bluuebunny/crossref_metadata_2025 huggingface dataset:
The Molecular Basis of Hypopituitarism
Authors: Radovick Sally , Cohen Laurie E. , Wondisford Fredric E.
Published: April 2003

Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. My laboratory and others have recently described several patients with combined pituitary hormone deficiency (CPHD) due to point mutations in the pit-1 gene. In addition to pit-1, other nuclear factors appear to be necessary for full expression of pituitary genes. A zinc finger transcription factor, Zn-15, is responsible with pit-1 for synergistic activation of the GH gene. The Prl gene is regulated synergistically by pit-1 and the estrogen receptor. Finally, the pit-1 gene itself is regulated by an enhancer element located >10 kb upstream of the transcriptional start. This element contains several pit-1 DNA binding sites and retinoic acid response elements (RAREs). On one of these elements, pit-1 and RAR interact functionally to mediate a synergistic response to RA. Recent data from our laboratory suggests that RA induction of the pit-1 gene can be impaired by pit-1 gene mutations. Study of pit-1 mutations and their diverse pathophysiological mechanisms should increase our understanding of anterior pituitary gland development and gene regulation in normal and disease states.
Growth Hormone Therapy in Patients with Turner Syndrome
Authors: Haeusler Gabriele
Published: April 2003

This article summarizes the published data on final height after growth-promoting therapy in Turner syndrome. Using growth hormone (GH) doses ranging between 0.5 and 1.2 IU/kg/week, final height after therapy is improved by 1.5–9.3 cm [final height after therapy vs. projected adult height (PAH)] within various studies. There is no obvious GH dose-response relationship, but a better estimated benefit from therapy seems to result in those studies that combined even rather low GH doses with the anabolic steroid oxandrolone. It is not possible to retrospectively define an optimal treatment regime out of the various published data due to different GH doses, age and dosage of estrogen replacement therapy and the variable methods for calculating the benefit from therapy. It seems to be essential to start estrogens at a safe bone age (> 13 years) in very low doses. Higher GH doses (up to 2.0 IU/kg/week) led to a better growth response during the first years of therapy but data on final height are still to be awaited.
Autonomic Neuropathy: Diagnosis and Impact on Health in Adolescents with Diabetes
Authors: Donaghue Kim C.
Published: April 2003

Symptomatic autonomic neuropathy and abnormal cardiovascular autonomic tests are associated with increased mortality due to vascular disease and increased risk of sudden deaths. Intensive therapy in the DCCT caused a significant risk reduction of developing autonomic nerve abnormalities at five years only in the Primary Prevention Group (4 vs. 9%). At the Royal Alexandra Hospital for Children, the prevalence of cardiovascular reflex abnormalities is 28%. Over 5 years, we have found no increase in the rate of single cardiovascular abnormalities and a low rate of persistence. Two or more abnormalities developed in 5%. Repeated measures of pupillary function showed a significant increase in abnormalities and a higher level of persistently abnormal tests. Spectral analysis and 24-hour BP monitoring may detect autonomic dysfunction at earlier stages but longitudinal studies are not yet available.
Macroangiopathy – Does It Play a Role in Young People?
Authors: Donaghue K.C. , Robinson J. , McCredie R. , Fung A. , Silink M. , Celermajer D.S.
Published: April 2003

Using a novel ultrasound method, brachial artery endothelial and smooth muscle physiology were studied in 20 adolescents with IDDM and in 20 nondiabetic subjects matched for age (13–22 years), gender and vessel size. Endothelium-dependent dilatation (EDD) was assessed in response to flow (EDD) and endothelium-independent vasodilatation after sublingual glyceryl trinitrate (GTN). Both EDD and GTN were reduced in those with IDDM compared with controls: 5 vs. 9%, (p = 0.0002) and 14 vs. 21% (p = 0.002). Abnormal EDD was found in 12 IDDM adolescents (diabetes duration 3.3–14.9 years). The mean urinary albumin excretion rate of the diabetic group with abnormal EDD was 5.76 ± 2.82 vs. 8.05 ± 4.88 µg/min in those with normal EDD (p = 0.25). In the diabetic adolescents there was no significant correlation observed between the test for early large vessel disease, HbA1c and tests for diabetic microangiopathy.
Approaches to Quality of Control in Diabetes Care
Authors: Chiarelli F. , Verrotti A. , di Ricco L. , de Martino M. , Morgese G.
Published: April 2003

Management methods for quality of diabetes care need new approaches because of the poor metabolic control of most of these patients. Poor quality of care generally results from poor instruction and training rather than from misbehaviour of both patients and their families. Structure quality of care (who and where?), process quality (how?, which are the goals, what resolution is taken and what advice for every-day life is given) and outcome quality (which measurements must be done for the evaluation of the progression of the disease and its control) must all be ameliorated and improved. Regional governments and communities should raise funds for the establishment of diabetes centers, giving recognition and economic support to diabetic children and their families and providing for educational programs on diabetic management and care. The educational aspect seems to be crucial for a good metabolic control not only for the practice of treatment (insulin dosage, home blood glucose monitoring, diet, insulin algorithms), but especially for the active involvement of patients and their families in the management of diabetes. It is also important to consider social and cultural differences among patients in order to arrange therapy according to the individual’s characteristics and needs.Improvement of quality of care in diabetic children and adolescents must be pursued; better glycemic control is, in fact, one of the major factors which can contribute to possibly reduce the frequency of macro- and microvascular diabetic complications in the coming years.
Structure Quality Management in Pediatric Diabetes Care
Authors: Borkenstein M.H. , Limbert Catarina , Reiterer Elke , Stalzer Christina , Zinggl E.
Published: April 2003

The aim of all diabetes treatment in childhood and adolescence is to counteract the development of complications (acute as well as late), to achieve normal growth and development, and to provide the patients with as good as possible a quality of life. Many studies have confirmed the benefits of intensified medical management regarding the prevalence and/or the progression of diabetic microvascular complications. Intensified medical management means of course much more than intensified insulin substitution; diabetes care includes diet, physical exercise, diabetes education, continuous monitoring, and psychosocial support. To improve the outcome of patients with diabetes mellitus, optimizing structure quality is one of the goals. A number of prerequisites (regarding the social-socioeconomic-health care system) are not yet fulfilled everywhere; structures necessary to provide qualified diabetes care (e.g. pediatric diabetes center, team of experts, outpatient care) are not yet sufficiently available in some areas. According to both the declarations of St. Vincent and of Kos, every effort should be made to enhance structure quality in an attempt to improve the situation and the outcome of our young patients with diabetes.
Improvements and New Potentials in Pharmacological Therapy of Diabetes mellitus in Children and Adolescents
Authors: Kiess Wieland , Kapellen Thomas , Siebler Thomas , Dost Axel , Deutscher Jens , Nietzschmann Ute
Published: April 2003

Subcutaneous insulin substitution is not physiological. Despite the many attempts using intensified insulin regimens to render current insulin substitution protocols more physiological, a nondiabetic circulating insulin profile cannot be simulated in patients with type 1 diabetes. Despite many efforts, the pharmacological treatment of type 1 diabetes consists of an unphysiological attempt to substitute only one of the hormones which are lost after beta-cell destruction, namely insulin. It is therefore mandatory to search for additional means to achieve physiological regulation of glucose homeostasis and overall metabolic status. Peptides which are being developed as additional new therapeutic compounds for type 1 diabetes include, for example, IGF-I, leptin, C-peptide and amylin. In addition, the application of insulin analogues has already been introduced into clinical practice. However, so far none of these pharmaceutical compounds has been shown to offer real clinical benefits and substantially improve metabolic control in patients with type 1 diabetes. The results of long-term clinical trials using the peptide compounds listed above for the treatment of type 1 diabetes are still not available.
Molecular Mechanism of Phenotypic Modulation of Smooth Muscle Cells
Authors: Sobue Kenji , Hayashi Ken’ichiro , Nishida Wataru
Published: April 2003

Phenotypic modulation of smooth muscle cells is closely associated with vasculogenesis, enterogenesis and some diseases such as atherosclerosis, hypertension and leiomyogenic tumorigenicity. During phenotypic modulation, smooth muscle cells change their morphology, cell function and biochemical characteristics. Recent studies have focused on the regulation mechanism of smooth muscle cell-specific genes at the levels of transcription and/or alternative splicing in a phenotype-dependent manner. Typical examples of such genes include caldesmon, α-tropomyosin, myosin heavy chain, SM22, calponin and α1 integrin. Cell adhesion molecules and growth factors/cytokines also play a critical role for controlling phenotype of smooth muscle cells via signal transduction pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinases.
International Standards for Growth Hormone
Authors: Bristow Adrian F.
Published: April 2003

Since 1955, with the establishment by the World Health Organization of the first International Standard (IS) for bovine growth hormone (GH) for bioassay, there have been a number of developments in the standardization of GH. Two GH ISs are in current use: the IS for human GH established in 1982 and the IS for somatropin (recombinant DNA-derived GH) established in 1994. The availability of two such standards does not encourage reproducibility of GH estimates between different laboratories. The author proposes that the international validation and adoption of the IS for somatropin, which has the advantage of an internationally agreed specific activity of 3 IU/mg, as the primary reference standard for all GH immunoassays would finally eliminate this source of variation in GH estimates.
What Clinicians Can Offer: Assessing and Communicating Probabilities for Individual Patient Decision Making
Authors: Timmermans Danielle R.M.
Published: April 2003

Accurate diagnostic and prognostic probabilities are important for physicians and their patients because of their impact on decisions. For individual patient decision making, physicians have to rely on their own judgement. Research has shown that physicians’ probability assessments are often not of high quality and that a variety of factors have a detrimental influence on their judgements. Using a formula or a model may produce superior assessments. Most treatment decisions involve uncertainty and value conflict in the sense that there is a trade off between the possible harms of alternative treatments and their benefits. The communication of diagnostic and prognostic probabilities to patients occurs largely in verbal terms, which can lead to ambiguity in communication. The precise words and context chosen for communication are very important and can have a major effect on patients’ decisions.
What Decision Analysis Can Offer the Clinical Decision Maker
Authors: Dowie Jack
Published: April 2003

Cognitive Continuum Theory can be used to explain why the relationship between research and practice is more problematic than is customarily assumed. The various possible sources of evidence for clinical decision making and the alternative approaches to such decision making can be located within the main modes of this continuum, each of which embodies a different balance of intuition and analysis. Decision analysis is the only technique that provides the analytical depth necessary to arrive at a decision that systematically identifies, structures and integrates all the relevant evidence on clinical parameters and patient preferences, within whatever mode that evidence is generated. The inappropriateness of using research criteria in action evaluations is pointed out. In order to illustrate the application of the Cognitive Continuum Theory and decision analysis to growth hormone (GH) therapy, and to stimulate discussion of this area, a primitive clinical decision analysis and prototype ‘clinical guidance tree’ for GH is presented here.
Endocrine and Non-Endocrine Activities of Growth Hormone Secretagogues in Humans
Authors: Ghigo Ezio , Arvat Emanuela , Broglio Fabio , Giordano Roberta , Gianotti Laura , Muccioli Giampiero , Papotti Mauro , Graziani Andrea , Bisi Gianni , Deghenghi Romano , Camanni Franco
Published: April 2003

Growth hormone (GH) secretagogues (GHS) are synthetic peptidyl and non-peptidyl molecules which possess strong, dose-dependent and reproducible GH releasing effects as well as significant prolactin (PRL) and adrenocorticotropic hormone (ACTH) releasing effects. The neuroendocrine activities of GHS are mediated by specific receptors mainly present at the pituitary and hypothalamic level but also elsewhere in the central nervous system. GHS release GH via actions at the pituitary and (mainly) the hypothalamic level, probably acting on GH releasing hormone (GHRH) secreting neurons and/or as functional somatostatin antagonists. GHS release more GH than GHRH and the coadministration of these peptides has a synergistic effect but these effects need the integrity of the hypothalamo-pituitary unit. The GH releasing effect of GHS is generally gender-independent and undergoes marked age-related variations reflecting age-related changes in the neural control of anterior pituitary function. The PRL releasing activity of GHS probably comes from direct pituitary action, which indeed is slight and independent of both age and gender. The acute stimulatory effect of GHS on ACTH/cortisol secretion is similar to that of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP). In physiological conditions, the ACTH releasing activity of GHS is mediated by central mechanisms, at least partially, independent of both CRH and AVP but probably involving GABAergic mechanisms. The ACTH releasing activity of GHS is gender-independent and undergoes peculiar age-related variations showing a trend towards increase in ageing. GHS possess specific receptors also at the peripheral levels in endocrine and non-endocrine human tissues. Cardiac receptors are specific for peptidyl GHS and probably mediate GH-independent cardiotropic activities both in animals and in humans.
Gonadotropin Releasing Hormone Agonist Treatment for Central Precocious Puberty
Authors: Carel Jean-Claude , Chaussain Jean-Louis
Published: April 2003

Several methodological problems complicate the evaluation of final statural height (FH) benefit after treatment with gonadotropin releasing hormone (GnRH) agonists for central precocious puberty (CPP). Since no controlled study has been performed, we have to rely on indirect methods, comparison with predicted height or with historical controls. FH of 58 girls, uniformly treated with triptorelin slow release formulation (triptorelin-SR, Decapeptyl®) for CPP were compared with predicted height before treatment and with FH of an historical group of patients not treated with GnRH agonist. The comparison with predicted height revealed an improvement of 4.8 ± 5.8 cm; comparison with the historical control group showed a mean improvement of 8.3 cm. The post-treatment growth spurt (ΔFH – height at the end of treatment) was a strong predictor of FH in multivariate analysis. The data suggest that continuing treatment beyond the age of 11 in girls does not improve and could actually decrease FH.
Dosing of Growth Hormone in Growth Hormone Deficiency
Authors: Ranke Michael B. , Schweizer Roland , Wollmann Hartmut A. , Schwarze Phillip
Published: April 2003

Growth hormone (GH) treatment of GH-deficient (GHD) children is to a certain extent standardized worldwide. Recombinant 22 kDa GH is injected once daily by the subcutaneous route, mostly in the evening. The amount of GH injected (calculated per kg body weight or body surface area, expressed in terms of IU or mg) in prepubertal children mimics the known production rate (approximately 0.02 mg [0.06 IU]/kg body weight per day). However, there is a wide variation in dosage, the reasons for which are partly unknown and partly due to national traditions and regimes imposed by authorities regulating reimbursement. The situation during puberty is less standardized, with most clinicians still not increasing the dosage according to known production rates. The results of these approaches in terms of adult height outcome are not always satisfactory. In order to achieve optimal height development during childhood, puberty and adulthood, strategies must be developed to individualize GH dosing according to set therapeutical goals taking into account efficacy, safety and cost. The implementation of prediction algorithms will help us to reach these goals. In addition, other response variables will have to be monitored during treatment in order to correct for deficits resulting from GHD.
The Diagnosis and Differential Diagnosis of Cushing’s Syndrome1
Authors: Newell-Price John , Jørgensen J.O.L. , Grossman Ashley
Published: April 2003

Cushing’s syndrome is defined as the symptoms and signs of glucocorticoid excess, but the precise diagnosis may be difficult to establish and harder to localise. The clinicial, biochemical and imaging features of the syndrome are discussed in the light of our own extensive experience and the published literature. We describe the optimal diagnostic routines currently recommended in major centres, and analyse the sensitivities and specialities of the various tests employed. Only by means of establishing a precise diagnosis can the disorder be successfully treated.
Compliance with Growth Hormone Treatment – Is It a Problem?
Authors: Hindmarsh P.C. , Brook C.G.D.
Published: April 2003

Treatments fail for a number of reasons. These include the failure of medicines at a molecular level, failure to achieve the correct diagnosis and therefore use of the correct medication, problems surrounding the doctor-patient relationship, and failure of the service to meet patients’ expectations. Compliance is characteristically viewed as the major cause of treatment failures but implicit in the use of the term compliance is the reliance on an imbalance of power where the patient follows what is ordered. Such an approach is likely to lead to failure. A better model is concerned with promoting the full participation of the patient to generate a therapeutic alliance. Despite the need for parental administration and a daily therapeutic regimen there appears to be little evidence to suggest that concordance is a major problem in growth hormone therapy. This is probably because treatment administration relies on the presence of a carer and there are tangible effects. However, concordance is likely to be an issue where there is mismatch between the patient’s expectations and those of the doctor. Such a situation may arise when the therapeutic margin is narrow or the therapeutic effect minimal. To resolve this situation, adequate pre-intervention discussion is essential, which should include a clear statement of short- and long-term treatment targets and the likelihood of these being achieved or not. Carefully constructed health care plans are the key and should include educational programmes, home support and regular reinforcement. When concordance problems are suspected, careful consideration needs to be given as to whether the diagnosis is correct, is the treatment really effective and appropriate and does the patient really want the treatment.
Determination of Insulin-Like Growth Factor-I in the Monitoring of Growth Hormone Treatment with Respect to Efficacy of Treatment and Side Effects: Should Potential Risks of Cardiovascular Disease and Cancer Be Considered?
Authors: Juul Anders
Published: April 2003

Insulin-like growth factor (IGF)-I has proven to be important in the diagnosis of childhood-onset growth hormone (GH) deficiency (GHD). However, the variability of IGF-I should be taken into account before it can be used in a clinical setting. GH replacement therapy in GHD patients increases IGF-I into the normal range, although there is a large variation. Excessively high (supranormal) GH-induced IGF-I levels are associated with increased prevalence of side effects in adults with GHD. Consequently, at most centres, GH doses are titrated according to IGF-I levels in GHD adults. Whether or not this should also be done in children has not been established. Due to the known variability of IGF-I, individual changes in IGF-I must exceed approximately 35% to be sufficiently significant to warrant a dose adjustment. Novel epidemiological studies have suggested that higher IGF-I levels are associated with an increased risk of prostate, breast and colorectal cancer compared with lower IGF-I levels in otherwise healthy subjects. Consequently, life-time exposure to IGF-I should be considered in all patients treated with GH, and IGF-I should preferably be kept within normal age-related ranges in children as well as in adults.
Growth Response to Recombinant Human Growth Hormone (GH) in Children with Idiopathic Growth Retardation by Level of Maximum GH Peak during GH Stimulation Tests
Authors: van den Broeck Jan , Arends Nicolette , Hokken-Koelega Anita
Published: April 2003

Due to their lack of reproducibility, it is unlikely that GH stimulation tests can provide reliable diagnostic information to distinguish partial isolated GH deficiency (GHD) from idiopathic short stature (ISS). We hypothesized that the classical distinction between these groups, essentially based on stimulatory GH peaks, is artificial and that, as a consequence, the average response to GH treatment will not be different between them. The hypothesized lack of prognostic validity of stimulatory GH peaks was studied in 435 prepubertal children with nonorganic growth retardation. Children were categorized as ‘severe GHD’, ‘partial GHD’ or ‘ISS’, if the maximum rise in their serum GH during two GH stimulation tests was 0– 10 mU/l, 10–20 mU/l, or >20 mU/l, respectively. Children with ‘partial GHD’ had short-term (1- and 2-year) and long-term (till final adult height) growth responses similar to those of children with ISS, significantly lower than the response seen in children with ‘severe GHD’. In children with stimulatory GH peaks >10 mU/l, including those currently considered partially GH deficient, the maximum GH peak was not a significant determinant of growth response in the short or the long term. In conclusion, ‘partial GHD’ is ill defined and cannot be distinguished from ISS based on the currently applied auxological or GH stimulation test criteria alone. More research is required for better identification of (all) children who will respond to GH treatment, whether or not GH deficient.
Growth Hormone and Growth Factors during Perinatal Life
Authors: Wollmann Hartmut A.
Published: April 2003

Pituitary growth hormone (GH) is present in early pregnancy in the fetal circulation. The concentrations are higher than ever found during life, due to an unrestrained, basal secretion. GH receptors develop around midpregnancy, when they are present in low concentrations, and there is a rapid increase during the first months of life. The function of fetal GH – characterized by a nearly complete GH resistance – is largely unclear: there is only a small effect on longitudinal growth, and the regulation of growth factors is independent of GH. Possibly, metabolic effects of GH on fat and glucose metabolism and body composition are of greater importance. During the first months of life, the rapid fetal (GH-independent, nutrition-dependent) growth decelerates, a process that is partly compensated by the onset of GH-dependent longitudinal growth.
Long-Term Results with Growth Hormone Therapy in Idiopathic Hypopituitarism
Authors: Bernasconi Sergio , Arrigo Teresa , Wasniewsk Malgorzata , Ghizzoni Lucia , Ruggeri Caterina , Di Pasquale Giuseppe , Vottero Alessandra , De Luca Filippo
Published: April 2003

More than 30 years after its introduction, growth hormone (GH) treatment is well established in children with GH deficiency. Nevertheless, the long-term results of this therapy, expressed as height, are generally considered unsatisfactory. We report on results obtained in a group of GH-deficient children who were treated with daily injections of recombinant GH within the first 5 years of life and who reached an adult height very close to their target height. The full catch-up growth to the target height demonstrated in these patients suggests that replacement therapy should be started early and continued until adulthood. Height at onset of puberty is an important variable which might significantly influence the adult height. The significant and prolonged influence of birth weight on growth response to GH therapy underlines the important role of fetal growth in planning early treatment of GH-deficient children.
Growth Hormone and Adipocyte Function in Obesity
Authors: Nam Su Youn , Marcus Claude
Published: April 2003

In obesity, growth hormone (GH) secretion is impaired which is considered a consequence rather than a cause of obesity. GH regulates the expression of GH receptor and the synthesis of insulin-like growth factor I (IGF-I) in adipocytes. Although GH hyposecretion in obesity may decrease the generation of IGF-I in each adipocyte, increased amounts of IGF-I and GH-binding protein could be secreted from the excessively enlarged amounts of adipose tissue. This may contribute to the normal/high serum-IGF-I and high GH-binding protein levels in obesity. Hyperinsulinemia and increased GH receptor activity may also affect the GH-IGF-I axis. Favorable effects of GH treatment have been observed in obese children and adults. GH treatment decreases adiposity, reduces triglyceride accumulation by inhibiting lipoprotein lipase and enhances lipolysis both via increased hormone-sensitive lipase activity and via induction of beta adrenoreceptors. GH treatment also has a favorable effect on obesity-associated dyslipidemia, but the effects on insulin sensitivity have been conflicting.
Serum Leptin in Short Children Born Small for Gestational Age: Dose-Dependent Effect of Growth Hormone Treatment
Authors: Boguszewski Margaret C.S. , de Zegher Francis , Albertsson-Wikland Kerstin
Published: April 2003

Objective: To study the effects of different regimens of growth hormone (GH) treatment on serum leptin levels in 78 short prepubertal children born small for gestational age (SGA). Methods: The children were originally included in two independent multicenter trials, one in Belgium and one in the Nordic countries. SGA children were randomized either to remain untreated or to be treated with GH at a daily dose of 0.1, 0.2 or 0.3 IU/kg for 2 years. Thereafter, treatment was continued for another 2 years in the Nordic children, whereas it was discontinued in the Belgian children. Results: In the GH treatment groups, a significant dose-dependent decrease in leptin levels was found during the first year of therapy, with a mean decrease of 13, 23 and 32% in the groups receiving GH at 0.1, 0.2 and 0.3 IU/kg, respectively. When high-dose treatment was interrupted, serum leptin increased within 1 year to pretreatment levels. Conclusion: Serum leptin levels in short children born SGA are transiently reduced by GH treatment in a dose-dependent fashion. The most pronounced changes in serum leptin were documented within the first year after initiation and withdrawal of high-dose GH treatment.
Progressive Deceleration in Growth as an Early Sign of Delayed Puberty in Boys
Authors: Du Caju M.V.L. , Op De Beeck L. , Sys S.U. , Hagendorens M.M. , Rooman R.P.A.
Published: April 2003

Objective: To describe the prepubertal growth pattern in boys with delayed puberty. Methods: Growth curves for height and height velocity covering the age range 4–14 years were constructed on the basis of retrospectively obtained data in 85 boys with delayed puberty, who attained a normal final height. Results: Between the age of 4 and 14 years the height in this cohort progressively deviated from the normal reference. At the age of 4 years, the height SDS was already significantly lower (median –0.8; p < 0.001) and progressively diminished during childhood, resulting in a median height SDS of –1.1 at the age of 12 years (p < 0.001). The median final height of this cohort (–0.4) was not different from their target height (–0.2). The degree of deceleration in growth during childhood was not determined by birth weight or birth height and did not influence final height. The decline of the height velocity with age in this group of boys with delayed puberty was significantly smaller (p < 0.001) than predicted by the model of Rikken and Wit. Conclusion: Late-maturing boys often show a prepubertal deceleration in growth that starts at an early age but that does not affect final height.
Effects of 22K or 20K Human Growth Hormone on Lipolysis, Leptin Production in Adipocytes in the Presence and Absence of Human Growth Hormone Binding Protein
Authors: Asada N. , Takahashi Y. , Honjo M.
Published: April 2003

Objective and Method: We studied the effects of human growth hormone (hGH) on leptin production and lipolysis stimulation in the presence or absence of human growth hormone binding protein (hGHBP) using 3T3- L1-hGHR adipocytes which efficiently express human growth hormone receptor. Results and Conclusion: It was clarified that (1) hGH decreases leptin secretion after hGH-induced lipolysis stimulation, and (2) the reduction of leptin production and lipolysis stimulation by 22K hGH was attenuated with hGHBP, whereas that by 20K hGH, which is a naturally occurring isoform of 22K hGH, was not affected with hGHBP.
Human Skin: An Independent Peripheral Endocrine Organ
Authors: Zouboulis Christos C.
Published: April 2003

The historical picture of the endocrine system as a set of discrete hormone-producing organs has been substituted by organs regarded as organized communities in which the cells emit, receive and coordinate molecular signals from established endocrine organs, other distant sources, their neighbors, and themselves. In this wide sense, the human skin and its tissues are targets as well as producers of hormones. Although the role of hormones in the development of human skin and its capacity to produce and release hormones are well established, little attention has been drawn to the ability of human skin to fulfil the requirements of a classic endocrine organ. Indeed, human skin cells produce insulin-like growth factors and -binding proteins, propiomelanocortin derivatives, catecholamines, steroid hormones and vitamin D from cholesterol, retinoids from diet carotenoids, and eicosanoids from fatty acids. Hormones exert their biological effects on the skin through interaction with high-affinity receptors, such as receptors for peptide hormones, neurotransmitters, steroid hormones and thyroid hormones. In addition, the human skin is able to metabolize hormones and to activate and inactivate them. These steps are overtaken in most cases by different skin cell populations in a coordinated way indicating the endocrine autonomy of the skin. Characteristic examples are the metabolic pathways of the corticotropin-releasing hormone/propiomelanocortin axis, steroidogenesis, vitamin D, and retinoids. Hormones exhibit a wide range of biological activities on the skin, with major effects caused by growth hormone/insulin-like growth factor-1, neuropeptides, sex steroids, glucocorticoids, retinoids, vitamin D, peroxisome proliferator-activated receptor ligands, and eicosanoids. At last, human skin produces hormones which are released in the circulation and are important for functions of the entire organism, such as sex hormones, especially in aged individuals, and insulin-like growth factor-binding proteins. Therefore, the human skin fulfils all requirements for being the largest, independent peripheral endocrine organ.
Nuclear Hormone Receptors and Mouse Skin Homeostasis: Implication of PPARβ
Authors: Michalik Liliane , Desvergne Béatrice , Basu-Modak Sharmila , Soon Tan Nguan , Wahli Walter
Published: April 2003

PPARβ is expressed in the mouse epidermis during fetal development, and progressively disappears from the interfollicular epidermis after birth. Interestingly, its expression is strongly reactivated in the adult epidermis in conditions where keratinocyte proliferation is induced and during wound healing. Data obtained on PPARβ heterozygous mice reveal that PPARβ is implicated in the control of keratinocyte proliferation and is necessary for rapid healing of a skin wound.
Association of Insulin Resistance with Hyperandrogenia in Women
Authors: Pugeat Michel , Ducluzeau Pierre Henri , Mallion-Donadieu Marika
Published: April 2003

In humans, the skin is a target tissue for androgen action; hair growth and sebum secretion are under active androgen control. An increased production or metabolism of testosterone, the main active androgen, shows up clinically in dermatological symptoms such as hirsutism, hyperseborrheic acne and alopecia. Polycystic ovary syndrome (PCOS) is the most frequent androgen disorder of ovarian function. PCOS patients have amenorrhea or severe oligomenorrhea, increased testosterone levels and most often enlarged polycystic ovaries on ultrasound examination. In addition, many PCOS patients have a tendency to accumulate abdominal fat and/or to develop obesity. Some also display a particular metabolic pattern including an atherogenic lipid profile, glucose intolerance and an increased fasting insulin level, which is known to be closely linked with an insulin resistant state. Several studies have now reported that PCOS patients show increased incidence of type 2 diabetes and cardiovascular disease. In addition to being a target for androgens the skin has abundant insulin receptors on the keratinocyte surface membrane and acanthosis nigricans is a common symptom of severe insulin resistance among patients with insulin receptor disorders. However, acanthosis nigricans could also be present in PCOS women given evidence of the intensity of their insulin resistance. This presentation will review the mutual relationship between hyperandrogenia and insulin resistance, with particular attention paid to: (1) insulin secretion and insulin sensitivity in PCOS; (2) the complexity of the molecular mechanisms involved in insulin resistance; (3) the paradoxical relationship between insulin resistance and hyperandrogenia; (4) the current genetic studies; and (5) new avenues for long-term treatment of PCOS women.
The Molecular Basis of Androgen Insensitivity
Authors: Nitsche Esther M. , Hiort Olaf
Published: April 2003

Androgen action is mediated in the peripheral target cell via the androgen receptor (AR). The AR is a nuclear transcription factor, combining a DNA-binding and a hormone-binding domain with a large transactivation unit. Androgen insensitivity syndrome (AIS) as the clinical entity of defective androgen action with variable phenotypes in 46,XY patients is caused by mutations of the X-chromosomal AR gene. Most variations in the AR gene are point mutations inhibiting either hormone or DNA binding. However, even within the same family, the phenotype for a given mutation can vary widely. Only few influential factors have been identified for the phenotypic diversity. For mutations affecting hormone binding, ligand concentration variability during fetal life may be an important influence on residual androgen action. A second factor is the occurrence of postzygotic de novo mutations, which are present at a high rate in single-case families. These somatic mutations lead to expression of both mutant and wild-type AR in a single patient and thus allow androgen action despite a deleterious mutation of the AR gene. Third, residual androgen response may be mediated by additional transcripts of the AR gene which are present in several cell types and can be affected in a different pattern by splice-site mutations. Whether differential expression of AR-interacting proteins has an influence on phenotype has not yet been proven. Moreover, little is known about the regulation of AR-dependent genes. Their identification is needed to understand post-AR action and, hence, androgenic control of sexual differentiation and maturation.
Maturity-Onset Diabetes of the Young (MODY): Genetic and Clinical Characteristics
Authors: Velho Gilberto , Robert Jean-Jacques
Published: April 2003

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of familial diabetes mellitus characterized by early onset, autosomal dominant inheritance and primary defects of insulin secretion. Mutations in six genes cause most of the MODY cases. These genes encode the enzyme glucokinase and the transcription factors hepatocyte nuclear factor 4α, hepatocyte nuclear factor 1α, insulin promoter factor-1, hepatocyte nuclear factor 1β and neuroD1. Additional MODY genes remain to be identified. The study of families with MODY has shown that the different MODY subtypes present different metabolic and clinical profiles.
Self-Efficacy and Diabetes: Why Is Emotional ‘Education’ Important and How Can It Be Achieved?
Authors: Howells Lesley A.L.
Published: April 2003

Adequate age-appropriate diabetes knowledge and skills are essential to the success of diabetes self- and parental care. Health professionals have a central role in providing diabetes education. A direct link between diabetes knowledge and diabetes regimen behaviour cannot be assumed. Health professionals have to help children and their parents to develop the emotional concept of ‘self-efficacy for diabetes self-care’, to ensure optimal diabetes control.
How Can We Adapt Education for Children across Different Countries?
Authors: Povlsen Lene
Published: April 2003

The development of educational material as part of major changes in the service of the diabetic clinic in Glostrup University Hospital turned out to be a very rewarding process for the multidisciplinary team. This material includes age-appropriate goals and guidelines for teaching and learning about diabetes, and advice on coping with diabetes in hand-outs designed for diabetic educators, parents/adults and teenagers. The paper briefly describes the developmental process, the concepts and designs of the material, and makes recommendations on how it can be applied. Part of the material was later translated into Polish and Russian in connection with educational projects in these countries, and the material as a whole was recently incorporated into the Novo Care website at www.d4pro.com – Childhood Diabetes [1]. Growing Internet access by diabetes patients, their relatives and health care professionals creates almost overwhelming possibilities, but also brings up many new questions. The development of diabetes educational material of the more ‘traditional’ type is discussed with regard to content, ideas and design, and focuses on how these concepts and projects can be influenced and adapted across different countries by Internet communication.
Recurrent Diabetic Ketoacidosis: Causes, Prevention and Management
Authors: Skinner T. Chas
Published: April 2003

Longitudinal studies indicate that 20% of paediatric patients account for 80% of all admissions for diabetic ketoacidosis (DKA). The frequency of DKA peaks during adolescence and, although individuals generally go into remission, they may continue to have bouts of recurrent DKA in adulthood. The evidence for insulin omission being the behavioural precursor to recurrent DKA is reviewed and discussed. Thereafter the range of possible psychosocial causes is explored and the evidence for each discussed. Approaches to assessing the individual and their family to identify aetiology and therefore appropriate intervention are considered and treatment options reviewed. Finally, the paper examines potential risk factors for recurrent DKA, possible strategies for identifying these early and how to use these assessments to prevent subsequent recurrent DKA.
Coeliac Disease in Children and Adolescents with Type 1 Diabetes mellitus: To Screen or Not, to Treat or Not?
Authors: Schober Edith , Rami Birgit , Granditsch Gerhard , Crone Julia
Published: April 2003

Coeliac disease is more prevalent in individuals with type 1 diabetes mellitus than in the normal population. It often presents in an atypical or silent form. Specific autoantibodies are found in almost all cases. Untreated coeliac disease may be associated with long-term health risks, so screening and early treatment with a gluten-free diet seem to be justified. However, extended follow-up is needed to document the clinical benefits of screening and treatment in diabetic patients.
Findings from the Hvidøre Study Group on Childhood Diabetes: Metabolic Control and Quality of Life1
Authors: Mortensen Henrik B.
Published: April 2003

The study involved 2,101 adolescents, aged 10–18 years, from 21 centres in 17 countries in Europe, Japan and North America. Adolescent quality of life (QOL) was assessed by a previously developed Diabetes Quality of Life Questionnaire for adolescents (DQOL), measuring impact of diabetes, worries about diabetes, satisfaction with life and health perception. Parents and health professionals assessed ‘family burden’ using newly constructed questionnaires. Mean HbA1c was 8.7% (range 4.8–17.4%). Lower HbA1c was associated with lower impact (p < 0.0001), fewer worries (p < 0.05), greater satisfaction (p < 0.0001) and better health perception (p < 0.0001) for adolescents. Girls showed increased worries (p < 0.01), less satisfaction and poorer health perception (p < 0.01) earlier than boys. Parent and health professional perceptions of burden decreased with age of adolescent (p < 0.0001). Lower HbA1c was significantly associated with better adolescent-rated QOL on all four subscales and with lower perceived family burden as assessed by parents and health professionals.
Comparison of Multivariate Tests for Genetic Linkage
Authors: Amos Christopher I. , de Andrade Mariza , Zhu Dakai K.
Published: April 2003

Objectives: Multivariate tests for linkage can provide improved power over univariate tests but the type I error rates and comparative power of commonly used methods have not previously been compared. Here we studied the behavior of bivariate formulations of the variance component (VC) and Haseman-Elston (H-E) approaches. Methods: We compared through simulation studies the bivariate H-E test with the unconstrained bivariate VC approach and with a VC approach in which the major-gene correlation is constrained to ±1. We also compared these methods to univariate methods. Results: Bivariate approaches are more powerful than univariate analyses unless the traits are very highly positively correlated. The power of the bivariate H-E test was less than the VC procedures. The constrained test was often less powerful than the unconstrained test. The empirical distributions of the bivariate H-E test and the unconstrained bivariate VC test conformed with asymptotic distributions for samples of 100 or more sibships of size 4. Conclusions: The unconstrained VC test is valuable for testing for preliminary linkages using multivariate phenotypes. The bivariate H-E test was less powerful than the bivariate VC tests.
Correlation between Molecular and Conventional Genealogies in Aicuña: A Rural Population from Northwestern Argentina
Authors: Bailliet Graciela , Castilla Eduardo E. , Adams Julian P. , Orioli Iêda M. , Martínez-Marignac Verónica L. , Richard Silvina M. , Bianchi Néstor O.
Published: April 2003

Aicuña is a village in the northwest of Argentina, located about 300 km south of La Rioja city, in the province of La Rioja. The population of Aicuña derives from a founder couple established in the uninhabited Aicuña valley in the early years of the 17th century. Due to land ownership litigation, the descendants maintained a well-documented genealogy that extends for 12 generations, comprising more than 8,000 individuals. From the historical pedigree of Aicuña, we selected 14 males with direct patrilineal descent from the 2 most ancient male founders, and 23 donors (9 females and 14 males) with direct matrilineal descent from the most ancient female founder. All 3 founders lived in the 17th century. We collected DNA from buccal swabs and characterized the mitochondrial DNA (mtDNA) and Y haplotypes using 14 Y-specific markers, 11 mtDNA polymorphic markers and sequencing of the mt hypervariable regions 1 and 2. We found four different Y haplotypes: Y1 and Y2 haplotypes of European origin corresponding to the founder ancestors Francisco Páez de Espinoza and Apolinario Ormeño, which were shared by 6 and 3 donors, respectively. Three males selected as Ormeño patrilineal descendants showed a different Y haplotype (Y3), probably originated by erroneous paternity registration due to illegitimacy. The remaining case (haplotype Y4), also assumed to belong to the Ormeño lineage, was probably also due to an erroneously registered paternity. Twenty-two donors showed an association of mtDNA markers corresponding to the Amerindian haplotype A2. The founder of this matrilineage could be traced back for more than 14 generations. The haplotype B of one remaining female did not correspond with the historical pedigree and could be due to an error in the genealogy registration. Our results showed an 85% agreement between conventional and molecular genealogies, with mtDNA markers being Amerindian, and Y markers being European. The methodology used in this report is a tool which could potentially be employed as a precedent for land ownership by Aicuña villagers and Amerindian populations.
The Complexity of Linkage Analysis with Neural Networks
Authors: Marinov Marin , Weeks Daniel E.
Published: April 2003

As the focus of genome-wide scans for disease loci have shifted from simple Mendelian traits to genetically complex traits, researchers have begun to consider new alternative ways to detect linkage that will consider more than the marginal effects of a single disease locus at a time. One interesting new method is to train a neural network on a genome-wide data set in order to search for the best non-linear relationship between identity-by-descent sharing among affected siblings at markers and their disease status. We investigate here the repeatability of the neural network results from run to run, and show that the results obtained by multiple runs of the neural network method may differ quite a bit. This is most likely due to the fact that training a neural network involves minimizing an error function with a multitude of local minima.