PubMed Health⌕ Search

Biomedical subjects

Martin O Savage

Publications and source records attributed to Martin O Savage.

At least 19 recordsLinked to original sources
PubMed2006

Final height in patients with idiopathic short stature and high growth hormone responses to stimulation tests.

UNLABELLED: Children with idiopathic short stature (ISS) may have normal or increased growth hormone (GH) responses to provocation tests and achieve a final height (FH) below -2.0 standard deviation score (SDS) if untreated. FH of subjects with high stimulated GH levels has not been studied in detail. AIM: It was the aim of this study to analyse FH in ISS patients with high GH peak responses to the provocation test. PATIENTS AND METHODS: We studied 16 patients (9 pre-pubertal) with ISS and a GH peak >or=40 mU/l to insulin-induced hypoglycaemia. The patients were recalled at age 19.7 +/- 2.5 years for measurement of FH when blood samples were obtained for serum insulin-like growth factor (IGF)-I, IGF binding protein 3, acid-labile subunit and GH binding protein measurements. GH bioactivity was determined using the Nb2 bioassay. RESULTS: FH was -3.1 +/- 1.0 SDS, being significantly lower than target height (TH). At FH, IGF-I levels were within -1.5 and +1.5 SDS for age and sex in 10 patients and higher than +1.5 SDS in 6 patients. IGF binding protein 3, acid-labile subunit, GH binding protein levels and GH bioactivity values were normal. SUMMARY: These data suggest that patients with ISS and high GH levels during a GH stimulation test may have a more compromised FH. The association of severe ISS with a peak GH >40 mU/l might suggest a degree of insensitivity for the GH-IGF-I axis.

Adolescent↗
PubMed2006

Deterioration of visual acuity associated with growth hormone therapy in a child with extreme short stature and high hypermetropia.

BACKGROUND: Growth hormone (GH) has long been implicated in the pathogenesis of diabetic retinopathy, although its precise role remains ill-defined. In 1998, an association between exogenous human GH and retinal pathology in non-diabetic subjects was described. CASE REPORT: A female child with extreme short stature of unknown aetiology (height -7.38 SD at 11.3 years) and severe hypermetropia developed retinopathy with visual deterioration during two separate empiric trials of GH therapy. On the first occasion, a relatively high dose of GH (10.5 mg/m2/week) administered from age 4.4 to age 4.7 years was associated with the development of central serous retinopathy, resulting in marked reduction in visual acuity. On cessation of GH, the macular oedema resolved, and visual acuity improved. At age 5.6 years, GH therapy was re-introduced at a lower dose (3.9 mg/m2/week) and her vision monitored closely. Bilateral retinal oedema recurred after 3 months, and GH therapy was stopped. Once again, the macular oedema regressed, and visual acuity improved following withdrawal of GH. These ophthalmic changes contra-indicated further GH therapy. CONCLUSION: We suggest that GH may be a risk factor in the development of retinopathy in certain non-diabetic patients, especially in the presence of a severe refractive error.

Child↗
PubMed2006

Pharmacokinetic studies of recombinant human insulin-like growth factor I (rhIGF-I)/rhIGF-binding protein-3 complex administered to patients with growth hormone insensitivity syndrome.

CONTEXT: GH insensitivity syndrome (GHIS), Laron syndrome, is characterized by severe short stature, high serum GH levels, and very low serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels associated with a genetic defect of the GH receptor. Recombinant human (rh) IGF-I treatment at doses of 80-120 microg/kg given sc twice daily is effective in promoting growth in these patients. We have investigated a newly developed drug, rhIGF-I/rhIGFBP-3, a 1:1 molar complex of rhIGF-I and rhIGFBP-3. OBJECTIVES: The objectives of the study were to determine IGF-I pharmacokinetics after the administration of rhIGF-I/rhIGFBP-3 in adolescents with GHIS and to evaluate its safety and tolerability. DESIGN: This was an open-label clinical study. SETTING: The study was conducted in a general pediatric ward of a university teaching hospital. PARTICIPANTS: Four patients (one female and three males; mean age, 14.9 yr; mean height sd score, -4.9) with confirmed molecular diagnosis of GHIS agreed to participate in the study. INTERVENTION: rhIGF-I/rhIGFBP-3 was administered in a single sc injection at 0.5 and 1.0 mg/kg.dose (equivalent to 100 and 200 microg/kg rhIGF-I) after breakfast with a 2-d interval between doses. RESULTS: IGF-I levels reached a maximum between 19 +/- 8.3 and 15 +/- 6.2 h for the low and high doses, respectively. The circulating IGF-I levels obtained with the low and high doses were similar, although a discrete dose-dependent increase in circulating IGF-I levels was observed. The IGF-I half-life in four subjects after a dose of 0.5 mg/kg rhIGF-I/rhIGFBP-3 was estimated to be 21+/- 4 h. There were no acute adverse events reported, and all blood glucose measurements were normal. CONCLUSION: These data demonstrated that the rhIGF-I/rhIGFBP-3 complex was effective in increasing levels of circulating total and free IGF-I into the normal range for a 24-h period after a single sc administration in patients with GHIS, and that administration of rhIGF-I/rhIGFBP-3 was safe and well tolerated.

Adolescent↗
PubMed2006

Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders.

Advances in the diagnosis and treatment of growth hormone insensitivity disorders have occurred in the past 15 years. We discuss the current status of endocrine and molecular evaluation, focusing on the pediatric age range. All the identified mutations of the growth hormone receptor are included. Treatment with recombinant human insulin-like growth factor (rhIGF) 1 in classical cases is summarized and new targets for treatment are discussed, together with therapy using the complex formed between rhIGF1 and rhIGF-binding protein 3.

Endocrine System↗
PubMed2006

Hypopituitarism in childhood and adolescence following traumatic brain injury: the case for prospective endocrine investigation.

Pituitary dysfunction is now well recognised after traumatic brain injury (TBI) in adults; however, little except anecdotal evidence is known about this potential complication in childhood and adolescence. Histopathological evidence exists for both hypothalamic and pituitary damage, but few data specific to children have been published. We review the available paediatric data, which shows that after both mild and severe TBI, hypopituitarism may occur, with GH and gonadotrophin deficiencies appearing to be most common. Precocious puberty has also been documented. Road-traffic accidents, falls, sport and child abuse are the most common aetiological factors for paediatric TBI. There are no published data on the incidence or prevalence, neither within a population of children with TBI, of hypopituitarism, nor on its natural history or response to hormone replacement. We urge paediatric endocrinologists, in collaboration with adult endocrinologists, to perform formal prospective research studies in patients suffering from TBI to clarify these questions.

Adolescent↗
PubMed2006

Clinical features affecting final adult height in patients with pediatric-onset Crohn's disease.

BACKGROUND: Growth failure is a recognized complication of pediatric-onset Crohn's disease, but there are few data on final adult height. OBJECTIVE: Our purpose with this work was to determine adult height and the clinical features that influence long-term growth impairment. METHODS: We retrospectively studied 123 patients with Crohn's disease (65 male and 58 female) who had reached adult height. All of the case subjects were diagnosed before age 16.0 years. Heights were converted to SD scores and univariate analysis performed of factors postulated to influence final height, that is, interval from onset of symptoms to diagnosis, prepubertal onset of symptoms, gender, jejunal disease present at diagnosis, systemic steroid therapy, intestinal surgery, and midparental height SD scores. Significant univariate factors were additional analyzed in regression models. RESULTS: Mean height deficit at diagnosis was -0.50 SD scores, which improved to -0.29 SD scores at final height. Mean final height compared with target height, calculated from parental height, was -2.4 cm (range: -20.0 to 9.0 cm). Nineteen percent of the case subjects achieved a final height >8.0 cm below target height. The length of the interval between symptom onset and diagnosis correlated negatively with height SD scores at diagnosis. Height SD scores at diagnosis were related to final height SD scores, independent of midparental height. The presence of jejunal disease was negatively related to final height. CONCLUSIONS: Mean final adult height showed a modest deficit compared with target height, but in one fifth of patients, final height was significantly less than target height. Earlier diagnosis and improved treatment of jejunal disease would be likely to improve final height.

Adolescent↗
PubMed2005

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the -174 IL-6 G/C polymorphism in children.

Inflammatory diseases frequently impair linear growth. Crohn's disease inhibits growth in up to one third of affected children. In rats with trinitrobenzenesulphonic acid-induced colitis, 40% of growth impairment is attributable to inflammation, with the rest being due to undernutrition. In transgenic mice without inflammation, raised IL-6 retards growth, suppressing insulin-like growth factor (IGF)-I. We hypothesized that IL-6, induced by intestinal inflammation, suppresses growth and inhibits IGF-I expression. Therefore, an anti-IL-6 Ab was given to rats with trinitrobenzene-sulphonic acid colitis. The Ab did not improve nutrient intake or decrease inflammation compared with untreated disease controls, but it significantly restored linear growth (P = 0.023) and increased IGF-I (P = 0.05). In humans, the IL-6 -174 G/C promoter polymorphism affects IL-6 transcription, with the GG genotype inducing the greatest IL-6 levels. Because IL-6 is increased in Crohn's disease, we further hypothesized that growth failure would vary with the IL-6 -174 genotype. At diagnosis, among 153 children with Crohn's disease, those with the IL-6 GG genotype were more growth-retarded than those with the GC or CC genotypes (height SD score, -0.51 vs. -0.10; P = 0.031). Also, the patients with the IL-6 GG genotype had higher circulating levels of C-reactive protein, an IL-6-induced product (36 vs. 18 mg/dl, P = 0.028). However, their risk of developing Crohn's disease was similar to other genotypes when compared with 351 healthy controls (P = 0.7). Thus, the IL-6 -174 genotype mediates growth failure in children with Crohn's disease.

Animals↗
PubMed2005

Diagnostic and therapeutic advances in growth hormone insensitivity.

Diagnostic and therapeutic advances in growth hormone insensitivity (GHI) have occurred principally in two areas: the molecular characterization of patients with GHI and treatment with recombinant human insulin like growth factor-I (IGF-I). This article discusses the current status of molecular diagnosis across the spectrum of the disorder. Treatment with recombinant human IGF-I in classical cases is summarized, and potential new targets for treatment are discussed together with the potential for therapy using the newly developed compound recombinant human IGF-I/IGF binding protein-3.

Drug Therapy, Combination↗
PubMed2005

Cushing's disease in children and adolescents: 20 years of experience in a single neurosurgical center.

OBJECTIVE: This is a retrospective analysis of 25 consecutive pediatric patients with Cushing's disease who underwent transsphenoidal surgery performed by a single neurosurgeon in a specialist center during a 20-year period. This article discusses the presentation of Cushing's disease, the endocrinological investigation with particular reference to bilateral inferior petrosal sinus sampling (BIPSS), the operative management with reference to specific pediatric difficulties of the transsphenoidal approach and the use of intraoperative image guidance, and the analysis of these cases as regards postoperative complications and outcomes of this rare condition in young patients. METHODS: All patients underwent detailed endocrine investigation and imaging in the form of computed tomography and/or magnetic resonance imaging. BIPSS was performed in 19 patients (76%), with successful lateralization of the side of the microadenoma in 14 (74%) and prediction of a central tumor in four (94% total prediction rate). Surgical removal was via the sublabial, paraseptal, transsphenoidal route. RESULTS: There were 15 male and 10 female patients, with a mean age of 13.4 years (range, 6.6-17.8 yr). Weight gain was the most common presentation (100%), and then growth impairment (96%), fatigue and skin changes (64%), and hypertension (32%). Postoperative complications included growth hormone deficiency (36%), transient diabetes insipidus (12%), panhypopituitarism (4%), and transient cerebrospinal fluid rhinorrhea (4%). The median follow-up period was 59.5 months (range, 6-126 mo). Overall, 15 patients (60%) achieved surgical cure or remission, of which 14 outcomes were obtained using the results of BIPSS. Ten patients (40%) required postoperative radiotherapy to achieve "remission." There were no cases of meningitis, no neurological deficits, no reoperations, and no mortality. CONCLUSION: Cushing's disease in children and adolescents is a rare illness. The accurate preoperative localization of the adenoma is essential for achieving good results. In this series, BIPSS was far more accurate in localizing the adenoma than computed tomography or magnetic resonance imaging. Imaging, however, is useful for the exclusion of other intracranial problems. Transsphenoidal surgery was safe and efficacious in achieving cure in the majority of cases. The challenge of transsphenoidal surgery in this age group is the small pituitary fossa and the absence of sphenoid sinus aeration in some cases. We found the use of intraoperative neuronavigation to be an excellent aid in overcoming such anatomic difficulties.

Adolescent↗
PubMed2005

Novel growth hormone receptor mutation in a Chinese patient with Laron syndrome.

Laron syndrome, growth hormone (GH) insensitivity syndrome, caused by a mutation of the GH receptor (GHR) gene, is extremely rare in the Chinese population. We report a Chinese girl diagnosed with Laron syndrome at age 1.9 years with height -4.9 SDS, basal GH 344 mIU/ml, IGF-I <12 ng/ml, IGFBP-3 <0.2 mg/ml, and undetectable GHBP. A novel mutation of the GHR, not previously described, was identified at the donor splice site of intron 6.

Amino Acid Substitution↗
PubMed2005

Factors influencing cure by transsphenoidal selective adenomectomy in paediatric Cushing's disease.

OBJECTIVE: Early diagnosis and effective treatment of paediatric Cushing's disease (CD) is necessary to minimise associated morbidity. Accepted first-line treatment is selective transsphenoidal microadenomectomy (TSS), which can be technically difficult, and cure rates vary considerably between centres. In our paediatric CD patient group we have assessed the possible factors which may influence cure by TSS. SUBJECTS AND METHODS: From 1983-2004, 27 paediatric patients (16 males, 11 females; mean age+/-s.d., 13.1+/-3.2 yr; range, 6.4-17.8 yr) with CD were managed in our centre and underwent TSS. Sixteen patients (59%), seven males and nine females (mean age+/-s.d., 14.2+/-2.5 yr; range, 8.2-17.8 yr), were cured (post-operative serum cortisol < 50 nM). Eleven patients, nine males and two females (mean age+/-s.d., 11.5+/-3.6 yr; range, 6.4-17.8 yr) had post-operative cortisol levels above 50 nM (2-20 days), with mean serum cortisol levels at 09:00 h of 537 nM (range 269-900 nM) indicating a lack of cure. These 11 patients received external beam pituitary radiotherapy (RT). One patient with a pituitary macroadenoma had a post-operative cortisol level of < 50 nM but 0.8 yr later showed an elevated cortisol and residual disease. RESULTS: The patients cured by TSS alone were significantly older than those not cured (P = 0.038; Student's t test). All patients had CT/MRI pituitary imaging: 14 were reported to have microadenomas and one macroadenoma, while 12 were reported as normal. Bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with i.v. corticotropin-releasing hormone (CRH) administration was introduced as a pre-operative investigation in 1986 and was performed in 21 patients (78%), on BSIPSS, 16 (76%) had evidence suggesting pituitary adrenocorticotropic hormone (ACTH) secretion (central to peripheral (IPS:P) ACTH ratio after CRH of > or = 3.0) and 16 (76%) showed lateralisation of ACTH secretion (IPSG of > or = 1.4). There was concordance between the BSIPSS finding and the position of the microadenoma at surgery in 17/21 (81%) patients. Of the 16 patients showing lateralisation of ACTH secretion, 12 (75%) were cured by TSS. Of the four without lateralisation of ACTH, suggesting a midline lesion, 3 (75%) were cured by TSS. Post-operative pituitary hormone deficiencies in the patients cured by TSS were: pan-hypopituitarism 1/16, isolated growth hormone deficiency (GHD) (peak GH on glucagon/ITT < 1-17.9 mU/l) 9/16 and diabetes insipidus 3/16. CONCLUSION: Over a 21-year period selective adenomectomy by TSS cured 59% of all paediatric CD patients, with higher age favouring cure. Introduction of BSIPSS resulted in the demonstration of a high rate of lateralisation of ACTH secretion consistent with the surgical identification of the adenoma, and therefore appears likely to have contributed to the higher surgical cure rate.

Adenoma↗
PubMed2004

Therapeutic applications of the insulin-like growth factors.

The potential therapeutic applications of the insulin-like growth factors (IGFs) are broad. This review focuses on treatment of humans with recombinant human IGF-I (rhIGF-I), and with a rhIGF-I/IGF binding protein-3 (IGFBP-3) complex. Several groups of patients have been treated effectively, including individuals with growth hormone insensitivity syndrome (GHIS) secondary to GH receptor deficiency, to IGF-I gene deletion, or to defects in GH signal transduction pathways, patients with type 1 and type 2 diabetes mellitus, or individuals with severe insulin resistance syndromes. In each of these conditions rhIGF-I therapy has been demonstrated to be of clear clinical benefit. Other conditions, which may potential targets for therapy with rhIGF-I or rhIGF-I/IGFBP-3, include chronic inflammatory or nutritional disorders such as Crohn's disease, juvenile chronic arthritis, or cystic fibrosis. Therapy with IGFs has not been attempted in these disorders yet, in part because of lack of adequate supplies. Recently, the newly developed rhIGF-I/IGFBP-3 complex has been used in early clinical studies. Pharmacokinetic analyses in patients with diabetes mellitus and GHIS have suggested that a more physiological profile of serum IGF-I results. Improved glycaemic control has been reported in type 1 and type 2 diabetes in adults. A therapeutic trial in naïve children with GHIS is currently under way.

Adolescent↗
PubMed2004

Anti-inflammatory and growth-stimulating effects precede nutritional restitution during enteral feeding in Crohn disease.

OBJECTIVES: Exclusive enteral feeding reduces inflammation and improves well being, nutrition and growth in children with active Crohn disease. Whether improved growth and increases in growth-related proteins are a consequence of improved nutrition or a reduced inflammation is not known. This study was undertaken to test the hypothesis that changes in growth-related proteins are related to decreased inflammation, rather than improvement in nutritional status. METHODS: Twelve children with active Crohn disease treated for 6-weeks with exclusive enteral feeding were studied at days 0, 3, 7, 14, 21, 28, and 56. The Paediatric Crohn's Disease Activity Index (PCDAI), weight, triceps skinfold thickness, and midupper arm circumference were recorded. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), insulin-like growth factor (IGF-I), IGF-binding protein (IGFBP-3), and leptin were measured at each visit. Wilcoxon matched-pairs signed-rank test was used to compare day 0 with follow-up data. RESULTS: Significant improvements (P < 0.05) occurred by day 3 in inflammatory parameters (ESR, IL-6) and by day 7 in PCDAI, CRP, and IGF-I. These changes preceded any significant changes in nutritional parameters (weight-for-age Z score and midupper arm circumference day 14, triceps skinfold thickness day 21). CONCLUSIONS: Early increases in IGF-I during treatment of Crohn disease are attributable to the anti-inflammatory effect of the enteral feed rather than nutritional restitution.

Adolescent↗
PubMed2004

Thyrotoxicosis after matched unrelated bone marrow transplantation.

Acquired hyperthyroidism is most commonly autoimmune in etiology. In the setting of allogeneic bone marrow transplantation (BMT), the use of radiotherapy (total body irradiation) as part of the regimen prior to BMT is known to cause endocrine dysfunction, especially hypopituitarism and hypothyroidism, but hyperthyroidism is rare. The authors report this unusual and late complication in a young boy after BMT for relapsed childhood lymphoblastic leukemia and discuss the possible etiologies.

Blood Grouping and Crossmatching↗
PubMed2004

Prepubertal Cushing's disease is more common in males, but there is no increase in severity at diagnosis.

Sex distribution and severity of biochemical indices at the diagnosis of Cushing's disease (CD) were analyzed in 50 patients (21 males and 29 females; aged <or=30 yr; range, 6.4-30.0 yr). Twenty-five (50%) presented aged 18 yr or younger (17 males and eight females) and 25 aged 18-30 yr (four males and 21 females). CD diagnosed at less than 18 yr occurred predominantly in males, contrasting with 18 yr or older, which was more common in females. The difference between the two groups was significant (P = 0.0003). There was a significant difference (chi(2)) in sex distribution depending on pubertal status (P = 0.0002); in prepubertal patients (n = 11) males predominated (91%) compared with postpubertal patients (n = 27), where females predominated (81%). In patients in puberty (n = 12), there was an equal sex incidence (50% males). In adult patients with CD, males have been reported to have more severe disease. We found no difference in hypercortisolemia or ACTH at diagnosis in males compared with females in the patients less than 18 yr of age [serum 0000 h cortisol, 510.5 +/- 75.2 vs. 415.6 +/- 63.7 nmol/liter (P = 0.52); plasma ACTH, 48.5 +/- 7.9 vs. 42.9 +/- 10.9 ng/liter (P = 0.54); percent suppression of serum cortisol during low dose dexamethasone suppression test, 57.2 +/- 8.6% vs. 33.5 +/- 13.1% (P = 0.14); high dose dexamethasone suppression test, 85.9 +/- 3.1% vs. 85.7 +/- 4.9% (P = 0.55); percent increase in cortisol after iv CRH, 180.3 +/- 15.3% vs. 189.9 +/- 20.3% (P = 0.67)]. In conclusion, female preponderance of CD in adult patients was not present in childhood. In patients 18 yr of age or younger, there was no difference in the severity of hypercortisolemia or ACTH at diagnosis between males and females.

Adolescent↗
PubMed2003

Relationships between serum IGF-1, IGFBP-2, interleukin-1beta and interleukin-6 in inflammatory bowel disease.

AIMS: To study the relationships between serum IGF-1, IGFBP-3 and IGFBP-2 and interleukin (IL)-1beta and IL-6 in inflammatory bowel disease (IBD). METHODS: Thirty-seven patients (18 males, 19 females, aged 8.8-26.1 years) with IBD (Crohn's disease, CD, n = 17, and ulcerative colitis, UC, n = 20) were studied. Patients were in relapse or remission according to established criteria. Serum IGF-1, IGFBP-3, IGFBP-2, IL-1beta and IL-6 levels were determined in patients and 15 healthy controls (aged 8.2-19.0 years). RESULTS: IGF-1 levels were lower in patients with CD in relapse compared with controls (p < 0.05). IGFBP-2 levels were higher in CD in relapse compared with other groups (all p < 0.05). In CD and UC patients (n = 37), IGF-1 levels were inversely correlated with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). IGFBP-2 levels correlated positively with ESR and IL-1beta. IL-6 levels correlated positively with ESR and CRP. IL-1beta levels were elevated in CD in relapse compared to controls (p < 0.05) and were higher in UC in relapse than in other groups (all p < 0.05). In combined CD/UC patients in relapse (n = 20), IL-1beta levels were higher (p < 0.05) in patients with recto-sigmoiditis (n = 5) than in other patients. CONCLUSIONS: IGF-1, IGFBP-2 levels were related to IL levels, disease activity and anatomical distribution, consistent with active inflammation modifying the IGF-IGFBP system, possibly relevant to disturbance of growth.

Adolescent↗