though gonadotropins were suppressed. Despite the lack of measurable oestrogen elevation the child developed distinct oestrogenic effects. After removal of large bilateral ovarian cysts endocrine aberrations normalized and precocity regressed.

Growth hormone therapy and leukaemia.

Following an initial report from Japan in 1987, 15 growth hormone (GH)-deficient patients developed leukaemia during or following GH treatment. Nearly all available pituitary and biosynthetic growth hormones have been used. In 14 of these 15 patients GH treatment was initiated in 1975 or later with doses between 4.5 and 18IU/m2 per week. The therapy period was between 0.17 and 8.0 years. Leukaemia occurred 0.2-11 years after the start of GH treatment. GH affects normally and abnormally growing blood cells in vitro and in animal experiments, but the clinical data in humans do not indicate GH induction of tumour growth. Seven out of the 14 patients under discussion had an additional increased leukaemia risk. Two other patients had been treated only for a very short time. Though no clear evidence of a strikingly augmented leukaemia incidence in GH-treated patients is found worldwide, the available data call for increased attention.

Thyroid function in prematures with respiratory distress syndrome (RDS).

Reports on thyroid function in newborns with respiratory distress syndrome (RDS) are controversial, the significance of obtained results is not clear. Therefore we conducted a longitudinal study of thyroid function in 35 infants with RDS (gestational age 24-36 weeks, birth weights 650-2770 g). 43 well prematures, matched for gestational age, served as controls. No significant differences were observed in cord blood TSH, T3, T4, TBG values and T4:TBG ratios between infants with and without RDS. Prematures with RDS showed lower levels of T3, T4, TBG and T4:TBG at 24 hours of age and increases of TSH values at 72 hours. Subsequently these prematures exhibited a spontaneous rise in thyroid hormone levels. Even non-surviving RDS-infants had initial T3, T4, T4:TBG and TSH values within the normal range. Thyroid hormone concentrations correlated significantly with the severity of pulmonary disease. Depressed thyroid hormone levels were found to be the result and not the cause of RDS. T4 or T3 therapy is not warranted in this condition.

Circadian fluctuation of plasma melatonin in Prader-Willi's syndrome and obesity.

In 3 groups of 8 children and adolescents each with Prader-Willi-Labhart's Syndrome (PW-S), obese patients matched for body weight (control I), and normal weight subjects matched for pubertal stage (control II) plasma concentrations of melatonin, cortisol, growth hormone (hGH), insulin, gonadal hormones, and gonadotropins were measured every 1 to 4 hours in 24-hour-profiles. All hormones were determined by radioimmunoassay. The specific melatonin antibody was raised in rabbits. Criteria of the melatonin assay were as follows: detection limit for plasma concentrations of 13 pg/ml, intraassay and interassay variations: 8.4 and 11.2%, respectively. PW-S-patients showed cortisol fluctuations within normal limits. hGH was lower than 5 micrograms/l even during sleep, insulin ranged between 5 and 170 mU/l, and no excessively high glucose levels were found. Estradiol and testosterone were low for age and for pubertal development in all patients except in two girls. Basal LH and FSH levels were in the low normal range and showed sluggish response to LHRH. Plasma melatonin was low during the day, increased at mid-night and peaked at 3 a.m. Melatonin levels in PW-S were not significantly different from those in both control groups. We concluded that the impairment of gonadotropin secretion in patients with PW-S is not due to elevated levels of plasma melatonin.

Cushing's disease due to an unusually large adenoma of the pituitary gland in infancy.

We report an 18-month-old girl with Cushing's disease caused by a large adenoma of the pituitary gland. Tumour size and extension were determined by X-ray, CT-scan and angiographic studies. The endocrinological findings were typical for this disease: elevated plasma levels of ACTH, cortisol, 17-Hydroxyprogesterone (17-OHP) and testosterone, elevated urinary excretion of 17-Ketosteroids (17-KS) and 17-Hydroxycorticoids (17-OHCS). Dexamethasone failed to suppress ACTH and cortisol plasma levels. TRH induced only a minimal TSH increase. Following LH-RH injection gonadotropin levels rose to pubertal values. The hGH response to insulin-induced hypoglycaemia was subnormal. After resection of the tumour the infant died because of non-treatable arrhythmia. Histological findings showed a non-differentiated adenoma with extension into the subarachnoid space and into nerve tissues. In vitro lysine-vasopressin (LVP) and arginine-vasopressin (AVP) exhibited only weak stimulatory effects on the ACTH secretion of the tumour cells.

Long-term follow-up of children with craniopharyngioma.

Management of craniopharyngiomas is still controversial. 28 children with this tumor were studied. GH deficiency was present in 22 patients following surgery, 10 of these GH-lacking patients had normal or accelerated growth (usually associated with rapid weight gain) postoperatively. Somatomedin levels were normal in three of six normally growing patients. After craniotomy their basal and TRH-stimulated prolactin levels were in the normal range, but their insulin secretion was markedly increased. Postoperatively there was a significant correlation between peak insulin levels following arginine infusion and growth velocity in all patients. Complete tumor removal could be performed in 28% of our patients. Altogether 36% of all patients had at least one tumor recurrence. Recent literature with the addition of our series showed tumor recurrence in 22% of patients with "total" tumor excision and in 72% of patients with partial tumor removal. Radiotherapy seems to be capable of destroying craniopharyngioma tissue. The recurrence rate was only 26% in patients with subtotal excision plus radiotherapy. Unless radical tumor removal can be attempted with safety, subtotal tumor removal plus radiotherapy appears to be the treatment of choice for craniopharyngioma.