How to Grow Taller
In this section, we use the human growth hormone gene as a target to illustrate how the inducible system can be utilized to regulate the expression of a secreted protein. We use the previously described reporter 17X4-TATA-CAT (18) as a parental vector and replace the CAT gene insert with a 2,1-kb human growth hormone (hGH) genomic DNA fragment (Fig. 3). This reporter contains only the minimal TATA promoter and will therefore significantly reduce the basal activity of the reporter gene. We will also describe the use of liver-specific promoter-enhancer to target the expression of regulator in a tissue specific manner. 2 3 pg of the plasmid pOGH (containing genomic human growth hormone sequence, from Nichols Institute) is digested with BamHl and blunt-ended with the Klenow fragment. The linearized DNA is precipitated and the DNA pellet is redissolved in TE. The DNA is then digested with EcoRl and separated on a 1 agarose gel (1X TAE buffer) The DNA fragment corresponding to the hGH...
Growth hormone (GH) is synthesized and secreted from somatotrophs located in the anterior pituitary. Its release is unique in that it is controlled by two peptide hypothalamic hypophysiotropic hormones, growth hormone-releasing factor (GHRF) and somatostatin (SRIF). SRIF, also known as growth hormone-release-inhibiting hormone (GHIH), was first isolated from ovine hypothalamus in 1974. It is a tetradecapeptide, containing a disulfide bridge linking the two cysteine residues. It is released predominantly from the periventricular and the PVN of the hypothalamus and inhibits GH release. SRIF has a wide extrahypothalamic distribution in brain regions, including the cerebral cortex, hippocampus and amygdala.
Premature infants will mostly attain their expected adult height. PIH may cause asymmetric IUGR as discussed above. In comparison to symmetrical IUGR, which is often the result of an underlying genetic or teratogenic cause, these infants are able to show catch up growth during the first 1-2 years. This catch up growth will depend on adequate nutrition. Some of these infants remain small despite adequate calorie and protein intake. These children respond to human growth hormone treatment by increasing their height velocity (Czernichow, 1997). However, it is not yet clear if final adult height is affected, but even if adult height is not changed the increase in a child's height during school years will increase their confidence.
The first plant hormone we will consider is auxin. Auxin deserves pride of place in any discussion of plant hormones because it was the first growth hormone to be discovered in plants, and much of the early physiological work on the mechanism of plant cell expansion was carried out in relation to auxin action.
Polyadenylation has been shown to enhance mRNA stability and translation in mammalian cells (18,19). Immediately following the reporter gene is a polyadenylation (poly A) sequence that signals the addition of200-250 adenylate residues to the 3'-end of an RNA transcript (20). Commonly used poly A sequences in reporter vectors are derived from the SV40 early and late genes, or the bovine growth hormone gene. For optimal expression, the SV40 late and the bovine growth hormone poly A sites have been shown to be five-, and threefold (21,22) more efficient than the SV40 early poly A at generating high levels of steady-state mRNA.
Growth hormone receptor key structural and functional features. Shown are the locations of five N-linked glycosylation sites (N) and seven cysteine residues (C) within the extracellular ligand binding domain of GHR. Ten tyrosines residues (Y) are present in the cytoplasmic region of rat GHR the six tyrosines that are conserved across species are numbered. Also shown are the extracellular WSXWS-like motif and the intracellular Box 1 (proline-rich domain) and Box 2 regions. Regions of GHR required for various functions, including STAT5b binding are indicated using the rat GHR numbering system. (Adapted from Carter-Su et al. Annu Rev Biochem 1996 58 187-207.) Fig. 4. Growth hormone receptor key structural and functional features. Shown are the locations of five N-linked glycosylation sites (N) and seven cysteine residues (C) within the extracellular ligand binding domain of GHR. Ten tyrosines residues (Y) are present in the cytoplasmic region of rat GHR the six tyrosines that are...
Mutations that confer pathophysiological relevant alterations in GHR's extracellular domain can lead to changes in cell surface expression of GHR or its GH binding activity. This can result in severe GH resistance, as seen in Laron syndrome, or in a less severe deficiency of GH action associated with a condition referred to as idiopathic short stature (Fig. 2). A frameshift mutation that yields a severely truncated GHR with only seven cytoplasmic domain residues has been described as a cause of familial short stature. This autosomal dominant mutation is analogous to the cytoplasmic domain truncated GHR splice variants discussed earlier and is proposed to generate a dominant-negative GHR that results in GH insensitivity by forming inactive heterodimers with the wild-type receptor (see next section).
Alele J, Jiang J, Goldsmith JF, Yang X, Maheshwari HG, Black RA, Baumann G, Frank SJ. Blockade of growth hormone receptor shedding by a metalloprotease inhibitor. Endocrinology 1998 139 1927-1935. Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silven-noinen O, Ihle JN, Carter-Su C. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 1993 74 237-244. Darnell JE, Jr. STATs and gene regulation. Science 1997 277 1630-1635. de Vos AM, Ultsch M, Kossiakoff AA. Human growth hormone and extracellular domain of its receptor crystal structure of the complex. Science 1992 255 306-312. Frank SJ, Yi W, Zhao Y, Goldsmith JF, Gilliland G, Jiang J, Sakai I, Kraft AS. Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor. J Biol Chem 1995 270 14776-14785. Gebert CA, Park SH, Waxman DJ. Termination of growth hormone pulse-induced STAT5b signaling. Mol Endocrinol 1999 13 38-56. Laron Z. Disorders of growth hormone resistance in...
Each different SEAP construct should be transfected (and subsequently assayed) in triplicate to minimize variability among treatment groups. The primary sources of such variability are differences in transfection efficiencies. When monitoring the effect of promoter and enhancer sequences on gene expression, it is critical to include an internal control that will distinguish differences in the level of transcription from variability in the efficiency of transfection. This is easily done by cotransfecting with a second plasmid that constitutively expresses an activity which can be clearly defined from SEAP. The level of the second enzymatic activity can then be used to normalize the levels of SEAP among different treatment groups. Reporter proteins frequently used for this purpose include E coli P-galactosidase, which is expressed intracellularly, and human growth hormone (hGH), which is secreted (5).
Examples of the use of the pairing process are so common they are taken for granted. Thus, for example, receptor sites such as that for the human growth hormone are constructed using a very sophisticated pairing-principle device that transmits information about the separation of partners to and through membranes. Another interesting example is provided by some families of repressor proteins that appear to derive their specificity in selecting sites on DNA helices by pairing of subunits so as to be sensitive to groove geometry and more specifically to local dynamical behavior (Sec. VLB.2). The so-called second genetic code appears to depend on matching of the fluctuations of repressor proteins and other proteins regulating DNA expression to local dynamical behavior of DNA. Complementarity in protein-protein association depends on matching of the fluctuations of surfaces, and the example of hemoglobin given in Sec. VI.C.4 describes one possible way such matching can be tailored to...
Decreased growth hormone (GH) response to pharmacological stimulation has been found in children and adolescents during an episode of major depressive disorder and after recovery. GH secretion is similarly altered in children and adolescents who had never experienced depression but were at high risk of developing depression 53 . These results suggest that the decreased GH response found in high-risk subjects may represent a trait marker for depression in children and adolescents. It is interesting to note that one of the candidate psychogenes identified by our work using convergent functional genomics 5 described below is insulin-like growth factor 1 (IGF1), a downstream effector in the GH pathway.
Extracellular Ca entry though VGCCs during AP firing contributes to the level of Ca2+ i in unstimulated cells. In GnRH-secreting neurons, each AP drives a transient increase in Ca2+ i, the magnitude of which is determined by the AP amplitude and duration (Fig. 9). In pituitary somatotrophs and lactotrophs, spontaneous AP activity and the associated Ca2+ i fluctuations contribute to basal growth hormone (GH) and prolactin release, respectively. In these and other cells, an increase in the AP frequency is followed by increases in the amplitude and duration of AP-driven Ca2+ i signals. This leads to the accumulation of Ca2+ i, which eventually reaches a new steady-state plateau level. The level of this plateau is proportional to the AP frequency. Both spontaneous AP firing and the associated Ca2+ i fluctuations are abolished in the absence of extracellular Ca2+ and by the addition of L-type calcium channel blockers. The spiking amplitude of spontaneous Ca2+ i fluctuations in cultured...
Sporadic cases of syndromes having multiple characteristics of premature (early-onset) or accelerated (rapid-progression) aging occur in humans (85,86). It is unclear how far any of these syndromes may be regarded as a genuine acceleration of timing mechanisms that determine senescence. They are apparently pleoitropic genetic defects, and when one of the major features is accelerated aging, they are designated as progeria. One such example is Wermer's Syndrome (WS). When accelerated aging is associated with other prevalent defects, such as mental retardation and short stature, they are called progeria-like or progeroid or segmental syndromes. One example is Down syndrome (85).
In the DBAR, 7 of families had more than one affected individual. Most of the familial cases displayed autosomal dominant pattern of inheritance. Somatic anomalies, excluding short stature, were found in 47 of patients. Of these, 50 were of the face and head (high-arched palate, cleft lip, hypertelorism and flat nasal bridge), 38 were upper limb and hand (flat thenar eminence, triphalangeal thumb), 39 genitourinary and 30 cardiac. Height was below the third centile for age in 30 .
Hormones, but the most important deficiency is growth hormone, because very similar effects are achieved by germline disruption in the growth hormone receptor (161). In turn, the most important consequence of growth hormone deficiency for life-span extension is the marked reduction in IGF-1 production (158). These mice also show a reduction in insulin levels (158). Moreover, cells from these animals are resistant to multiple exogenous stresses, although it is not known whether this stress resistance is due to reduced senescence or reduced apoptosis (162). Mice that are constitutively deficient in growth hormones and IGF-1 suffer from dwarfism, compromised fertility, and other problems (163). However, mouse models in which there is a more modest reduction in IGF-1 signaling, for example, mice in which only one copy of the IGF-1 receptor was genetically inactivated, are phenotypically normal yet long lived (164). In this case, however, life span extension was also modest (16-33 )....
Tory sequence of metallothionein was fused with the gene for growth hormone, expressed high levels of hormone m their blood when a diet containing cadmium chloride or zmc sulfate was given. The increased level of growth hormone in blood caused increase in their size to twice that of their normal littermates (9).
The deep lung has been investigated as a site for delivering large molecule proteins and peptides as it is believed that the morphology of the alveolar epithelium predisposes it to absorb large molecule compounds. The pulmonary route has been explored for the delivery of insulin and human growth hormone, and absorption was found to be greatest in those subjects with the highest penetration index, implying that deep central deposition is a prerequisite for absorption50 51. The pharmacokinetics of these materials, which have extremely short intravenous half-lives of 3 and 40 minutes respectively, were dominated by the slower limiting pulmonary absorption rate.
For example, companies with orphan drug protection sometimes charge very high prices, which may not be always appropriate. In situations where the medicine had a reasonably strong patent, such as with Retrovir (zidovudine), the orphan drug designation and exclusivity was not of consequence to the company, at least not for market protection. For drugs such as growth hormone, erythropoietin,
Growth is associated with an increasing capacity of the fetus to sustain prolonged episodes of breathing. Moreover, bouts of breathing become less fragmented. Parallel to this, the intervals between bouts also increase in duration long apneic intervals become a consistent feature of fetal breathing around mid-gestation. It is established that breathing movements are the first movements to disappear in compromised and growth-restricted fetuses, where energy and oxygen consumption have to be spared for more delicate areas 28 . A concomitant increase in blood flow to the brain, heart and adrenals is usually observed in such cases and is taken as a clinical indicator of fetal compromise 28 . The increased spacing between episodes of breathing could also acquire pathological significance in the premature infant and occasionally also in the neonate. In only too many ways a premature infant is a fetus born at an untimely age. Under particular circumstances the premature infant, but also the...
As m stable cell lines using various target genes encoding intracellular proteins, chloramphenicol acetyl transferase (CAT), tyrosine hydroxylase or a secretory protein, the human growth hormone (hGH) in response to RU486. In addition, this regulatory system has been validated in vivo via ex vivo transplantation of a stable cell line containing both the regulator and a reporter gene into rats The dosage of RU486 used is significantly lower than that required for antagonizing progesterone action. In this chapter, we demonstrate that the application of the inducible system in regulating the expression of therapeutic protein in mammalian cells using an intracellular protein (tyrosine hydroxylase) and a secretory protein (human growth hormone) as examples. In addition, we will also describe how to use tissue-specific promoters in directing the expression of the transactivator (regulator protein). The purpose of this chapter is to provide protocols that
J Colloid Interface Sci 72 81-97 Brash J, Horbett TA (1995) Proteins at Interfaces II Fundamentals and Applications. American Chemical Society, Washington DC, USA Britt DW, Buijs J, Hlady V (1998) Tobacco mosaic virus adsorption on self-assembled and Langmuir-Blodgett monolayers studied by TIRF and SFM. Thin Solid Films 329 824-828 Buijs J, Britt DW, Hlady V (1998) Human growth hormone adsorption kinetics and conformation on self-assembled monolayers. Langmuir 14 335-341 Burns TE, Dennison JR (1998) Physisorbed CO on ionic crystals an extended BEG spinlattice model of adsorbed dipolar molecules. Surf Sci 395 46-59 Burns TE, Dennison JR, Kite J (2004) Extended BEG model of monhalogenated methanes
Dietary supplements Human growth hormone Prevent PIH is conserved. After birth examination shows a baby with a large head relative to body size. There is soft tissue wasting, reduced muscle bulk and large hands and feet. IUGR newborns are at risk of both early and late complications. Initial problems are an increased risk of perinatal asphyxia, polycythemia, hypoglycemia and hypothermia. The late complications of short stature and fetal programming of adult-onset disease will be discussed later in this chapter.
Chronic renal disease may also affect metabolism, not necessarily because of impaired metabolism in the kidney, but because of an indirect effect of renal failure on liver metabolism. For example, in animals with renal failure it was observed that there was a decrease in hepatic cytochromes P-450 content, and consequently zoxazolamine paralysis time and ketamine narcosis time were prolonged. Cardiac failure may also affect metabolism by altering hepatic blood flow. However even after heart attack without hypotension or cardiac failure, metabolism may be affected. For example, the plasma clearance of lidocaine is reduced in this situation. Other diseases such as those which affect hormone levels hyper- or hypo-thyroidism, lack of or excess growth hormone, and diabetes can alter the metabolism of foreign compounds.
Both genetic and biochemical studies have shown that SHP-2 from vertebrates and its orthologs encoded by the corkscrew (csw) and ptp-2 genes from Dro-sophila and C. elegans, respectively, are required for signaling through multiple RTKs and cytokine receptors. SHP-2 has been shown to function downstream of receptors for epidermal growth factor (EGF), insulin, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and numerous cytokines such as IL-3, IL-2, IL-5, and growth hormone.
Many cases of mullerian anomalies present for the first time during adolescence with primary amenorrhea (Figs. 12.1-12.5). Fifteen percent of these women will have abnormal pelvic exams. Breast development, normal growth and pubarche in the presence of a blind-ending or absent vagina suggests either mullerian agenesis, transverse vaginal septum, or imperforate hymen. Lagging thelarche or pubarche in a young woman with tall stature and a blind-ending vagina may suggest androgen insensitivity syndrome.
The Epo receptor belongs to the cytokine receptor superfam-ily. Like other members of this family (growth hormone, prolactin and G-CSF), Epo was thought to induce dimerization of cell-surface receptors (EpoRs), triggering autophosphorylation and activation of the Janus family of protein tyrosine kinases (JAK2). More recent data suggest an alternative model in which unliganded EpoR dimers exist in a conformation that prevents activation of JAK2, but the receptor may undergo a ligand-induced conformational change that allows JAK2 to be activated. JAK2 and or other kinases then phosphorylate specific tyrosine residues in the EpoR, creating docking sites for the SH2 domains of several signal transduction proteins, which eventually results in the activation of at least three signal transduction pathways STAT5, Ras MAP kinase and PI3 kinase (Figures 2.7 and 2.8).
Martin and Tupper (1975) described the results of conservative management in 55 women with severe pre-eclampsia before 36weeks gestation. The patients were treated with bed rest, oral phen-tobarbital, diuretics, and antihypertensive agents. Parenteral MgSO4 was used if there was maternal hyperreflexia or if maternal blood pressure exceeded 170 over 110 mmHg. These authors reported that they could prolong such pregnancies for an average of 19.2 days. Their study was, however, complicated by three stillbirths and two neonatal deaths, resulting in a perinatal mortality of 8.9 . In addition, 56.6 of the neonates were severely growth restricted and 9 were asphyxiated.
Insulin resistance, a common finding with polycystic ovarian syndrome (PCOS). Other important features to note are a buffalo hump (Cushing's syndrome) short stature, webbed neck, and shield chest (Turner's syndrome). Finally, a complete pelvic examination is crucial during the initial visit and should include evaluation for Mullerian defects, pelvic or abdominal masses, or tenderness, cervical abnormalities, and nodularity in the cul-de-sac. One should consider performing a cervical culture as well due to the association of chlamydia cervicitis and PID.
Children with SCD are born with normal weight but fall behind other children by the end of the first year. The weight deficit persists through adulthood and imparts a thin habitus to the typical patient, although obesity is seen in some cases. The rate of growth is lower than normal in SCD patients, and the pubertal growth spurt is delayed by 1-2 years, but the final adult height is normal. Delays also occur in skeletal maturation and onset of puberty, and female patients achieve menarche 1-2 years later than their peers.
Release and secretion of calcitonin is mainly regulated by extracellular calcium concentration 89 . Other substances, such as pentagastrin, b-adrenergic agonists, growth hormone-releasing hormone and other gastrointestinal peptides 90-92 ,can stimulate cal-citonin release from C cells.
Currently, the hypothesis that the efficacy of androgen-targeting therapies can be improved by combining them with IGF targeting therapies is under investigation. Other possible IGF-related approaches include the use of suppressors of IGF-1 expression (including GHRH antagonists and somatostatin analogs), IGF receptor blocking or antisense strategies, growth hormone antagonists and the use of IGF binding protein protease inhibitors. Inducers of expression of IGF binding proteins, including vitamin D-related compounds and the enhancement of cytotoxic chemotherapy by coadmin-istration of agents that reduce IGF bioactivity, given the known antiapoptotic properties of IGF, are also under active investigation. This line of research has been stimulated by the results of preclinical studies and subsequent clinical trials that demonstrate enhanced efficacy of cytotoxic drugs in the presence of blockers of the HER2 receptor.58-60 Small molecule inducers of IGF binding protein expression and of...
In women with pre-eclampsia, the loss or reversal of EDF in the UA signals the need for daily surveillance by experienced clinicians working in units capable of managing preterm growth-restricted neonates. As such it is a seminal finding. Baschat, A.A. (2004). Doppler application in the delivery timing of the preterm growth-restricted fetus another step in the right direction. Ultrasound Obstet. Gynecol., 23, 111-18. Baschat, A. A., Gembruch, U., Weiner, C. P. and Harman, C. R. (2003). Qualitative venous Doppler waveform analysis improves prediction of critical perinatal outcomes in premature growth-restricted fetuses. Ultrasound Obstet. Gynecol., 22, 240-5. Ferrazzi, E., Bozzo, M., Rigano, S., et al. (2002). Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus. Ultrasound Obstet. Gynecol., 19, 140-6. Vergani, P., Roncaglia, N., Andreotti, C., et al. (2002). Prognostic value of uterine...
Chemiluminescent substrates have been successfully used for highly sensitive quantitation of reporter enzyme activity (see Chapters 5 and 6) and in enzyme-linked immunoassays for highly sensitive detection of many analytes (1-6). CSPD chemiluminescent 1,2-dioxetane substrate (7) for alkaline phosphatase has been used with Sapphire-II enhancing reagent for enzyme-linked immunoassay detection of chloramphenicol acetyltransferase and human growth hormone reporter gene products. These chemiluminescent reporter gene assay systems provide nonradioactive, simple, sensitive detection methods, performed in microplate or tube luminometers. The human growth hormone (hGH) reporter gene product offers the advantage of being a secreted protein, which permits detection m a sample of cell culture medium and allows cells to remain viable for further experimentation. It is a convenient control for normalizing expression of a second reporter gene. Quantitative assays for hGH have nearly exclusively been...
Shwachman and Bodian and their colleagues first reported this disease independently in 1964. It is now recognized as an autosomal recessive disorder characterized by exocrine pancreatic insufficiency (100 ), bone marrow dysfunction (100 ) and other somatic abnormalities (particularly involving the skeletal system). Signs of pancreatic insufficiency (malabsorption, failure to thrive) are apparent early in infancy (note that the pancreatic function can improve in a subset of Shwachman-Diamond syndrome (SDS) patients by 4 years of age). Other common somatic abnormalities include short stature ( 70 ), protuberant abdomen and an ichthyotic skin rash ( 60 ). Metaphyseal dysostosis is seen on radiographs in 75 of patients. Other abnormalities include hepatomegaly, rib thoracic cage abnormalities, hypertelorism, syndactyly, cleft palate, dental dysplasia, ptosis and skin pigmentation.
Imprecise, inaccurate and subject to significant operator variability. The need for large prospective clinical trials to properly evaluate current criteria used to define pre-eclampsia, and to identify subgroups at particular risk of severe sequelae, have been highlighted (Anonymous, 2000). In addition, internationally agreed upon diagnostic criteria for disease subsets, such as early-onset pre-eclampsia or those with a growth restricted fetus, need to be developed (von Dadelszen et al., 2003).
Female breast), and growth hormone (which triggers growth in children and metabolic changes in adults). When the thyroid gland is activated, hormones such as thyroxine and triiodothyronine are released to accelerate cellular metabolism, an event which may occur in certain situations such as stress or fight-or-flight encounters.
The metabolic adaptations of systemic inflammation, namely an acute phase response (as discussed above), oxidative stress, hyperlipidemia and insulin resistance, also occur during normal pregnancy. Markers of oxidative stress (Morris et al., 1998 Zusterzeel et al., 2000) are increased at least in the third trimester. In normal pregnancy insulin resistance develops early and persists until delivery (Stanley et al., 1998). To some extent this parallels the development of systemic inflammation during pregnancy outlined above. Hypertriglyceridemia, as occurs in systemic inflammation, also becomes detectable in the second trimester (Martin et al., 1999). The cause of the insulin resistance is undecided (Hornnes, 1985). Recently the list of potential placental factors has been enlarged by the inclusion of human placental growth hormone (Barbour et al., 2002) and the discovery that the adipokine resistin, which causes insulin resistance, is also expressed in the human placenta, particularly...
Like many neuroendocrine tumors, MTC tumors express somatostatin receptors 11 . Somatostatin is a neuropeptide that was discovered in 1978 12 and has been found to have an inhibitory effect on growth hormone receptors. In animals this peptide appears to inhibit the growth of various malignant tumors 13 .
Indicating that the uORF plays a role in the translational response to spermine. Similar experiments were performed with AdoMetDC 5' leader-luciferase constructs, and, in this case, removal of the uORF did not result in an increase in luciferase expression when spermine was depleted, suggesting that the 2.5-fold observed increase in AdoMetDC expression in the absence of the uORF resulted from stabilization of the enzyme rather than any effect on translation (22). Introduction of the uORF sequence into the 5' leader of the human growth hormone mRNA was sufficient to impart polyamine-regulated translation on this mRNA (30).
Pinocytosis (cell sipping) has been thought to be a nonspecific, nonsaturable, non-carrier-mediated form of membrane transport via vesicular uptake of bulk fluid into cells from the surrounding medium (22, 23). This mechanism is most relevant to large particles and polymer conjugates. The term pinocytosis has fallen from favor and one suspects that many events previously ascribed to nonspecific pinocytosis are now recognized as being due to specific receptor-mediated endocytosis. Endocytosis is specific and intrinsic to the mechanism of action of many macromolecular drugs. This process is also used to deliver small molecules as prodrugs, and mediates the distribution and clearance of many contemporary pharmacological agents, including many biotechnology products, most peptide hormones, and cytokines (e.g., insulin, growth hormone, erythropoetin, granulocyte colony-stimulating factor, and interleukins) (24).
Thyroid growth is induced by other stimuli, including - among others - thyrotropin (TSH), epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), prostaglandins, and growth hormone (GH) 32 , which are thought to have a growth-promoting effect in benign thyroid disease. It is not clear to date that these stimuli have an effect on the development of WDTC, with the notable exception of TSH, which is believed to be a bona fide growth stimulator for most WDTCs 32 .
Adrenarche is the result of adrenal androgen production (androstenedione, DHEA, and particularly DHEAS), which begins prior to changes in gonadotropin secretion at 6-8 years of age and continues through the mid-teens. During female puberty, growth in height occurs at a rate of 4-5 cm year in early puberty. As estrogen production increases, growth hormone increases, resulting in increased IGF-1 and IGFBP-3, which mediates skeletal growth. Maximal growth velocity occurs in girls at age 12 and usually results in about a 9 cm increase in height. Menarche (initiation of menses) occurs on the downward arm of the growth curve at a median age of 12.5 years (white 12.6 years black 12.15 years Mexican American 12.3 years). A variety of additional factors affect pubertal onset, such as weight, stress, and extreme physical activity. Some authors have noted a younger age of onset of breast development and possibly menarche in African-American girls that may be attributable to a greater BMI.
Coagulopathies and immunodeficiencies. It is also used in the assessment of fetal infection, the alloimmunized fetus and non-immune hydrops. Assessment of fetal wellbeing from blood acid-base parameters in the growth restricted fetus has no longer been found to be helpful.
The diagnosis and classification of obesity has come to focus on the evaluation of the body mass index, (BMI). BMI is a practical approach for assessing body fat in a clinical setting. The BMI provides a more accurate measurement of total body fat compared with assessment by weight alone. However, the BMI can be an overesti-mation of adiposity in persons of short stature or who are very muscular, and an underestimation in persons who have lost muscle mass. BMI disregards gender, age, and ethnicity, but these factors do not markedly influence the validity of BMI for classifying individuals into broad categories of overweight and obesity. Overweight is categorized by a BMI of 25-29.9 kg m2 and obesity as BMI 30 kg m2. The BMI can quickly be determined by using a BMI table or calculated by multiplying weight in lbs. by 703 and dividing by height in inches, squared, which gives a BMI as kg m2. There are two physical classifications of body fat distribution gynecoid and android. Gynecoid...
In the well-transfused child, early growth and development are normal and splenomegaly is minimal. However, without adequate iron chelation therapy, there is a gradual accumulation of iron and the effects of tissue siderosis start to appear by the end of the first decade. The adolescent growth spurt fails to occur and hepatic, endocrine and cardiac complications of iron overloading produce a variety of complications, including diabetes, hypoparathyroidism, adrenal insufficiency and progressive liver failure. Secondary sexual development is delayed, or does not occur at all. The short stature and lack of sexual development may lead to serious psychological problems. By far the commonest cause of death, which usually occurs towards the end of the second or early in the third decade, is progressive cardiac damage. Ultimately, these patients die either in protracted cardiac failure or suddenly due to an acute arrhythmia, often precipitated by infection.
2005), right-sided diaphragmatic hernia (Velasco et al. 1990), growth hormone deficiency and diabetes insipidus (Herniaz Driever et al. 1997), intestinal malrotation, cardiopulmonary anomalies, central nervous system anomalies (hydrocephalus, arrhin-encephaly, microphthalmia) (Schlesinger and Parker 2003), renal anomalies (Kroes and FesteN 1998), laryngo-tracheo-bronchial clefts (Ryan et al. 1991 Samuel et al. 1997), limb reduction defects (Cunniff et al. 1993), Pierre Robin sequence and partial trismus (Giurgea et al. 2000). Isolated congenital microgastria is extremely rare.
Adipose tissue is a metabolically active endocrine and paracrine organ, and hence more than just a repository for fat. Experimentation on this tissue would undoubtedly increase our understanding of the pre-eclampsia phenotype. Abdominal fat biopsied from women with normal pregnancy exhibits an increase in basal and hormone-stimulated rates of lipolysis in vitro compared to abdominal fat from non-pregnant women (Williams and Coltart, 1978). To date, however, there has been little study of adipose tissue of women with normal, pre-eclamptic, or fetal growth-restricted pregnancy. The role of novel lipid-regulatory factors such as peroxisome proliferator-activated receptors, resistin, and adiponectin in pregnancy adaptation and pathogenesis also await evaluation. Fascinating interactions between adipogenesis and angiogenesis have been noted (Fukumura et al., 2003). Circulating endothelial progenitor cells likely contribute to ongoing endothelial maintenance and repair in the adult...
Another hormone that greatly influences human behavior and development is human growth hormone (HGH). This hormone is produced by the anterior pituitary (adenohypophysis) gland under the control of the hypothalamus. HGH production peaks during adolescence, corresponding to the growth spurt. While it is produced throughout life, it declines with age in all species studied to date. In humans, HGH production tends to drop quickly beginning in the thirties so that by age sixty, HGH production is only about 25 percent of what it was earlier in life, and it continues to decline until death. The decrease in HGH production with age has been tied to thinning of skin and wrinkle formation, muscle wasting, sleep problems, cognitive and mood changes, decreased cardiac and kidney function, lessening of sexual performance, and weakening ofbones, contributing to osteoporosis. Nutritional supplements including the amino acids arginine, lysine, and glutamine are being investigated as growth hormone...
Recombinant human growth hormone (rhGH) has also been shown to increase the mechanical strength of granulation tissue in incisional skin wounds of rats up to 94 that of unwounded skin (Jorgensen and Oxlund, 1996). The increase was dose-dependent and was associated with a nearly 150 increase in the deposition rate of collagen in the wound. Local application of rhGH in subcutaneous wound chambers, or systemic administration of the hormone, stimulated the formation of granulation tissue (Steenfos and Jansson, 1992). Human growth hormone was reported to accelerate healing of donor skin sites in burned children (Herndon et al., 1990 Gilpin et al., 1994). The effects of rhGH may be both local and systemic. Growth hormone stimulates the production of IGF-I by the liver, elevating the serum level of IGF-I, which as a cell cycle competence factor would then stimulate fibroblast proliferation (Jorgensen and Oxlund, 1996). rhGF may also have a direct effect on fibroblast proliferation, since...
Down syndrome was first described by John Langdon Down in 1866, and although heredity was suspected in its etiology, it was not until 1959 that it was discovered that Down syndrome patients had one extra chromosome, for a total of forty-seven instead of the normal forty-six. Down syndrome occurs at a frequency of about one in one thousand births and is the single most prevalent cause of mental retardation. The great majority of Down syndrome patients have three chromosomes number 21 instead of two (a condition called trisomy 21). The physical features associated with Down syndrome are easily recognizable short stature, a short neck with excessive loose skin, thick lips, epicanthal folds of the eye, malformed ears, poor muscle tone, and a flattened facial profile. Major physical problems include heart and kidney defects, deafness, and gastrointestinal blockages. Developmental milestones are delayed, and mental retardation is common. Intelligence varies...
Other pituitary conditions that can present with hyperprolactinemia are acromegaly and Cushing's disease. Acromegaly is caused by a growth hormone secreting adenoma. About 30-40 of such adenomas cosecrete prolactin. This is not a surprise given the common embryologic origin of the somatotrophic cells (GH secreting cells) and the mammotrophic cells (PRL secreting cells) of the anterior pituitary. The associated hyperprolactinemia partially explains the hypogonadism observed in acromegalic patients. Cushing's disease, caused by an ACTH secreting pituitary adenoma, can also be associated with hyperprolactinemia. Although the association is infrequent, mixed adenomas secreting both ACTH as well as PRL have been reported.
25-OHD is converted in the proximal renal tubule to the active metabolite 1,25-dihydroxyvitamin D (calcitriol, 1,25-(OH)2D), which should be considered a hormone. The main stimuli for calcitriol synthesis are PTH, PTHrP and hypophosphataemia (directly) and hypocalcaemia (indirectly via PTH). Other factors including insulin-like growth factor I, oestrogens, prolactin, and growth hormone also have a stimulatory role and occasionally, abnormal levels of 1,25-(OH) 2D may be formed by macrophages invading patches of subcutaneous fat necrosis. Calcitriol production is inhibited by elevated levels of calcium and phosphorus. The principal actions of calcitriol are to stimulate calcium absorption from the intestine and to aid mineral deposition into bone. The latter requires alkaline phosphatase.
Marfan syndrome is an autosomal dominant disease caused by mutation of the gene located in chromosome 15 (15q21.1). The disease leads to skeletal abnormalities, including scoliosis, chest wall deformity, tall stature, and abnormal joint mobility. Ectopia lentis occurs in up to 80 of patients and almost always is bilateral. The leading cause ofpremature death is progressive dilation of the aortic root and ascending aorta causing aortic incompetence and dissection.
FIGURE 32.5 Simulated effects of increasing basal growth hormone (GH) concentrations on measured total GH concentrations at various times during and after an 8-minute infusion of rhGH using basal concentrations 10 times (A) and 100 times ( ) the observed preinfusion value of 0.042 ng mL. (Reproduced with permission from Bright GM et al. J Clin Endocrinol Metab 1999 84 3301-5.)
FIGURE 32.8 Hypothetical model of the effects of insulin-like growth factor-1 (IGF-1). Open arrows show regulating influences. Plasma IGF-1 consists of free and bound IGF-1. Insulin-like growth factor-binding protein-3 (IGFBP-3) exists in two forms, a 42-kDa complete form or a 31-kDa fragment. IGF-1 drives the reaction toward binding with the acid-labile subunit (ALS) to form a ternary complex, which is retained in the intravascular space. IFG-1 also suppresses growth hormone (GH) secretion, decreasing the synthesis of IGFBP-3. (Reproduced with permission from Blum WF et al. Acta Paediatr Suppl 1993 82(suppl 391) 15-9.)
The relationship between circulating protein concentrations following exogenous administration and pharmacodynamic endpoints, either for efficacy or for safety, has been explored for a number of molecules, such as growth hormone, IGF-1, recombinant Factor VIII, interleukins (IL-2, IL-12), and mABs (24). Several conclusions emerge from the currently published data these relationships are complex and not easily explained by a simple Emax model, the endpoints are not clear cut (except for those macromolecules intended to substitute for endogenous proteins that are deficient), and there is a high likelihood of regimen dependency.
Precocious puberty is defined as the onset of puberty before the age of 8 in girls and age 9 in boys. These ages are 2.5 standard deviations below the mean age of puberty in North American children. This disorder is five times more common in girls than boys. It is classified as either central (GnRH-dependent) or peripheral (GnRH-independent) depending on whether the inciting event has activated the H-P-G axis. In central precocious puberty (CPP), activation of the hypothalamic-pituitary axis occurs, leading to premature sexual development that typically follows the normal pattern of puberty except that it is early. In peripheral precocious puberty (PPP), steroid production is independent of activation of the central axis, as is the case in gonadal or adrenal tumors or McCune-Albright syndrome. Precocious puberty is often idiopathic, especially in girls, however, a work-up is indicated in order to rule out significant pathology. If left untreated, final adult height will be compromised...
In a sense, the pituitary hormones are involved in autonomic-type functions, but on a more prolonged time scale. For instance, thyroid hormone is catabolic growth hormone is anabolic FSH, LH, and oxytocin relate to sexual functioning, and antidiuretic hormone relates to blood pressure.
Glucagon infusion can cause hypokalaemia, vomiting, increased myocardial contractility, and increases growth hormone. Growth hormone For management of growth hormone deficiency associated with hypoglycaemia and to prevent growth failure (a paediatric endocrinologist should decide whether use is appropriate).
As well as the sex hormones already mentioned (see above) many other hormones seem to affect the metabolism of foreign compounds and therefore may have effects on toxicity. A number of pituitary hormones may directly, as well as indirectly, affect metabolism, for example growth hormone, follicle stimulating hormone, adrenocorticotrophic hormone, luteinizing hormone and prolactin. Thus, hypophysectomy in male rats results in a general decrease in metabolism, but the effects of some of the individual hormones may depend on the sex of the animal and the particular enzyme or metabolic pathway. For example, ACTH administration decreases oxidative metabolism in males but increases N-demethylation in female rats. Removal of the adrenal gland reduces metabolism, such as ethylmorphine demethylation and aniline 4-hydroxylation, and this can be partly restored by the administration of corticosteroids. However, there are probably many factors involved as well as the loss of a particular hormone....
Somatostatin is a cyclic 14-amino acid peptide that was initially found in the hypothalamus, which has an inhibiting effect on growth hormone secretion 45 . Receptors for somatostatin can be found in the brain, pituitary gland, gastrointestinal tract, endocrine and exocrine pancreas, and the thyroid 46, 47 . Somatostatin receptors have also been found in a large number of human tumors 48 . Unfortunately, somato-statin has a short plasma half-life, therefore analogs such as octreotide and DOTATOC have been developed. The structural formulas of somatostatin, oc-treotide, and DOTATOC are shown in Fig. 11.1.
For a long time, interest in biotechnology centered on the production and properties of administered hormones ranging from tripeptides, e.g. cortico-trophin releasing factor (CRF) through nonapep-tides, such as vasopressin analogues to longer polypeptide chains, e.g. insulins and growth hormones. As the length of the molecule increases, the three-dimensional structure becomes an important determinant of in vivo activity and properties. In addition to insulin, various other hormones made by recombinant methods have been approved or are under development. The most commonly prescribed examples at present include growth hormone (somatrem, Protropin , Genentech, Inc.) or erythropoietin (epoeitin a, Epogen Amgen Inc.).
There have been advances in the development of antibiotic therapy, but neonatal sepsis is still a major problem. PIH pregnancies often result in the delivery of premature infants with IUGR requiring respiratory support and intravenous therapy. These infants are at high risk of neonatal sepsis and despite appropriate antibiotic therapy many still die due to deficiencies in their immune system responses. It has been recognized for some time that neutropenia often occurs in infants born to mothers with PIH. This is usually transient, but may persist for a month. The degree of neutropenia is more profound in the more premature or growth-restricted infants, and especially so in mothers with significant hypertension or HELLP syndrome. The etiology in PIH is thought to be reduced neutrophil production due to intrauterine hypoxia, possibly compounded by release of a specific inhibitor. This is made worse in premature infants since they have functionally immature neutrophils with reduced...
Weight for gestational age distribution curves are very different when fetal weights are imputed from prenatal ultrasound data and are compared to birthweight for gestational age distribution curves for infants born in a similar population (Bernstein et al., 1994). Ultrasound estimates of fetal weights are valid, in that the 95 percent confidence intervals for individual estimates are +15 percent, errors are not systematic, and estimates of the mean population fetal weight in a large sample are accurate (Hadlock et al., 1984). Comparison of these curves demonstrates that at the lower gestational ages, infants delivered preterm as a group are much smaller than fetuses that remained in utero and delivered closer to fullterm. A change from the use of data generated from infants born at a given gestational age less than 36 weeks to the use of weight data estimated from prenatal ultrasounds at that gestational age increases the proportion of infants diagnosed at birth as being small for...
Several genetic diseases involve imprinted genes. The classic examples of diseases arising from imprinting are Prader-Willi and Angelman syndromes, which involve mutations on chromosome 15q11-q13. Prader-Willi syndrome (PWS OMIM 176270), which affects approx 1 in 10,000 to 1 in 15,000 newborns, is characterized by hypotonia, short stature, polyphagia, obesity, small hands and feet, hypogonadism, and mild mental retardation. Most cases of PWS are sporadic. In 70 of cases, a cytogenetically visible deletion of 15q11-q13 is present in the paternal chromosome in a region that includes the SNRPN gene, which is a candidate gene for this disease. Whether deletion of this gene alone is responsible for the disorder is presently uncertain. The maternal chromosome 15q is imprinted in this region, and therefore subjects with a deletion of this region of the paternal chromosome have no functional copy of the genes that are deleted.
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