bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosis and Management of Intrauterine Growth Retardation
Authors: Lepercq J. , Mahieu-Caputo D.
Published: April 2003

Intrauterine growth retardation (IUGR) is associated with significant perinatal morbidity and mortality. This condition can be a sign of genetic disorders, fetal infection, uteroplacental insufficiency, or constitutionally small fetuses. Correct determination of gestational age is the first step in prenatal screening of growth-retarded fetuses. The discovery of a small-for-gestational age fetus necessitates fetal assessment for the evaluation of the etiology and prognosis, and for the determination of the optimal timing for delivery of these fetuses at risk of perinatal asphyxia. IUGR is more frequent in multiple-gestation pregnancies (23–34%) and will be discussed separately. There is no medical treatment for IUGR. Early aspirin treatment reduces the incidence of IUGR in a high-risk population but should not be used routinely in all pregnant women.
High-Dose Growth Hormone Therapy in Idiopathic Short Stature
Authors: Kamp G.A. , Wit J.M.
Published: April 2003

This article reviews the available data on the effect of growth hormone (GH) administration on the growth of children with idiopathic short stature. The 1st year growth response appears clearly dose dependent, if the mean values from various clinical trials are combined. Dose dependency has also been shown in prospective trials. The dose dependency of the long-term growth response was less convincing in a large prospective study. The effect on final height cannot be proven with certainty in uncontrolled studies. If all available results from clinical trials are combined, a positive correlation between response and dose appears likely.
The Effect of Different Growth Hormone Administration Frequencies on Growth in Growth Hormone-Deficient Patients
Authors: Cavallo L. , De Luca F. , Bernasconi S. , Arrigo T. , Gurrado R. , Zecchino C.
Published: April 2003

In two different groups of clinically prepubertal children (bone age ≤8 years) with isolated growth hormone deficit we have evaluated either if the substitutive therapy administered by pump (permitting between 20.00 and 08.00 h the association of continuous and intermittent subcutaneous growth hormone administration) could improve growth (study A) or if a 3 times/week schedule treatment could be performed without any negative effect on growth with respect to 6 injections/week (study B). All patients had been previously successfully treated for at least 2 years by the same dose used during both studies (0.6 IU/kg/week) administered at bedtime 6 times/week. Study A: Each child underwent at bedtime both pump administration (6 months) and single daily injection (6 months). The circulating IGF-I pattern as well as the growth velocity and the ratio bone age increase/height age increase did not differ during the two treatment regimens. Study B: No differences were observed in auxological parameters during the treatment schedule on 3 times/week compared to the previous year on 6 times/week. In conclusion: Our treatment, consisting of the association of continuous and intermittent subcutaneous growth hormone administration, did not improve growth velocity with respect to single daily subcutaneous injection; the growth hormone administration 3 times/week, starting at the 3rd year of substitutive therapy or later, seems to have no negative effect on growth with respect to 6 injections/week.
Safety of High Doses of Recombinant Human Growth Hormone
Authors: van Loon Karel
Published: April 2003

Recombinant human growth hormone (r-hGH) is given as substitution therapy to growth hormone-deficient children at 0.01–0.025 mg/kg/day. Higher doses are used for short stature due to Turner’s syndrome and for idiopathic short stature (approximately 0.05 mg/kg/day). For metabolic indications such as AIDS-associated wasting and severe burns, even higher doses are required, up to 0.2 mg/kg/day. Worldwide experience with low and medium doses of r-hGH is well documented. Data on long-term treatment with pharmacological doses of r-hGH are scarce. Serono’s clinical program for AIDS-associated wasting provides placebo-controlled data on 355 treated patients. The total experience in clinical trials covers more than 100 person-years of treatment on approximately 600 patients. The most common side effects were tissue turgor complex and musculoskeletal discomfort. Leukopenia was found more frequently in placebo patients. Neoplasm, hyperglycemia, hypertriglyceridemia, carpal tunnel syndrome, pseudotumor cerebri and hypercalcemia were not found to be more significant than with substitution therapy.
Genetic Markers of Increased Susceptibility to Diabetic Nephropathy
Authors: Doria Alessandro
Published: April 2003

The effect of exposure to diabetes on the kidney appears to be modulated by genetic factors determining a variable degree of susceptibility to diabetic nephropathy. Multiple loci are probably involved. Some of them might be found among the genes coding for components of the renin angiotensin system (renin, angiotensinogen, angiotensin I-converting enzyme, angiotensin receptors), some may regulate the way in which cells manage hyperglycemia (e.g. aldose reductase). Various genes have been examined to date, mainly by means of association studies. Positive results have been found for some of them (e.g. ACE, AGTR1, aldose reductase), but have not been confirmed in other populations. Thus, no genetic marker of increased susceptibility to diabetic nephropathy having clinical utility is currently available. New insights are expected from the systematic scanning of the genome for linkage with diabetic nephrophathy.
Laboratory Standards in the Assessment of the Quality of Care
Authors: Aanstoot Henk-Jan
Published: April 2003

Diabetes mellitus requires constant care. The main goal of this is prevention of interference with daily life and prevention of long-term complications. Laboratory methods mostly used include HbA1c and microalbuminuria testing. Several methods exist for these determinations. Moreover, no worldwide standards are available. Studies have shown that with the current techniques improvement of laboratory standardization is clearly required, but have also shown that this is possible even without ‘synthetic standards’, the ultimate standards which will not be available within the next 3–5 years.
Cell Adhesion and Reproduction
Authors: Taga Michiyoshi , Suginami Hiroshi
Published: April 2003

Cell adhesion is essential for the regulation of many cellular functions. The adhesion molecule plays a critical role as a fundamental substance in various processes of reproduction such as trophoblast-endometrial interaction. Our understanding of the physiology of adhesion molecules will be helpful for clinical application of these molecules in the treatment and assessment of disorders of many processes of reproduction. We will briefly review integrins, cadherins, and laminin, which were the principal subjects of discussion in this conference.
Wide Distribution of Laminin-5 γ2 Chain in Basement Membranes of Various Human Tissues
Authors: Mizushima Hiroto , Koshikawa Naohiko , Moriyama Kayano , Takamura Hiroyuki , Nagashima Yoji , Hirahara Fumiki , Miyazaki Kaoru
Published: April 2003

Laminin 5 (LN5), a heterotrimer of laminin α3, β3, and γ2 chains, is a laminin isoform which strongly promotes adhesion, migration, and scattering of cells through binding to integrins α3β1, α6β1 and α6β4. To get an insight into the physiological functions of LN5, we prepared a mouse monoclonal antibody to human laminin γ2 chain and used it for immunohistochemical analysis of laminin γ2 chain in normal human tissues. The basement membranes of various epithelial tissues, such as the skin, lung, small intestine, stomach, kidney and prostate, were immunostained with the anti-laminin γ2 chain monoclonal antibody. In addition, the basement membrane of the surface germinal epithelium in the ovary was also positive for laminin γ2 chain. These results suggest general roles of LN5 in the anchorage of various types of epithelial cells to the underlying basement membrane and in the expression of their cellular functions. Moreover, deposition of laminin γ2 chain around small arteries and veins was observed in the thymus and spleen. This lymphatic organ-specific expression of vascular LN5 might provide a novel function of LN5 in immune responses.
Studies on the Role of Adhesive Proteins in Maintaining Pregnancy
Authors: Asahina Toshihiko , Kobayashi Takao , Okada Yoshichika , Itoh Mariko , Yamashita Miwa , Inamoto Yutaka , Terao Toshihiko
Published: April 2003

It is well known that maternal fibrinogen (Fg) and factor X III are essential for maintaining early pregnancy. We studied their role by analysis of clinical reports and immunohistochemical investigation. Methods: (1) We analyzed the pregnancy cases of congenital afibrinogenemia and congenital factor X III deficiency. (2) Immunohistochemical staining of Fg, subunit A of factor X III (X IIIA) and fibronectin (Fn) were performed in the human implantation site, placenta, and endometrial cells cultured in serum-free medium. Results: (1) Afibrinogenemia needed to be administrated Fg from 4 weeks’ gestation (4 wG), and factor X III deficiency needed factor X III concentrate from 5 wG, in order to prevent abortion. (2) Implantation tissues: Fg, cellular X IIIA and Fn were present at the decidual stroma around invasive cytotrophoblasts at 5 wG. X IIIA-positive cells coincided with LN-5-positive macrophages. Placenta: Fg, cellular X IIIA and Fn were present in the decidual layer. Endometrial culture cells: Fn was secreted by spindle-like shaped cells. X IIIA was secreted by round-shaped cells. Conclusion: Maternal Fg and factor X III are essential just after 4∼5 wG, and in that period they and Fn are present abundantly in decidual stroma around invasive cytotrophoblasts. It is concluded that when cytotrophoblasts invade endometrium maternal Fg, factor X III and Fn are concerned with cytotrophoblasts’ anchoring as adhesive proteins.
Growth Hormone Heterogeneity in Human Pituitary and Plasma
Authors: Baumann Gerhard
Published: April 2003

Several isoforms of growth hormone (GH) have been identified in humans. There are many reasons for this heterogeneity. At the genetic level, two genes encode GH: GH-N, expressed in the pituitary, and GH-V, expressed in the placenta. At the mRNA level, GH-N undergoes alternative splicing into 20K and 22K isoforms. Post-translationally, 22K GH undergoes modifications, such as acetylation at its amino terminus, deamidation, and oligomerization. The picture is complicated further in the circulation, where GH binds to two GH-binding proteins, each with different affinities for the GH isoforms. In addition, a highly heterogeneous mixture of GH fragments has been demonstrated. The implications of this heterogeneity relate to differences between GH immunoassays, such that assay results cannot be compared between laboratories. The reasons for GH heterogeneity and its practical and clinical implications are considered here.
Towards Better Decision Making in Growth Hormone Therapy
Authors: Pliskin Joseph S.
Published: April 2003

Controlled clinical trials are not always possible or warranted. Other sources of data include observational studies, meta-analyses, expert opinions, subjective judgements, and mathematical/statistical models developed from large databases. Decision analysis is presented as a preferred methodology for analysis in situations of uncertainty, in combination with cost-benefit and cost-effectiveness analyses. Special emphasis is given to quality-of-life considerations in growth hormone (GH) therapy and ways to measure it and express patient preferences.
Patient Attitudes and Preferences Regarding Treatment: GH Therapy for Childhood Short Stature
Authors: Finkelstein Beth S. , Singh Jagdip , Silvers J.B. , Marrero Ursula , Neuhauser Duncan , Cuttler Leona
Published: April 2003

This paper examines the role of parents’ attitudes and preferences regarding growth hormone therapy for childhood short stature. Four main questions are addressed. First, what are the demographic characteristics of families seeking medical advice for their child’s short stature? Second, what are parents’ attitudes towards short stature? Third, what are parents’ treatment preferences (i.e. what characteristics of growth treatments are important to parents)? Finally, how do the attitudes of parents affect physician decision making? Several studies are reviewed and data are presented to answer these questions.
Growth Hormone Secretagogues in Critical Illness
Authors: van den Berghe Greet
Published: April 2003

Alterations within the somatotropic axis occurring during the course of critical illness follow a biphasic pattern. The initial stress response consists of activated growth hormone (GH) release whereas circulating levels of GH-dependent insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 fall and IGFBP-1 concentrations rise. In contrast, in the chronic intensive care-dependent phase of severe illness, pulsatile GH secretion substantially decreases whereas the non-pulsatile fraction remains relatively elevated, resulting in an abnormally flat GH secretory pattern and low-normal mean nocturnal GH serum concentrations. Specifically the reduced amount of GH released in pulses is found to be related to low circulating levels of IGF-I, IGFBP-3 and acid-labile subunit (ALS), which suggests that a relative hyposomatotropism may participate in the pathogenesis of the wasting syndrome distinctively in the chronic phase of critical illness. The relative hyposomatotropism seems at least in part of hypothalamic origin since the whole somatotropic axis has been found to be very responsive to continuous infusion of GH releasing peptide (GHRP), administered alone or in combination with GH releasing hormone (GHRH), as evidenced by reactivated pulsatile GH secretion followed by substantial increases in circulating levels of IGF-I, IGFBP-3 and ALS. GHRH alone, however, is unable to exert the same effect, which may point to an underlying reduced availability of the endogenous ligand for the GHRP receptor. The presence of considerable responsiveness to restored endogenous pulsatile GH secretion using GHRPs not only further delineates the distinct pathophysiological paradigm of the chronic phase of critical illness, as opposed to the acute phase, which is thought to be primarily a condition of GH resistance, but may also have important therapeutic consequences. Recent data revealed that this novel strategy evokes metabolic improvement related to the balanced endocrine responses. Whether GH secretagogues also enhance clinical recovery of protracted critically ill patients remains to be elucidated.
IGFs and Human Cancer: Implications Regarding the Risk of Growth Hormone Therapy
Authors: Shim Melanie , Cohen Pinchas
Published: April 2003

Perturbations of the insulin-like growth factor (IGF) axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs) and IGFBP proteases such as prostate specific antigen (PSA), and cathepsin D have been identified in prostate, lung and breast cancer cells and tissues. Serum IGFBP-3 levels have been found to be negatively correlated to the risk of cancer. Interestingly, IGFBP-3 is a potent inhibitor of IGF action and also mediates apoptosis via an IGF-independent mechanism. Recent case-control studies have found an approximately 10% increase in the serum levels of IGF-I in patients with prostate, breast and lung cancers, which are among the most frequently diagnosed cancers. While the studies indicate an association between serum IGF-I levels and cancer risk, causality has not been established. Thus, serum IGF-I level may actually be a confounding variable, serving as a marker for autocrine tissue IGF-I production. Growth hormone (GH) therapy raises both IGF-I and IGFBP-3 levels in serum. However, the role of GH in controlling prostate, breast and lung growth and carcinogenesis remains unclear from animal studies. Increased GH levels as seen in acromegaly have been associated with benign prostatic hyperplasia but not with prostate, breast or lung cancers, although colon cancer mortality may be increased. Should serum IGF-I levels be proven to play a causal role in the pathogenesis of cancer, interpreting the risk associated with therapies such as GH replacement must take into account both the duration of exposure and the risk magnitude associated with the degree of serum IGF-I elevation. Since GH-deficient patients often have a subnormal IGF-I serum level, which normalizes on therapy, their cancer risk on GH therapy probably does not increase substantially above that of the normal population. Until further research in the area dictates otherwise, ongoing surveillance and routine monitoring of IGF-I levels in GH recipients should become standard of care.
A Role for Leptin in Sexual Maturation and Puberty?
Authors: Kiess W. , Reich A. , Meyer K. , Glasow A. , Deutscher J. , Klammt J. , Yang Y. , Müller G. , Kratzsch J.
Published: April 2003

Leptin, the ob gene product, is involved in the regulation of body weight in rodents, primates and humans. It provides a molecular basis for the lipostatic theory of the regulation of energy balance. White adipose tissue and placenta are the main sites of leptin synthesis. There is also evidence of ob gene expression in brown fat. Leptin seems to play a key role in the control of body fat stores by coordinated regulation of feeding behaviour, metabolic rate, autonomic nervous system regulation and body energy balance. Apart from the function of leptin in the central nervous system on the regulation of energy balance, it may well be one of the hormonal factors that signal to the brain the body’s readiness for sexual maturation and reproduction. During late pregnancy and at birth when maternal fat stores have been developed, leptin levels are high. During these developmental stages leptin could be a messenger molecule signalling the adequacy of the fat stores for reproduction and maintenance of pregnancy. At later stages of gestation leptin could signal the expansion of fat stores in order to prepare the expectant mother for the energy requirements of full-term gestation, labour and lactation. Leptin serum concentrations change during pubertal development in rodents, primates and humans. In girls, leptin serum concentrations increase dramatically as pubertal development proceeds. The pubertal rise in leptin levels parallels the increase in body fat mass. In contrast, leptin levels increase shortly before and during the early stages of puberty in boys and decline thereafter. Testosterone has been found to suppress leptin synthesis by adipocytes both in vivo and in vitro. The decline of leptin levels in late puberty in boys accompanies increased androgen production during that time and most likely reflects suppression of leptin by testosterone and a decrease in fat mass and relative increase in muscle mass during late puberty in males. This overview focuses on those topics of leptin research which are of particular interest in reproductive and adolescent medicine.
Final Height of Growth Hormone-Treated GH-Deficient Children and Girls with Turner’s Syndrome: The Dutch Experience
Authors: de Muinck Keizer-Schrama Sabine , van den Broeck Jan , Sas Theo , Hokken-Koelega Anita
Published: April 2003

In the Dutch growth hormone (GH) registration database there are currently 552 GH-deficient children being treated, subcutaneously, with recombinant human GH six to seven times per week. Of those, 112 who have been treated for at least 2 years have reached final height. Mean age at start of therapy was 11.70 years. Mean GH dose was 15.5 IU/m2 body surface per week. Mean final height was 173.2 cm (boys) and 159.7 cm (girls) and –1.36 SD of the population mean. Of the patients, 73.2% and 63.4%, respectively, reached a final height above –2 SD of the population or within target limits. FH-SDS was higher compared with the results of earlier cohorts with different treatment regimens. Target height, GH peak value at diagnosis, age at start of GH therapy, height SDS (HSDS) at start of puberty, and duration of GH therapy were significantly correlated with final height. These results, combined with those of a prospective GH dose-response study, suggest that better long-term results can be obtained with early and prolonged treatment and if the GH dose is individually adapted to the short-term growth response. In an ongoing dose-response study, 68 girls with Turner’s syndrome, aged 2–11 years, were randomized into three dosage groups with a daily GH dose of: (group A) 4 IU/m2 body surface; (group B) 4 IU/m2 in the first year of therapy and 6 IU/m2 thereafter; (group C) 4 IU/m2 in the first year, 6 IU/m2 in the second year, and 8 IU/m2 thereafter. After 4 years of GH therapy, girls aged 12 years or older started low-dose oestrogen therapy. After 7 years of GH therapy, mean HSDS in all three groups had increased to values above the third percentile for healthy girls. Mean final height and final height gain of 25 girls was 159.1 and 12.5 cm, 161.8 and 14.6 cm, and 162.7 and 16.0 cm in groups A, B and C respectively. These long-term and final height results are more favourable than the results of earlier Dutch Turner’s syndrome studies. Possible explanations are the higher GH doses and/or the younger age at start of GH therapy.
Children with Septo-Optic Dysplasia – How to Improve and Sharpen the Diagnosis
Authors: Hellström Ann , Aronsson Marita , Axelson Cecilia , Kyllerman Mårten , Kopp Svenni , Steffenburg Susanne , Strömland Kerstin , Westphal Otto , Wiklund Lars-Martin , Albertsson Wikland Kerstin
Published: April 2003

The data in this article are based on investigations performed in 25 children with suspected septo-optic dysplasia (SOD). There are many signs and methods that help in the diagnosis of SOD. In particular, the ocular fundus, abnormalities of the hypothalamo-pituitary axis and other midline brain structures should be described. In order to achieve a more holistic and functional diagnosis, the degree of neurological, neuropsychiatric and psychological involvement should also be stated. It has been suggested that SOD is associated with autosomal recessive inheritance, and it can be speculated that it is the result of genetic and environmental influences early in gestation. An early diagnosis can favourably influence the outcome of the affected child.
Molecular Genetics of Septo-Optic Dysplasia
Authors: Dattani Mehul T. , Martinez-Barbera Juan-Pedro , Thomas Paul Q. , Brickman Joshua M. , Gupta Rajeev , Wales Jeremy K.H. , Hindmarsh Peter C. , Beddington Rosa S.P. , Robinson Iain C.A.F.
Published: April 2003

Septo-optic dysplasia (SOD) is a highly variable condition characterized by midline neurological abnormalities associated with pituitary hypoplasia and optic nerve hypoplasia. The aetiology is unknown. Mutant mice, in which a novel homeobox gene, Hesx1, has been disrupted, exhibit a phenotype that resembles the phenotype of SOD. We therefore wished to explore the possibility that this gene is implicated in SOD. We cloned and sequenced the human homologue HESX1 and screened for mutations in affected individuals using single-stranded conformational polymorphism analysis, followed by cloning and sequencing of any exons which showed a band shift. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain, leading to a loss of in vitro DNA binding. Subsequently, we have identified heterozygous mutations in HESX1 that are associated with milder pituitary phenotypes. Our studies indicate a vital role for Hesx1/HESX1 in forebrain and pituitary development in mouse and man, and hence in some cases of SOD.
How Can Molecular Biology Contribute to the Management of Congenital Adrenal Hyperplasia?
Authors: Ritzén E. Martin , Lajic Svetlana , Wedell Anna
Published: April 2003

The most common form of congenital adrenal hyperplasia is due to a deficiency of 21-hydroxylase (21OHD) activity and is caused by a mutation in the CYP21 gene. By genotyping patients, new and important information can be gained, including presence or absence of 21OHD in borderline cases, determining the severity of disease and identifying heterozygote carriers. Current management of patients with 21OHD involves administering sufficient glucocorticoids to suppress excess adrenal androgen secretion, but not so much that bone growth and mineralization are impaired. New management strategies have been proposed and include administering only substitution doses of corticosteroids and counteracting side-effects by administering an anti-androgen and aromatase inhibitor. Adrenalectomy has also been proposed. Further investigation into these approaches is necessary.
Metabolic Consequences of Growth Hormone Treatment in Paediatric Practice
Authors: Saenger Paul
Published: April 2003

No metabolic side-effects of clinical significance have been reported during a 5-year study of growth hormone (GH) therapy in children with GH deficiency, Turner syndrome, idiopathic short stature or chronic renal insufficiency. In particular, insulin levels increase but remain within the normal range, as do glucose and haemoglobin A1c. A recent study showed that the effects of growth on insulin sensitivity in prepubertal children with idiopathic short stature represent the changes in carbohydrate tolerance observed during normal adolescence. Thus, GH treatment may lead to prolongation of the physiological state of insulin resistance observed in normal puberty. Insulin levels during the fasting state and 2 h after a standard glucose load showed no further rise after the first 3 years of continuous GH therapy. The hyperinsulinaemia observed during GH therapy may, therefore, amplify the anabolic effects of insulin on protein metabolism during puberty.
Growth Hormone Response to a Growth Hormone-Releasing Hormone Stimulation Test in a Population-Based Study following Cranial Irradiation of Childhood Brain Tumors
Authors: Schmiegelow M. , Lassen S. , Poulsen H.S. , Feldt-Rasmussen U. , Schmiegelow K. , Hertz H. , Müller J.
Published: April 2003

Children with brain tumors are at high risk of developing growth hormone deficiency (GHD) after cranial irradiation (CI) if the hypothalamus/pituitary (HP) axis falls within the fields of irradiation. The biological effective dose (BED) of irradiation to the HP region was determined, since BED gives a means of expressing the biological effect of various irradiation treatment schedules in a uniform way. Hypothalamic versus pituitary damage as cause of GHD was distinguished in 62 patients by comparing the growth hormone (GH) peak response to an insulin tolerance test (ITT)/arginine stimulation test and the GH response to a growth hormone-releasing hormone (GHRH) stimulation test. Peak GH response to a GHRH test was significantly higher (median 7.3 mU/l; range: 0.5–79.0 mU/l) than that of an ITT/arginine test (median 4.7 mU/l; range: 0.01–75.0 mU/l) (p = 0.017). Peak GH after a GHRH test was significantly inversely correlated to follow-up time (rs = –0.46, p < 0.0001) and to BED (Rs = –0.28, p = 0.03), and both were found to be of significance in a multivariante regression analysis. We speculate that a significant number of patients developed hypothalamic radiation-induced damage to the GHRH secreting neurons, and secondary to this the pituitary gland developed decreased responsiveness to GHRH following CI in childhood.
Acute Thyroiditis in a Child: Misleading Result of Fine-Needle Aspiration Biopsy
Authors: Tomasi Paolo A. , Piga Sergio , Tecleme Paolo , Fanciulli Giuseppe , Delitala Giuseppe
Published: April 2003

We report a case of acute thyroiditis in a 6-year-old girl, whose initial borderline clinical and sonographic data, coupled with the absence of leucocytes and bacteria on the fine-needle aspiration biopsy, led to the reversal of the initial diagnostic impression of acute thyroiditis and the institution of an inappropriate glucocorticoid treatment. Since both diseases are rare in the paediatric age group and therapy is completely different, we conclude that in borderline cases careful clinical observation and the response to the initial antibiotic therapy should be considered more reliable than any single morphologic or microbiologic result. We also suggest that acute bacterial thyroiditis could be usefully classified into two forms, suppurative and non-suppurative.
Transcription Factors in Pituitary Gland Development and Their Clinical Impact on Phenotype
Authors: Mullis Primus-E.
Published: April 2003

Objective: Several genes encoding homeobox transcription factors are important for normal pituitary gland development and eventually for hormone production. Methods and Results: By interacting with each other on the basis of a distinct temporal and spatial expression pattern, as well as with other extrinsic and intrinsic signals, they control cell determination, cell differentiation and eventually maintenance of cell function which is most important for the lifelong secretion of the pituitary-derived hormones in an appropriate manner. The different phenotypes, as mainly studied in the mouse, may help to analyze the consequences of disruption of a known or yet unknown individual transcription factor in humans. Conclusion: Therefore, to study the different steps in morphogenesis will shed light onto developmental processes which will open a most fascinating time not only for basic scientists and biologists, but also for clinicians seeing all these patients.
Influence of Sex and Age at Onset on Autoantibodies against Insulin, GAD65 and IA2 in Recent Onset Type 1 Diabetic Patients
Authors: Bilbao J.R. , Rica I. , Vázquez J.A. , Busturia M.A. , Castaño L.
Published: April 2003

Methods: Autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and tyrosine phosphatase IA2 (IA2A) were measured in sera from 448 recent onset patients with type 1 diabetes mellitus (DM) subdivided according to sex (194 female and 254 male) and age at onset (134 patients diagnosed before 10 years, 187 between 10 and 20 years, 66 between 20 and 30 years and 61 over 30 years. Results: Autoantibodies were more frequent in female DM patients (93.8 vs. 86.6%, p = 0.013) due to an increased prevalence of both GADA (86.1 vs. 70.1%) and IA2A (59.3 vs. 49.2%), with GADA levels also significantly higher in women (0.24 vs. 0.18 U, p = 0.0003). When age groups were compared, there was a reduction in prevalence in patients over 20 years for both IAA (70% for patients diagnosed under 20 and 36% for older patients) and IA2A (65 and 25%, respectively). These differences also affected IAA levels, with the highest antibody titres in the youngest group (1,214.1 nU/ml in children under 10 compared to 546.9, 345.6 and 341.1 nU/ml in the subsequent groups; p < 10–4). GADA prevalence did not differ significantly between age groups but, nevertheless, autoantibody levels were highest among the oldest type 1 DM patients (0.327 U compared to 0.216, 0.197 and 0.176 U in the decreasing age groups; p < 10–4). Conclusion: There are sex- and age-related differences affecting the presence and/or titres of β cell autoantibodies. We speculate that these differences could reflect the severity and specificity of the autoimmune attack against the endocrine pancreas and might influence the rate of progression to type 1 DM or the risk of developing other autoimmune diseases.
Significant Gene Expression of Insulin-Like Growth Factor II and Proliferating Cell Nuclear Antigen in a Rapidly Growing Recurrent Pituitary ACTH-Secreting Adenoma
Authors: Hashimoto Kozo , Nagano Isao , Asaba Koichi , Inoue Mari , Nishioka Tatsuya , Takao Toshihiro , Nakajo Takahito , Mori Takahisa , Kurisaka Masahiro , Otsuka Fumio
Published: April 2003

Background: We quantified the expression of various growth-related factors in an adrenocorticotropic hormone (ACTH)-secreting adenoma that had recurred very rapidly as invasive macroadenoma. Methods/Results: A 43-year-old woman underwent successful transsphenoidal surgery for Cushing’s disease. Seven years later, she was admitted to our ward for further endocrine examinations. In spite of a very high plasma ACTH level, the serum cortisol level was normal. Discrepancies between ACTH and cortisol levels were detected on the basis of diurnal rhythms, dexamethasone suppression tests, and corticotropin-releasing hormone test. The patient showed no clinical features of Cushing’s disease. Magnetic resonance imaging of the pituitary showed an almost empty sella, and no microadenoma was found. These results, along with those of Sephadex column gel filtration and high-performance liquid chromatography of plasma-immunoreactive ACTH, suggested that the patient’s residual corticotrophs secreted biologically inactive ACTH. Two years later, the patient suddenly developed diplopia and right abducens nerve palsy. She was slightly moonfaced and centrally obese. Her plasma ACTH and serum and urinary free cortisol levels were elevated, although discrepancies between ACTH and cortisol still existed. Magnetic resonance imaging revealed a large pituitary mass with suprasellar and cavernous sinus extensions. The tumor was excised, and the proopiomelanocortin gene and the expression of growth-related factors were analyzed. No mutations were found in the ACTH-coding region of the proopiomelanocortin gene. A significant expression of insulin-like growth factor II and proliferating cell nuclear antigen mRNAs was demonstrated. A high MIB-1 antibody labeling index was also detected in the adenoma tissue, suggesting high Ki-67 expression. Conclusion: These growth- and proliferation-related factors might be involved in the rapid growth and aggressiveness of this patient’s pituitary adenoma.
Peroxisome Proliferator-Activated Receptors and Skin Development
Authors: Rosenfield Robert L. , Deplewski Dianne , Greene Marianne E.
Published: April 2003

PPARs are nuclear hormone receptors. PPAR subtypes (α, γ, δ, the latter a xPPARβ homologue) were initially investigated in skin because of their known role in regulating lipid metabolism. Studies adding specific PPAR ligand activators to cultured skin or skin cells are compatible with the concepts that PPARα activation mediates early lipogenic steps common to the function of both skin epidermal cells (keratinocytes) and sebaceous cells (sebocytes), PPARγ activation plays a unique role in stimulating sebocyte lipogenesis, and PPARδ activation may contribute to lipid biosynthesis in both sebocytes and keratinocytes under certain circumstances. Epidermal keratinocytes appear to express small amounts of PPARα and PPARδ mRNA and a trace of PPARγ mRNA which is up-regulated with differentiation. Sebocytes express all subtypes; PPARγ gene expression excedes that in epidermis. The emerging data on PPAR protein expression suggests that epidermis normally expresses predominantly PPARα, while sebocytes express more PPARγ than PPARα. These expression patterns may change during hyperplasia, differentiation and inflammation. Gene disruption studies in mice are compatible with a contribution of PPARα to skin barrier function, suggest that PPARγ is necessary for sebocyte differentiation, and indicate that PPARδ can ameliorate inflammatory responses in skin. PPARs appear to play a role in keratinocyte synthesis of the lipids that they export to the intercellular space to form the skin permeability barrier. They also appear to be important for sebocyte formation of the intracellular fused lipid droplets that constitute the holocrine secretion of the sebaceous gland. In addition, they may play roles in keratinocyte growth and differentiation and the inhibition of skin inflammation by diverse mechanisms not necessarily related to fat metabolism.
Targeted Somatic Mutagenesis in Mouse Epidermis
Authors: Indra Arup Kumar , Li Mei , Brocard Jacques , Warot Xavier , Bornert Jean-Marc , Gérard Christelle , Messaddeq Nadia , Chambon Pierre , Metzger Daniel
Published: April 2003

Gene targeting in the mouse is a powerful tool to study mammalian gene function. The possibility to efficiently introduce somatic mutations in a given gene, at a chosen time and/or in a given cell type will further improve such studies, and will facilitate the generation of animal models for human diseases. To create targeted somatic mutations in the epidermis, we established transgenic mice expressing the bacteriophage P1 Cre recombinase or the tamoxifen-dependent Cre-ERT2 recombinase under the control of the human keratin 14 (K14) promoter. We show that LoxP flanked (floxed) DNA segments were efficiently excised in epidermal keratinocytes of K14-Cre transgenic mice. Furthermore, Tamoxifen administration to adult K14-Cre-ERT2 mice efficiently induced recombination in the basal keratinocytes, whereas no background recombination was detected in the absence of ligand treatment. These two transgenic lines should be very useful to analyse the functional role of a number of genes expressed in keratinocytes.
Genetics of Peutz-Jeghers Syndrome, Carney Complex and Other Familial Lentiginoses
Authors: Stratakis Constantine A.
Published: April 2003

Peutz-Jeghers syndrome (PJS, #175200) and Carney complex (CNC, OMIM#160980) are the two most common multiple neoplasia syndromes associated with lentiginosis. Both disorders are inherited in an autosomal dominant manner and they have recently been elucidated at the molecular level. PJS and CNC share manifestations with Cowden syndrome (or Cowden disease) (CS, OMIM#158350) and Bannayan-Riley-Ruvalcaba syndrome (BRR, OMIM#153480). The endocrine tumors of CS and PJS, which could classify these disorders as variant types of multiple endocrine neoplasias (MENs), are not present in most CS and BRR patients, but lentigines are shared by PJS, CNC and BRR. The serine-threonine kinase STK11 (or LKB1), located on 19p13, is mutated in more than half of all PJS kindreds. The R1α subunit of c-AMP-dependent protein kinase A, located on 17q22–24, is mutated in 40% of CNC kindreds. The protein phosphatase PTEN is mutated in most cases of CS and in almost 50% of BRR kindreds, despite significant clinical heterogeneity in these syndromes. The molecular elucidation of the lentiginoses and their related syndromes identifies new pathways of growth control and cellular regulation that are important for endocrine signaling, tumorigenesis, cutaneous function and embryonic development.
Type 2 Diabetes in Children: Clinical Aspects and Risk Factors
Authors: Arslanian Silva
Published: April 2003

In the past, type 2 diabetes mellitus was considered a disease of adults and older individuals, not a paediatric condition. Over the last decade, however, in the USA and the rest of the world there has been a disturbing trend of increasing cases of type 2 diabetes in children, mirroring increasing rates of obesity. The risk factors for paediatric type 2 diabetes are: (1) obesity and increased body mass index; (2) family history of type 2 diabetes; (3) membership of ethnic minority; (4) puberty (mean age of diagnosis is ∼13.5 years); (5) female gender; and (6) features of ‘syndrome X’. The common link among these risk factors is insulin resistance, which plays a pivotal role in the pathophysiology of type 2 diabetes. Both insulin resistance and β-cell failure are present in the fully established diabetes state. Data will be presented on how these risk factors impact on insulin sensitivity and insulin secretion in childhood, ultimately leading to type 2 diabetes. The clinical presentation of type 2 diabetes in children and its distinction from type 1 diabetes will be discussed.
Insulin Analogues – State of the Art
Authors: Standl E.
Published: April 2003

The use of insulin analogues is rapidly expanding. At present, there are two short-acting analogues available for practical use, insulin aspart and insulin lispro, and one long-acting analogue, insulin glargine. Another long-acting analogue, insulin detemir, is still under development. The time action profile of short-acting analogues is both much more rapid and shorter than that of human insulin; the prominent feature of the long-acting analogues is their peakfree and fairly constant action. Insulin analogues offer alternative options for the whole spectrum of insulin therapy in type 1 and type 2 diabetes patients. The perception by many patients is strikingly positive, in particular regarding the overall quality of life. In objective efficacy terms, however, the potential to improve the degree of metabolic control appears to be only minor, yet demonstrable, provided the analogues are used according to their specific time action profile. This ensured, analogues are instrumental in minimizing the side effects of insulin therapy, i.e. the risk of (nocturnal) hypoglycaemia or problems with body weight control. Although there are no indications of safety concerns with insulin analogues, the availability of long-term outcome data based upon observations in human patients would be very valuable.
IL-5 Synthesis by T Cells of Allergic Subjects Is Regulated at the Transcriptional Level
Authors: Ogawa Koji , Kaminuma Osamu , Kikkawa Hideo , Akiyama Kazuo , Mori Akio
Published: April 2003

Background: IL-5 plays a central role in allergic diseases associated with eosinophilic inflammation. We have previously reported that IL-5 production by peripheral blood mononuclear cells (PBMC) is greatly enhanced in both atopic and nonatopic asthmatics compared to control subjects. Method: Concanavalin A (Con A) blast lymphocytes were derived from PBMC of allergic and control subjects. Transcriptional regulation of the IL-5 gene was investigated by transient transfection assay. Results: A significant amount of IL-5 was produced by Con A blast lymphocytes derived from allergic subjects upon stimulation with phorbol ester and Ca2+ ionophore, whereas the cells derived from control subjects did not produce a detectable amount of IL-5. Production of IL-2 and IL-4 was not significantly different between the two groups. A luciferase reporter plasmid containing the human IL-5 promoter/enhancer region was transcribed by Con A blast lymphocytes derived from allergic subjects, but not by the cells from control subjects, upon activation. Conclusion: IL-5 synthesis by nontransformed T cells of allergic subjects is enhanced at the level of gene transcription. Elucidation of the molecular mechanism of IL-5 gene transcription by allergic T cells may delineate the pathogenesis of allergic disease for the future therapeutic intervention.
Nerve Growth Factor Induces Airway Hyperresponsiveness in Mice
Authors: Braun Armin , Quarcoo David , Schulte-Herbrüggen Olaf , Lommatzsch Marek , Hoyle Gary , Renz Harald
Published: April 2003

Background: Previous studies indicated an upregulation of nerve growth factor (NGF) production during allergic inflammation. However, the function of NGF in the lungs is currently poorly understood. It was suggested that NGF could play an important role in the pathophysiology of airway hyperresponsiveness. The regulatory network between immunological events and altered neuronal control of airway smooth muscle contractility remains to be defined. Methods: NGF was delivered into the airways of mice either by nasal instillation or by genetic engineering. Airway reactivity was then measured by electrical field stimulation. Results: Treatment of mice with NGF induced airway hyperresponsiveness to a similar extent as demonstrated in allergen-sensitized mice. NGF-transgenic mice, overexpressing NGF in Clara cells, were hyperreactive in comparison to wild-type mice. Conclusion: These data suggest that NGF by itself determines the induction of airway hyperresponsiveness in the absence of airway inflammation in mice.
IgG-Mediated Histamine Release from Canine Mastocytoma-Derived Cells
Authors: Takahashi Tomoko , Kitani Seiichi , Nagase Masayuki , Mochizuki Manabu , Nishimura Ryohei , Morita Yutaka , Sasaki Nobuo
Published: April 2003

Background: Recent data suggest that normal tissue mast cells can express functional receptors for IgG under certain conditions. However, little is known about IgG receptor expression and functional consequences in mast cell neoplasms. Methods: In this study, neoplastic mast cells were obtained from a dog with cutaneous mastocytoma (CM-MC) and from a dog with visceral mastocytoma (VI-MC). Both cell populations were characterized morphologically and functionally. Results: Most cells proliferated constantly in suspension without particular supplements. Doubling times of CM-MC and VI-MC were 52.2 and 27.5 h, respectively. Both cell types were sensitive to formalin fixation, did not contain heparin and were tryptase and chymase positive. Electron microscopy showed fine granules with electron-dense content in both cell populations. The total histamine content of CM-MC and VI-MC was 0.25 and 0.10 pg/cell, respectively. Calcium ionophore A23187 and substance P induced dose-dependent histamine release, whereas compound 48/80 had no effect. Most significantly, both cell types, when sensitized with monomeric dog IgG, released histamine upon stimulation by anti-dog IgG. Conclusions: Dog mastocytoma-derived cells may be useful to study the regulation of neoplastic mast cell growth and differentiation, as well as IgG receptor-mediated activation in neoplastic mast cells. Further research is required to clarify the pathophysiological significance of constitutive expression of IgG receptors in neoplastic (canine) mast cells.
Food-Dependent Exercise-Induced Anaphylaxis: Clinical and Laboratory Findings in 54 Subjects
Authors: Romano Antonino , Di Fonso Marina , Giuffreda Francesca , Papa Giuseppe , Artesani Maria Cristina , Viola Marinella , Venuti Alberto , Palmieri Vincenzo , Zeppilli Paolo
Published: April 2003

Background: In some subjects, specific foods trigger anaphylaxis when exercise follows ingestion (specific food-dependent exercise-induced anaphylaxis, FDEIAn). Skin test and/or RAST positivity to foods suggest an IgE-mediated pathogenic mechanism. Others suffer from anaphylaxis after all meals followed by exercise, regardless of the food eaten (nonspecific FDEIAn). We sought to identify the culprit foods with a diagnostic protocol. Methods: We collected detailed histories and performed skin prick tests (SPT) with 26 commercial food allergens, prick plus prick tests (P+P) with 15 fresh foods (including 9 assessed with SPT), and RAST for 31 food allergens. Treadmill stress tests were administered after a meal without any positive food (food plus exercise challenge, FEC). Results: Among the 54 patients, 6 could not recall any suspect food. The other 48 suspected a specific food in at least one episode. The most frequent were tomatoes, cereals and peanuts. Fifty-two subjects were positive to at least one food (22 to more than 20), whereas 2 showed no positive results. All suspect foods were positive. SPT, P+P and RAST displayed different degrees of sensitivity. Each test disclosed some positivities not discovered by others. Two subjects reacted to FEC. Overall, 48 patients probably had specific FDEIAn and the other 6 nonspecific FDEIAn. Conclusions: It is useful to test both in vivo and in vitro an extensive panel of foods. Avoidance of foods associated with skin test and/or RAST positivity for at least 4 h before exercise has prevented further episodes in all our patients with specific FDEIAn.
Uterine Myomectomy in Pregnant Women
Authors: De Carolis Sara , Fatigante Gabriella , Ferrazzani Sergio , Trivellini Carmen , De Santis Lidia , Mancuso Salvatore , Caruso Alessandro
Published: April 2003

Objective: To determine whether myomectomy during pregnancy in selected patients improves outcome. Methods: Retrospective analysis of 18 patients who underwent myomectomy between the 6th and 24th week of gestational age. Surgical management of tumors was required on the basis of the characteristics of the myomas and symptoms. The dimensions and site of myomas, symptoms of the patients, time and mode of delivery, and pregnancy outcome were analyzed. Results: One woman was lost to follow-up, and one suffered a miscarriage. The remaining 16 patients delivered healthy babies between the 36th and 41st week; 14 delivered by cesarean section, and 2 vaginally. Conclusion: We suggest that myomectomy during pregnancy may be considered safe in selected patients. Moreover, it permits good pregnancy outcome with healthy babies delivered at term.