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1.
Pediatr Obes ; 10(5): e8-10, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25820269

ABSTRACT

BACKGROUND: Detailed measures of infant body composition are needed for understanding the impact of genes and environment on growth early in life. OBJECTIVE: The purpose of this study was to compare the accuracy and bias of body composition in infants. METHODS: Dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) were used to determine body composition and the trunk depot. The depots measured were total fat mass (FM), total fat-free mass (FFM) and trunk FM and FFM using DXA and MRI in 14 infants. RESULTS: None of the regression lines between DXA and MRI significantly deviate from the line of identity for any of the depots studied. However, Bland-Altman analyses revealed bias for trunk FM and trunk FFM. CONCLUSION: Our data showed DXA to be accurate (regression not significantly deviating from the line of identity), with high agreement (indicated by high R(2) ) and without bias (non-significant Bland-Altman) when estimating total FM and FFM. This could not be said for trunk estimates.


Subject(s)
Absorptiometry, Photon , Electric Impedance , Magnetic Resonance Imaging , Adipose Tissue , Body Composition , Female , Humans , Infant , Linear Models , Male , Reproducibility of Results
2.
J Clin Endocrinol Metab ; 93(11): 4210-7, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18782877

ABSTRACT

OBJECTIVE: Our objective was to summarize important advances in the management of children with idiopathic short stature (ISS). PARTICIPANTS: Participants were 32 invited leaders in the field. EVIDENCE: Evidence was obtained by extensive literature review and from clinical experience. CONSENSUS: Participants reviewed discussion summaries, voted, and reached a majority decision on each document section. CONCLUSIONS: ISS is defined auxologically by a height below -2 sd score (SDS) without findings of disease as evident by a complete evaluation by a pediatric endocrinologist including stimulated GH levels. Magnetic resonance imaging is not necessary in patients with ISS. ISS may be a risk factor for psychosocial problems, but true psychopathology is rare. In the United States and seven other countries, the regulatory authorities approved GH treatment (at doses up to 53 microg/kg.d) for children shorter than -2.25 SDS, whereas in other countries, lower cutoffs are proposed. Aromatase inhibition increases predicted adult height in males with ISS, but adult-height data are not available. Psychological counseling is worthwhile to consider instead of or as an adjunct to hormone treatment. The predicted height may be inaccurate and is not an absolute criterion for GH treatment decisions. The shorter the child, the more consideration should be given to GH. Successful first-year response to GH treatment includes an increase in height SDS of more than 0.3-0.5. The mean increase in adult height in children with ISS attributable to GH therapy (average duration of 4-7 yr) is 3.5-7.5 cm. Responses are highly variable. IGF-I levels may be helpful in assessing compliance and GH sensitivity; levels that are consistently elevated (>2.5 SDS) should prompt consideration of GH dose reduction. GH therapy for children with ISS has a similar safety profile to other GH indications.


Subject(s)
Growth Disorders/diagnosis , Growth Disorders/therapy , Adult , Body Height , Body Weight , Child , Endocrinology/methods , Female , Gonadotropin-Releasing Hormone/therapeutic use , Growth Disorders/classification , Growth Disorders/psychology , Humans , Insulin-Like Growth Factor I/deficiency , Male , Mass Screening , Reference Values
3.
J Endocrinol Invest ; 29(1 Suppl): 16-20, 2006.
Article in English | MEDLINE | ID: mdl-16615302

ABSTRACT

About 5% of newborns are small for gestational age (SGA) and 10-15% of them do not naturally catch up on growth by 2 yr of age. The growth of the fetus from conception to birth results from complex interactions of maternal and fetal genes with the environment, and factors such as malnutrition are well known to influence fetal growth. Specific genetic disorders such as Leprechaunism, Bloom syndrome, Fanconi anemia are inherited, but are very rare causes of intrauterine growth retardation. Recent published research on the actions of IGF-I in humans and the phenotypes of children with genetic defects in the GH/IGF axis establish IGF-I signaling via its receptor (IGF-IR) as the critical growth-controlling element in man. The aim of this article is to review certain SGA disorders of Mendelian genetic origin, with an emphasis on defects in the insulin and IGF pathways which may be implicated in the persistence of short stature in some children born SGA.


Subject(s)
Body Height/genetics , Infant, Small for Gestational Age , Female , Fetal Development/genetics , Gestational Age , Growth Disorders/genetics , Growth Disorders/metabolism , Humans , Infant, Newborn , Insulin/metabolism , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Pregnancy
4.
J Pediatr Gastroenterol Nutr ; 33(5): 576-81, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11740232

ABSTRACT

OBJECTIVES: Malnutrition is common in cystic fibrosis (CF) and adversely affects survival. Because insulinlike growth factor-1 (IGF-1) has insulinlike effects in terms of carbohydrate metabolism and is growth promoting, the authors hypothesized that its use would increase linear growth rate and decrease insulin requirements in children with CF. METHODS: The authors used a double-blind placebo-controlled crossover design. Seven prepubertal children aged 9.6 to 13 years (5 boys and 2 girls) were treated with placebo or IGF-1 for 6 months. After a 6-month washout period, patients received the alternative therapy for 6 months. The primary outcome measure was linear growth rate. Secondary outcome measures were changes in body mass index, body composition determined by dual energy x-ray absorptiometry, forced expiratory volume (FEV(1)), and the blood glucose/insulin ratio. RESULTS: The mean height z score at baseline was -1.5 +/- 0.8. At entry, the mean serum IGF-1 level was 124 +/- 25 ng/mL (normal range, 110-771 ng/mL). With treatment, mean serum IGF-1 levels increased twofold to threefold for all patients. The half-life for IGF-1 was 10.3 hours. We observed no significant difference in linear growth rate, weight gain, rate of accretion of lean body mass, or mean FEV(1) during treatment with IGF-1 compared with placebo. The glucose/insulin ratio, an indirect index of insulin sensitivity, was significantly increased with IGF-1 treatment compared with placebo ( P < 0.02). No adverse events related to IGF-1 were detected. CONCLUSIONS: Treatment with IGF-1 for 6 months did not promote linear growth in prepubertal children with CF. However, the glucose/insulin ratio was increased without changing blood glucose levels with IGF-1 treatment suggesting increased insulin sensitivity.


Subject(s)
Body Height/drug effects , Cystic Fibrosis/drug therapy , Insulin-Like Growth Factor I/therapeutic use , Insulin/blood , Nutrition Disorders/drug therapy , Absorptiometry, Photon , Adolescent , Blood Glucose , Body Composition/drug effects , Child , Cross-Over Studies , Cystic Fibrosis/blood , Double-Blind Method , Female , Growth , Humans , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/adverse effects , Insulin-Like Growth Factor I/analysis , Insulin-Like Growth Factor I/pharmacokinetics , Intestinal Absorption , Male , Nutrition Disorders/blood , Respiratory Function Tests
6.
J Endocrinol Invest ; 24(9): 676-80, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11716154

ABSTRACT

From a pediatrician's perspective, the dominant feature of growth GH deficiency has always been slow growth with severe dwarfism unless GH is replaced. In the early years of GH therapy the hormone was so scarce that only severely affected children were offered treatment using dosing regimens considered modest by today's standards. The major goal of treatment was to stimulate linear growth, hopefully reaching a final height within the normal range, but generally accepting stature below that expected based on the parents' heights. The only indication for GH apart from this was to prevent hypoglycemia in GH-deficient infants. The advent of recombinant GH irrevocably altered the approach to individuals with GH deficiency. Treatment could be given at an early age, continuously and optimized for growth. Though the metabolic effects of GH have been known for years, it has only been over the last decade that the phenotype of adult GH deficiency has been defined and the beneficial effects of GH replacement proven for those who have completed skeletal growth. Now that we are in a new era of GH therapy for adults, physicians caring for children with GH deficiency must consider which patients may benefit from life-long replacement with GH. The use of GH for adults has been the subject of published consensus statements and reviews. The objective here is to focus on the issues that relate to the management of patients who are at the transitional stage of GH therapy, i.e. where linear growth in nearly complete or satisfactory and the issue of continuing GH for non-statural indications is at hand. What follows is brief discussion of what is known and what is not known concerning the use of GH during transition from adolescence to adulthood, accompanied by the Author's suggestions for management.


Subject(s)
Human Growth Hormone/deficiency , Human Growth Hormone/therapeutic use , Adolescent , Adult , Body Height , Growth , Hormone Replacement Therapy , Humans , Insulin-Like Growth Factor I/analysis
7.
Endocrinology ; 142(10): 4420-7, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11564706

ABSTRACT

Recent studies support a critical role for the paracrine IGF/IGF-binding protein system in the regulation of vascular smooth muscle cell growth. In this study we have explored the hypothesis that the abundance of individual IGF-binding proteins in smooth muscle is subject to regulation during postnatal life and in response to injury. IGF-binding protein-2 was the predominant binding protein secreted by neonatal rat vascular smooth muscle cells, whereas IGF-binding protein-4 was most prevalent in adult vascular smooth muscle cells coincident with increased IGF-binding protein-4 protease activity. After arterial injury, IGF-binding protein-4 mRNA increased, associated with greater IGF-binding protein-4 proteolytic activity, resulting in stable steady state levels of the IGF-binding protein-4 protein. Expression of pregnancy-associated plasma protein A mRNA, recently identified as an IGF-binding protein-4 protease, was expressed at higher levels in adult than neonatal vascular smooth muscle cell lines, but did not change significantly after arterial injury. The peak of immunoreactive pregnancy-associated plasma protein A from hydrophobic interaction chromatography fractions of smooth muscle cell-conditioned medium coincided, but did not fully overlap, with the fractions containing maximal IGF-binding protein-4 protease activity. In conclusion, our data point to a developmental switch from IGF-binding protein-2 to IGF-binding protein-4 in vascular smooth muscle cells postnatally. Moreover, IGF-binding protein-4 expression is coregulated with IGF-binding protein-4 protease activity, suggesting that biosynthesis and degradation of this binding protein are coordinated events important for regulating biological activity of IGF-I.


Subject(s)
Insulin-Like Growth Factor Binding Protein 4/physiology , Metalloendopeptidases/physiology , Muscle, Smooth, Vascular/physiology , Animals , Cells, Cultured , Gene Expression Regulation/physiology , Insulin-Like Growth Factor Binding Protein 2/physiology , Muscle, Smooth, Vascular/pathology , Pregnancy-Associated Plasma Protein-A , RNA, Messenger/physiology , Rats
8.
Diabetes ; 50(5): 1110-8, 2001 May.
Article in English | MEDLINE | ID: mdl-11334415

ABSTRACT

Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism. To study the metabolic consequences of IGF-I deficiency, we used the liver IGF-I-deficient (LID) mouse model. The LID mice show a marked reduction (approximately 75%) in circulating IGF-I and elevated growth hormone (GH) levels. Interestingly, LID mice show a fourfold increase in serum insulin levels (2.2 vs. 0.6 ng/ml in control mice) and abnormal glucose clearance after insulin injection. Fasting blood glucose levels and those after a glucose tolerance test were similar between the LID mice and their control littermates. Thus, the high levels of circulating insulin enable the LID mice to maintain normoglycemia in the presence of apparent insulin insensitivity. Insulin-induced autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate (IRS)-1 were absent in muscle, but were normal in liver and white adipose tissue of the LID mice. In contrast, IGF-I-induced autophosphorylation of its cognate receptor and phosphorylation of IRS-1 were normal in muscle of LID mice. Thus, the insulin insensitivity seen in the LID mice is muscle specific. Recombinant human IGF-I treatment of the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. Treatment of the LID mice with GH-releasing hormone antagonist, which reduces GH levels, also increased insulin sensitivity. These data provide evidence of the role of circulating IGF-I as an important component of overall insulin action in peripheral tissues.


Subject(s)
Gene Deletion , Insulin-Like Growth Factor I/physiology , Insulin/physiology , Liver/physiology , Muscle, Skeletal/physiology , Animals , Blood Glucose/metabolism , Glucose Tolerance Test , Growth Hormone/blood , Insulin/blood , Insulin/pharmacology , Insulin Resistance , Insulin-Like Growth Factor Binding Proteins/blood , Insulin-Like Growth Factor I/deficiency , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/pharmacology , Islets of Langerhans/cytology , Islets of Langerhans/physiology , Male , Mice , Mice, Knockout , Models, Biological , Signal Transduction , Transcription, Genetic
10.
J Clin Endocrinol Metab ; 85(7): 2439-45, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10902791

ABSTRACT

Clinical trials of recombinant human GH therapy in Turner syndrome that began more than a decade ago show that GH accelerates the linear growth rate. Several studies indicate that final height is also improved, although the magnitude of the increase has been debated. The age at which feminization is induced could be an important factor in determining the patient's ultimate growth response. To test this, 60 patients from a large (n = 117), previously unreported, clinical trial of GH treatment were randomly assigned to begin conjugated estrogens at either 12 or 15 yr of age. The 60 patients were all less than 11 yr of age at entry (mean, 9.5 yr) and received 0.375 mg/kg x week of GH for nearly 6 yr on a daily or three times weekly regimen. Height gain was calculated by comparing the study patients' final or near final heights to their pretreatment projected heights as well as to those of a separate set of age-matched, historical control patients. Patients in whom estrogen treatment was delayed until age 15 yr gained an average of 8.4 +/- 4.3 cm over their projected height, whereas those starting estrogen at 12 yr gained only 5.1 +/- 3.6 cm, on the average (P < 0.01). Analysis of the interval data showed that growth was stimulated for approximately 2 yr after estrogen initiation, but then declined in association with bone age advancement. Patients who were older than 11 yr at entry (n = 57) all initiated estrogen 1 yr after beginning GH and showed a mean gain in adult height of 4.7 cm, similar to those given estrogen at age 12 yr. Multivariate analysis revealed that the number of years of GH therapy before estrogen treatment was a strong factor in predicting height gained, indicating that the timing of estrogen introduction is an important determinant of final height in this cohort of GH-treated patients with Turner syndrome matched for baseline age and other characteristics.


Subject(s)
Aging/physiology , Estrogen Replacement Therapy , Growth Hormone/therapeutic use , Turner Syndrome/drug therapy , Adolescent , Body Height/drug effects , Bone Development/drug effects , Child , Double-Blind Method , Female , Feminization/drug therapy , Humans , Male , Retrospective Studies , Treatment Outcome
11.
Endocrinology ; 141(7): 2674-82, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10875273

ABSTRACT

Insulin-like growth factor I (IGF-I) is an important growth factor for bone, yet the mechanisms that mediate its anabolic activity in the skeleton are poorly understood. To examine the effects of locally produced IGF-I in bone in vivo, we targeted expression IGF-I to osteoblasts of transgenic mice using a human osteocalcin promoter. The IGF-I transgene was expressed in bone osteoblasts in OC-IGF-I transgenic mice at high levels in the absence of any change in serum IGF-I levels, or of total body growth. Bone formation rate at the distal femur in 3-week-old OC-IGF-I transgenic mice was approximately twice that of controls. By 6 weeks, bone mineral density as measured by dual energy x-ray, and quantitative computed tomography was significantly greater in OC-IGF-I transgenic mice compared with controls. Histomorphometric measurements revealed a marked (30%) increase femoral cancellous bone volume in the OC-IGF-I transgenic mice, but no change in the total number of osteoblasts or osteoclasts. Transgenic mice also demonstrated an increase in the osteocyte lacunea occupancy, suggesting that IGF-I may extend the osteocyte life span. We conclude that IGF-I produced locally in bone osteoblasts exerts its anabolic effect primarily by increasing the activity of resident osteoblasts.


Subject(s)
Femur/anatomy & histology , Insulin-Like Growth Factor I/metabolism , Osteoblasts/cytology , Osteoblasts/metabolism , Animals , Body Weight/physiology , Bone Development/physiology , Cell Division/physiology , Gene Expression , Humans , Insulin-Like Growth Factor I/genetics , Mice , Mice, Transgenic/genetics , Osteoblasts/physiology , Osteocalcin/genetics , Osteocytes/cytology , Transgenes/physiology
12.
Acta Paediatr Suppl ; 88(433): 130-2, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10626564

ABSTRACT

It is now clear that parenteral growth hormone (GH) therapy stimulates growth and increases the adult stature of girls with Turner syndrome. In addition, oestrogens are given to almost all girls with this syndrome because of primary hypogonadism. Oestrogens influence both growth and maturation of the epiphyseal growth plates. Therefore, the form and timing of oestrogen therapy may have an important impact on the outcome of other growth-promoting therapies. To examine the impact of the timing of oestrogen initiation on growth, a randomized trial was conducted in patients with Turner syndrome who were receiving GH. Some patients received oestrogen at 12 years of age, while in others this treatment was not started until 15 years of age. Those girls that received oestrogen later were significantly taller as adults. The single most important factor in determining height gain appeared to be the number of years of GH therapy prior to the initiation of oestrogen treatment.


Subject(s)
Body Height , Estradiol Congeners/therapeutic use , Turner Syndrome/drug therapy , Age Factors , Body Height/drug effects , Bone and Bones/drug effects , Estradiol Congeners/pharmacology , Female , Human Growth Hormone/therapeutic use , Humans , Treatment Outcome , Turner Syndrome/physiopathology
13.
J Cell Physiol ; 177(1): 47-57, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9731744

ABSTRACT

We have previously shown that the insulin-like growth factors (IGFs) stimulate both proliferation and differentiation of skeletal muscle cells in culture, and that these actions in L6A1 muscle cells may be modulated by three secreted IGF binding proteins (IGFBPs), IGFBP-4, -5, and -6. Since we found that the temporal expression pattern of IGFBP-4 and IGFBP-5 differed dramatically during the transition from proliferating myoblasts to differentiated myotubes, we undertook the current study to examine the effects of purified IGFBP-4 and IGFBP-5 on IGF-stimulated actions in L6A1 muscle cells. As has been shown for other cell types, we found that IGFBP-4 had only inhibitory actions, inhibiting IGF-I and IGF-II-stimulated proliferation and differentiation. In contrast, IGFBP-5 exhibited both inhibitory and stimulatory actions. When added in the presence of 30 ng/ml IGF-I, IGFBP-5 (250 ng/ml) inhibited all markers of the early proliferative response: the tyrosine phosphorylation of the cytoplasmic signaling molecules IRS-1 and Shc, the activation of the MAP kinases, ERK1 and 2, the elevation of c-fos mRNA, the early inhibition of the elevation in myogenin mRNA, and the increase in cell number. In contrast, IGFBP-5 stimulated all aspects of the myogenic response to IGF-I: the later rise in myogenin mRNA, the elevation of creatine kinase activity, and the fusion of myoblasts into myotubes. This dual response to IGFBP-5 was greatest when it was added at a molar ratio of IGFBP-5 to IGF-I of 2:1. In contrast, when IGFBP-5 was added in the presence of IGF-II, it inhibited both proliferation and differentiation. Neither IGFBP had any effect when added in the presence of R3 IGF-I, an analog with substantially reduced affinity for IGFBPs. Our results suggest that the role of IGFBP-4 is mainly to sequester excess IGFs, and thus inhibit all actions. IGFBP-5, however, is capable of eliciting a dual response, possibly due to its unique ability to associate with the cell membrane.


Subject(s)
Adaptor Proteins, Signal Transducing , Adaptor Proteins, Vesicular Transport , Insulin-Like Growth Factor Binding Protein 4/pharmacology , Insulin-Like Growth Factor Binding Protein 5/pharmacology , Insulin-Like Growth Factor I/physiology , Mitogen-Activated Protein Kinases , Muscle Fibers, Skeletal/cytology , Signal Transduction/drug effects , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Cell Differentiation/drug effects , Cell Division/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Gene Expression/drug effects , Humans , Insulin Receptor Substrate Proteins , Insulin-Like Growth Factor Binding Protein 4/physiology , Insulin-Like Growth Factor Binding Protein 5/physiology , Insulin-Like Growth Factor I/pharmacology , Insulin-Like Growth Factor II/pharmacology , Mitogen-Activated Protein Kinase 1 , Mitogen-Activated Protein Kinase 3 , Muscle Fibers, Skeletal/enzymology , Myogenin/genetics , Phosphoproteins/metabolism , Phosphorylation , Proteins/metabolism , Proto-Oncogene Proteins c-fos/genetics , RNA, Messenger/metabolism , Shc Signaling Adaptor Proteins , Src Homology 2 Domain-Containing, Transforming Protein 1 , Tyrosine/metabolism
14.
Endocrinology ; 139(5): 2605-14, 1998 May.
Article in English | MEDLINE | ID: mdl-9564877

ABSTRACT

Insulin-like growth factor I (IGF-I) has been postulated to function as a smooth muscle cell (SMC) mitogen and to play a role in the pathogenesis of bladder hypertrophy, estrogen-induced uterine growth, and restenosis after arterial angioplasty. IGF-binding protein-4 (IGFBP-4) inhibits IGF-I action in vitro and is the most abundant IGFBP in the rodent arterial wall. To explore the function of this binding protein in vivo, transgenic mouse lines were developed harboring fusion genes consisting of a rat IGFBP-4 complementary DNA cloned downstream of either a -724 bp fragment of the mouse smooth muscle alpha-actin 5'-flanking region (SMP2-BP-4) or -1074 bp, 63 bp of 5'-untranslated region, and 2.5 kb of intron 1 of smooth muscle alpha-actin (SMP8-BP-4). SMP2-BP-4 mice expressed low levels of the exogenous IGFBP-4 messenger RNA (mRNA), which was not specifically targeted to SMC-rich tissue environments, and were therefore not analyzed further. Six SMP8-BP-4 transgenic lines derived from separate founders were characterized. Mating of hemizygous SMP8-BP-4 mice with controls produced about 50% transgenic offspring, with equal sex distribution. Expression of IGFBP-4 mRNA in nontransgenic littermates was maximal in liver and kidney. By contrast, transgenic IGFBP-4 mRNA expression, distinguished because of a smaller transcript size, was confined to SMC-containing tissues, with the following hierarchy: bladder > aorta > stomach = uterus. There was no transgene expression in skeletal muscle, brain, or cardiac myocytes. The abundance of IGFBP-4 measured by Western ligand blotting or by immunoblotting, was 8- to 10-fold higher in aorta and bladder of SMP8-BP-4 mice than in their nontransgenic littermates, with no change in plasma IGFBP-4 levels. Transgenic mice exhibited a significant reduction in wet weight of SMC-rich tissues, including bladder, intestine, aorta, uterus, and stomach, with no change in total body or carcass weight. In situ hybridization showed that transgene expression was targeted exclusively to the muscular layers of the arteries, veins, bladder, ureter, stomach, intestine, and uterus. Overexpression of IGFBP-4 was associated with SMC hypoplasia, a reciprocal phenotype to that of transgenic mice overexpressing IGF-I under control of the same promoter (SMP8-IGF-I). Double transgenic mice derived from mating SMP8-BP-4 with SMP8-IGF-I animals showed a modest decrease in wet weight at selected SMC tissues. Although we cannot exclude that the effects of IGFBP-4 may be IGF independent, these data suggest that IGFBP-4 is a functional antagonist of IGF-I action on SMC in vivo.


Subject(s)
Actins/genetics , Gene Expression , Insulin-Like Growth Factor Binding Protein 4/genetics , Muscle, Smooth/metabolism , Animals , Aorta/metabolism , Aorta/pathology , Female , Gastric Mucosa/metabolism , In Situ Hybridization , Male , Mice , Mice, Transgenic , Muscle, Smooth/pathology , Organ Size , RNA, Messenger/metabolism , Recombinant Fusion Proteins , Stomach/pathology , Urinary Bladder/metabolism , Urinary Bladder/pathology , Uterus/metabolism , Uterus/pathology
15.
Am J Med Genet ; 77(4): 257-60, 1998 May 26.
Article in English | MEDLINE | ID: mdl-9600731

ABSTRACT

We present two sibs with partial trisomy 1 (q31.1-q32.1) due to a familial insertion. Patient 1 is a girl who presented at age 9 months with minor anomalies, short stature, and normal psychomotor development. Karyotype was 46,XX,der(4)ins(4;1) (p14;q31.1q32.1)pat. The father had a balanced inverted insertion of 1q into 4p, with karyotype 46,XY,ins(4;1)(p14;q31.1q32.1). At age 5 years, patient 1 was found to have short stature with documented growth hormone deficiency and ectopic pituitary. Her growth velocity responded well to treatment with growth hormone. Cognitive testing at 5 9/12 years showed normal intelligence with an IQ of 90. Patient 2, the brother of patient 1, presented with intrauterine growth retardation. He has the same chromosomal insertion as his sister, with partial trisomy 1q. We suggest that there is a recognizable phenotype of trisomy 1(q31.1-q32.1) which includes prenatal and postnatal growth retardation, narrow palpebral fissures, microphthalmia, microstomia, pituitary abnormalities, and normal intelligence in some individuals.


Subject(s)
Chromosomes, Human, Pair 1 , Human Growth Hormone/deficiency , Intelligence/genetics , Trisomy , Child, Preschool , Female , Humans , Infant
16.
J Pediatr ; 132(2): 319-24, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9506648

ABSTRACT

OBJECTIVE: To carry out a multicenter, prospective, randomized trial of human growth hormone (GH), alone or in combination with oxandrolone (OX), in patients with Turner's syndrome (TS). METHODS: In an initial phase lasting 12 to 24 months, 70 girls with TS, verified by karyotype, were randomly assigned to one of four groups: (1) observation, (2) OX, (3) GH, or (4) GH plus OX. After completion of the first phase, group 3 subjects continued to receive GH only. All other subjects were treated with GH plus OX. Subjects were followed up until attainment of adult height and/or cessation of treatment. Data from this trial were compared with growth characteristics of 25 American historical subjects with TS (matched for age, height, parental target height, and karyotype) who never received either GH or androgens. RESULTS: Of the 70 subjects enrolled, 60 completed the clinical trial. The 17 subjects receiving GH alone all completed the trial and reached a height of 150.4+/-5.5 cm (mean +/- SD), 8.4+/-4.5 cm taller than their mean projected adult height at enrollment (95% confidence interval [CI]: 6.3 to 10.6 cm). The 43 subjects receiving GH plus OX attained a mean height of 152.1+/-5.9 cm, 10.3+/-4.7 cm taller than their mean projected adult height (95% CI: 8.9 to 11.7 cm). The historical control subjects had a mean adult height of 144.2+/-6.0 cm, precisely matching their original projected adult height of 144.2+/-6.1 cm. CONCLUSIONS: GH, either alone or in combination with OX, is capable of stimulating short-term growth and augmenting adult height in girls with TS. With early diagnosis and initiation of treatment, an adult height of more than 150 cm is a reasonable goal for most girls with TS.


Subject(s)
Anabolic Agents/therapeutic use , Body Height , Growth Hormone/therapeutic use , Oxandrolone/therapeutic use , Turner Syndrome/drug therapy , Child , Child, Preschool , Drug Therapy, Combination , Female , Humans , Prospective Studies , Treatment Outcome , Turner Syndrome/physiopathology
17.
Am J Pathol ; 151(3): 715-24, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9284820

ABSTRACT

Insulin-like growth factor (IGF)-I has profound effects on tissue repair. IGF-II is felt to exert its influence predominately during fetal development. The purpose of this study was to localize and quantify the expression of IGF-I and IGF-II mRNA and protein during early wound healing in diabetic and nondiabetic mice. The hypothesis is that IGF-I and IGF-II are up-regulated in the healing wound, but their expression is inhibited in diabetics. Full-thickness cutaneous wounds were made on genetically diabetic (C57BL/ KsJ-db/db) mice and their nondiabetic littermates. At various times after wounding, one-half of each wound was fixed and paraffin embedded for immunohistochemistry and in situ hybridization. The other half was flash-frozen for quantification of IGF mRNA by competitive reverse transcriptase polymerase chain reaction and protein by radioimmunoassay. IGF-I mRNA rose sharply in nondiabetics at day 3. Expression in diabetic wounds was significantly delayed until 14 days after wounding. Even then, diabetic IGF-I mRNA levels were 50% less than those in the nondiabetics at their peak. Although not usually considered active in adult life, IGF-II mRNA expression was augmented after wounding, peaking at 3 days in nondiabetics. As with IGF-I, diabetic wounds exhibited a delay in IGF-II mRNA expression, with maximal levels at 10 days after wounding. Interestingly, peak concentrations of IGF-II mRNA were four times greater in diabetics versus nondiabetics. Trends in IGF-I protein expression followed the patterns of mRNA expression. IGF-I levels in nondiabetics were initially double those in diabetics and peaked at 5 days. Diabetic wound concentrations of IGF-I did not peak until 21 days after wounding, at which time they rose to nondiabetic levels. IGF-I and IGF-II proteins were localized to the advancing epithelial edge, to the epithelial cells of adjacent hair follicles, and to the granulation tissue of the wounds. IGF-I and IGF-II mRNA expression was noted in the epithelial edge and in the hair follicles adjacent to the wound, paralleling protein expression. Both IGF-I and IGF-II are up-regulated in the healing wound. A delay in IGF-I and -II presence is noted in the diabetic wound. The impairment in tissue repair in diabetic animals is at least partially due to a deficiency in the production of the IGFs.


Subject(s)
Diabetes Mellitus/metabolism , Diabetes Mellitus/physiopathology , Insulin-Like Growth Factor II/metabolism , Insulin-Like Growth Factor I/metabolism , Skin/injuries , Skin/metabolism , Wound Healing , Animals , Diabetes Complications , Immunohistochemistry , In Situ Hybridization , Mice , Mice, Inbred C57BL , Polymerase Chain Reaction , RNA, Messenger/metabolism , Radioimmunoassay
18.
J Clin Invest ; 100(6): 1425-39, 1997 Sep 15.
Article in English | MEDLINE | ID: mdl-9294108

ABSTRACT

Smooth muscle cells (SMC) of the vascular wall, bladder, myometrium, and gastrointestinal and respiratory tracts retain the ability to proliferate postnatally, which enables adaptive responses to injury, hormonal, or mechanical stimulation. SMC growth is regulated by a number of mesenchymal growth factors, including insulin-like growth factor I (IGF-I). To explore the function of IGF-I on SMC in vivo, the mouse SMC alpha-actin promoter fragment SMP8 (-1074 bp, 63 bp of 5'UT and 2.5 kb of intron 1) was cloned upstream of rat IGF-I cDNA, and the fusion gene microinjected to fertilized eggs of the FVB-N mouse strain. Mating of hemizygous mice with controls produced about 50% transgenic offspring, with equal sex distribution. Transgenic IGF-I mRNA expression was confined to SMC-containing tissues, with the following hierarchy: bladder > stomach > aorta = uterus > intestine. There was no transgene expression in skeletal muscle, heart, or liver. Radioimmunoassayable IGF-I content was increased by 3.5- to 4-fold in aorta, and by almost 10-fold in bladder of transgenic mice at 5 and 10 wk, with no change in plasma IGF-I levels. Wet weight of bladder, stomach, intestine, uterus, and aorta was selectively increased, with no change in total body or carcass weight of transgenic animals. In situ hybridization showed that transgene expression was exquisitely targeted to the smooth muscle layers of the arteries, veins, bladder, ureter, stomach, intestine, and uterus. Paracrine overproduction of IGF-I resulted in hyperplasia of the muscular layers of these tissues, manifesting in remarkably different phenotypes in the various SMC beds. Whereas the muscular layer of the bladder and stomach exhibited a concentric thickening, the SMC of the intestine and uterus grew in a longitudinal fashion, resulting in a marked lengthening of the small bowel and of the uterine horns. This report describes the first successful targeting of expression of any functional protein capable of modifying the phenotype of SMC in transgenic mice. IGF-I stimulates SMC hyperplasia, leading to distinct patterns of organ remodeling in the different tissue environments.


Subject(s)
Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Muscle, Smooth/metabolism , Animals , Aorta/metabolism , Aorta/pathology , Body Weight/genetics , Chloramphenicol O-Acetyltransferase , Female , Gastric Mucosa/metabolism , Hyperplasia , In Situ Hybridization , Intestinal Mucosa/metabolism , Intestines/pathology , Mice , Mice, Transgenic , Muscle, Smooth/pathology , Promoter Regions, Genetic , RNA, Messenger/analysis , Radioimmunoassay , Stomach/pathology , Tissue Distribution , Urinary Bladder/metabolism , Urinary Bladder/pathology , Uterus/metabolism , Uterus/pathology
19.
Pediatr Transplant ; 1(1): 73-9, 1997 Aug.
Article in English | MEDLINE | ID: mdl-10084790

ABSTRACT

Malnutrition adversely affects mortality and morbidity before and after liver transplantation. Outcome might be improved if liver transplant recipients were in a better nutritional state at the time of transplantation. In this review, we will examine the potential use of GH and IGF-I to improve nutritional status in patients with cirrhosis. Patients with cirrhosis have low circulating IGF-I levels in the face of elevated serum GH concentrations. IGFBP-3 levels are low while IGFBP-1 levels are high. In patients with cirrhosis, IGF-I levels do not increase in response to treatment with GH. Patients with cirrhosis are insensitive to GH, and rhGH treatment is not likely to reverse malnutrition. The pathobiology of GH insentivity may reflect decreased nutritional intake, low GH receptor density, decreased IGF-I half-life and hepatic insensitivity to insulin.


Subject(s)
Growth Hormone/blood , Insulin-Like Growth Factor I/analysis , Liver Cirrhosis/blood , Liver Transplantation , Nutritional Status , Nutritional Support , Child , Chronic Disease , Humans , Insulin-Like Growth Factor Binding Proteins/blood , Liver Cirrhosis/therapy
20.
J Pediatr ; 131(1 Pt 2): S51-5, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9255229

ABSTRACT

Mutations in the GHR locus may play a role in the cause of idiopathic short stature (ISS) by impairing growth-hormone (GH) receptor (GHR) function. At one extreme, mutations that nullify the function of the GH receptor are linked to complete GH insensitivity syndrome, or Laron syndrome, and we hypothesized that less-disruptive mutations could contribute to partial GH insensitivity syndrome. Low levels of GH binding protein may indicate mutations in the extracellular domain of the receptor, and by focusing on 14 children with ISS who had low GH binding protein and insulin-like growth factor I levels, we found three heterozygotes and one compound heterozygote for mutations in the extracellular domain of the receptor. We have since extended our study to a broader spectrum of patients, adding 76 patients with ISS who were treated with GH in a phase II study of the safety and efficacy of recombinant human GH in ISS and also adding 10 patients who were ascertained as having ISS by pediatric endocrinologists in private practice. The GHR gene has thus been analyzed in 100 patients with ISS, eight of whom were found to carry mutations: four in our original study and four with normal or elevated levels of GH binding protein. The latter group consists of three carriers of heterozygous extracellular domain mutations and one carrier of a heterozygous intracellular domain mutation. Family data suggest that the carriers of these mutations have a range of phenotypes, supporting our hypothesis that the expression of these heterozygous mutations as partial GH insensitivity syndrome depends on the genetic makeup of the person.


Subject(s)
Body Height/genetics , Growth Disorders/genetics , Human Growth Hormone/genetics , Mutation/genetics , Receptors, Somatotropin/genetics , Carrier Proteins/blood , Carrier Proteins/genetics , Child , Child, Preschool , Chromosome Mapping , Female , Gene Expression Regulation , Genes/genetics , Growth Disorders/drug therapy , Growth Hormone/therapeutic use , Heterozygote , Human Growth Hormone/blood , Human Growth Hormone/therapeutic use , Humans , Insulin-Like Growth Factor I/analysis , Insulin-Like Growth Factor I/genetics , Male , Phenotype , Polymorphism, Genetic/genetics , Polymorphism, Single-Stranded Conformational , Receptors, Somatotropin/physiology , Safety , Syndrome
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