bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Study of the Calcium Adenosine Triphosphatase of Basal Membranes of Human Placental Trophoblasts from Normotensive and Preeclamptic Pregnant Women
Authors: Casart Ysabel , Proverbio Teresa , Marín Reinaldo , Proverbio Fulgencio
Published: April 2003

The Ca-ATPase activity of plasma membranes from human trophoblast is diminished in about 50% in preeclamptic women, as compared to normotensive pregnant women. This diminution is not due to changes in the behavior of the enzyme towards the free calcium concentration, the pH or the temperature of the incubation medium. Neither does it appear to be due to the presence of some condensing factor in the membranes, since the apparent energies of activation for the two tested ranges of temperature (10–20 and 20–37°C) are similar for both normotensive and preeclamptic patients. The possibility of a diminution in the turnover rate of the Ca-ATPase in the plasma membranes from the preeclamptic patients is considered.
Assessing the Influence of Payment on Motivations of Women Participating as Oocyte Donors
Authors: Lindheim Steven R. , Chase Jennie , Sauer Mark V.
Published: April 2003

We report on the motivations of potential ovum donors entering an assisted reproduction program and discuss the potential ramifications of escalating payments to donors. From July 1995 to July 1998, recruitment of ovum donors was directed at healthy women between 21 and 34 years of age. Financial remuneration for services rendered was USD 2,500 from July 1995 through March 1998 and increased to USD 5,000 after that. Donors were screened and consented according to established SART guidelines. The demographic background of the women was similar for women paid USD 2,500 to those receiving USD 5,000. The financial motivation was greater in those receiving USD 5,000 (68%) than USD 2,500 (39%). Some form of expressed altruism was similarly present in both groups (USD 5,000 90%, and USD 2,500 91%). However, altruism expressed as the sole motivation occurred more in those receiving USD 2,500 (61%) compared to USD 5,000 (32%). Financial reimbursement has escalated for the services of ovum donors in order to maintain the increasing demand. While money has become a dominant factor motivating ovum donors, its seductive nature requires even greater attention to adequate informed consent. Young donors may be unable to adequately weigh the risks of ovarian hyperstimulation and oocyte retrieval against the monetary reward.
Value of Subcutaneous Drainage System in Obese Females Undergoing Cesarean Section Using Pfannenstiel Incision
Authors: Al-Inany Hesham , Youssef Gamal , Abd ElMaguid Ahmed , Abdel Hamid Moustapha , Naguib Ahmed
Published: April 2003

Objective: To determine whether closed subcutaneous drainage systems were efficacious in reducing the rate of wound breakdown of Pfannenstiel incision after cesarean section (CS) in obese females. Design: Prospective controlled clinical trial. Participants: 118 obese pregnant females with a body mass index >32 undergoing CS were divided into two groups: group I (n = 78) with closed subcutaneous drainage system and group II (n = 40) without drainage system. Incision closure technique was standardized. Prophylactic antibiotics were given routinely to both groups. Outcome Measures: Primary outcomes were the incidence of wound breakdown in both groups together with rate of hematoma formation and occurrence of fever. Secondary outcomes were amount of fluid drained, need for redressing. Results: Wound breakdown occurred in 9 cases in group I (11.5%), while it happened in 5 cases in group II (12.5%) (p > 0.05). Relative risk was 0.92 (95% CI 0.26–3.75). Hematoma formation was observed in only 1 case in the nondrainage group (group II). Fever was observed in 18 cases in group I (23.1%) in the first 24 h postoperative while in group II, 13 cases developed fever (32.5%) (p > 0.05). The need for redressing within the first 24 h was only in 2.5% of cases in group I while it was 17.9% in group II (p < 0.05). Conclusion: We found no significant benefit in using a subcutaneous drain as a prophylactic measure against wound breakdown in obese pregnant females undergoing CS as long as they received a prophylactic antibiotic.
Konservative Behandlungsmöglichkeiten ektoper Schwangerschaften und Präsentation eines komplizierten Verlaufes mit einer Peritonitis unter Methotrexat
Authors: Eulgem K.C. , Knitza R.
Published: April 2003

Die Behandlung der Extrauteringravidität hat durch die Verbesserung der Diagnostik und durch die Verfeinerung endoskopischer Operationsverfahren eine Entwicklung weg von der Salpingektomie, hin zum organerhaltenden Vorgehen durchlaufen. Als Alternative zur operativen Intervention bestehen darüber hinaus seit einigen Jahren verschiedenste Möglichkeiten der medikamentösen Therapie. Neben einer allgemeinen Übersicht über die konservativen Behandlungsmöglichkeiten wird über 1 Patientin berichtet, bei der es nach laparoskopischer Sicherung einer proximal-isthmischen Schwangerschaft unter systemischer Bahandlung mit Methotrexat zu einer ausgeprägten Peritonitis kam.
Reduction of QT Dispersion by Losartan in Patients with Mild to Moderate Hypertension
Authors: Dieterle Thomas , Vakil-Gilani Darius , Battegay Edouard J. , Martina Benedict
Published: April 2003

Background: QT dispersion (QTd) is the difference between the longest and the shortest QT interval in the standard 12-lead ECG. QTd may be a measure of spatial dispersion of repolarization in the myocardium, and may be influenced by antihypertensive treatment. Objective: To study the effects of losartan in comparison to amlodipine on QTd in mildly to moderately hypertensive patients, and to assess correlations of reduced QTd with echocardiographic left ventricular mass (LVM). Methods: Twenty-eight adult patients with mild to moderate hypertension were randomly assigned to a double-blind treatment either with losartan 50 mg titrated to losartan 50 mg-hydrochlorothiazide 12.5 mg or amlodipine 5 mg titrated to amlodipine 10 mg. Blood pressure and echocardiographic LVM were measured before and after 16 weeks of treatment. QTd was measured by two independent examiners blinded to patient data, study phase and treatment. Results: Systolic and diastolic blood pressure were significantly reduced in the losartan and amlodipine groups. Treatment with losartan significantly reduced LVM (from 311 ± 31 to 252 ± 16 g, mean ± SE; p < 0.01), cardiac mass index and QTd (from 42.3 ± 5.4 to 27.8 ± 2.2 ms, mean ± SE; p < 0.05). Conclusion: Losartan significantly reduced QTd after 16 weeks of treatment in patients with mild to moderate hypertension. This reduction was not significantly correlated with the reduction in LVM.
Pediatric Endocrinology Update: An Overview
Authors: MacGillivray Margaret H. , Morishima Akira , Conte Felix , Grumbach Melvin , Smith Eric P.
Published: April 2003

The goals of this presentation are to review the essential roles of aromatase, estrogens and the estrogen receptor in pubertal growth. Estrogen deficiency due to mutations in the aromatase gene (CYP19) and estrogen resistance due to disruptive mutations in the estrogen receptor gene have no effect on normal male sexual maturation in puberty. However, they lead to absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, continued growth into adulthood and very tall adult stature in both sexes. Gonadotropin and androgen levels are elevated in patients with either estrogen deficiency (aromatase deficiency) or estrogen resistance (estrogen receptor mutation). Glucose intolerance, hyperinsulinemia and lipid abnormalities are also present. Skeletal integrity is compromised. Increased bone turnover, reduced bone mineral density and osteoporosis develop in both sexes. Sexual orientation is appropriate in males and females. In females, aromatase deficiency in the ovary causes pubertal virilization and multicystic ovaries because of elevated gonadotropins and androgens. Simultaneously, secondary sexual maturation fails to occur. Placental aromatase deficiency results in virilization of the mother and her female fetus because of the accumulation of potent androgens which are not converted to estrogens. The male fetus has normal genitalia. In conclusion, estrogens are essential for normal female secondary sexual maturation, bone maturation, epiphyseal fusion, pubertal growth spurt and achievement of normal bone mineral mass. Estrogens also influence insulin sensitivity and lipid homeostasis. However, estrogens do not appear to be essential for fetal survival, placental growth, or female sexual differentiation.
Review on the Physical Growth in Primates
Authors: Iwamoto Mitsuo
Published: April 2003

J.M. Tanner concluded in 1962 that the growth velocity curve in body weight shows two peaks in primates but only one peak in the other mammals, and that the first peak in primates corresponds phylogenetically to the peak in the other mammals. Many reports on the physical growth of primates have been accumulated in the past 70 years. Using some of them as a basis, the author illustrated the normative velocity curves (increment curves) of the weight of monkeys, chimpanzees and humans, and reconsidered Tanner’s conclusion. However, there are still some as yet obscure aspects to be interpreted in future.
Intrauterine Growth Restriction: Definition and Etiology
Authors: Wollmann Hartmut A.
Published: April 2003

Intrauterine growth restriction (IUGR) is a frequent cause of perinatal morbidity as well as of impaired growth during childhood. Therefore, a clearcut definition of IUGR to identify those babies at risk is essential: The label IUGR generally should be assigned only to those infants with birth weight and/or birth length below the 10th percentile for GA with a pathologic restriction of fetal growth. According to the recent literature, clinical classification of the retarded babies seems to be less significant. Among the etiologic factors responsible for IUGR, one-third of the variations in birth weight are determined by genetic variables, two-thirds by environmental factors. In spite of the fact that a long list of established, different etiologic factors is known, in at least 40% of children no underlying pathology can be identified. Among the preventable, environmental causes of IUGR, smoking of the mother during pregnancy is by far the most important one, which is responsible for more than one third of all IUGR newborns.
Long-Term Consequences of Intrauterine Growth Retardation
Authors: Reynolds R.M. , Phillips D.I.W.
Published: April 2003

Recent studies in Europe, North America and the developing world have shown that low birth weight or other indices of abnormal fetal growth in babies born at term are linked with a higher prevalence of raised blood pressure, non-insulin-dependent diabetes and cardiovascular disease in late adult life. These findings have led to the ‘fetal origins’ hypothesis which proposes that fetal adaptations to an adverse intrauterine environment programme persistent physiological and metabolic changes which predispose to these diseases. The mechanisms are unknown, but evidence from animal studies and preliminary evidence in humans suggest that impaired fetal nutrient supply permanently alters neuroendocrine development in the offspring resulting in long-term changes in the set point of adrenocortical and sympathoadrenal hormonal activity.
Genetics of Silver-Russell Syndrome
Authors: Wakeling E.L. , Abu-Amero S. , Price S.M. , Stanier P. , Trembath R.C. , Moore G.E. , Preece M.A.
Published: April 2003

The Silver-Russell syndrome (SRS) is generally sporadic, but with sufficient reported cases of dominant and recessive patterns of inheritance to suggest a genetic cause in some cases, at least. No consistent cytogenetic abnormalities have been found although some features of the syndrome have been reported to be associated with structural abnormalities of distal 15q. More recently it has been shown that about 10% of SRS patients have maternal uniparental disomy of chromosome 7 which suggests the presence of a maternally imprinted gene on chromosome 7 that is associated with SRS. In the majority of patients with normal biparental inheritance of chromosome 7 the same gene could be involved if the paternal copy were deleted or mutated so that it is disabled and the maternal copy is silent because of the imprinting.
Growth Hormone Treatment of Russell-Silver Syndrome
Authors: Stanhope Richard , Albanese Assunta , Azcona Cristina
Published: April 2003

Russell-Silver syndrome represents a special group of children with intrauterine growth retardation (IUGR) who do not experience catch-up growth and have characteristic dysmorphic features. They also have characteristics of abnormal growth hormone pulsatility, absence of catch-down growth after growth hormone therapy and inappropriate advancement of bone age during the middle childhood years. Data from children with Russell-Silver syndrome should certainly be analysed as a separate group from short children due to nondysmorphic IUGR. Initial data suggests that final height outcome will be improved by using pharmacological doses of biosynthetic human growth hormone. Indeed, the recent data supports the hypothesis of Blizzard’s group in 1974 that if growth hormone became available in sufficient quantities, then final height could be altered in IUGR children. In addition, the early recognition and treatment of spontaneous nocturnal hypoglycaemia may well improve the educational achievement of such children.
Management of Recombinant Human Growth Hormone Therapy at Puberty
Authors: Albers Norbert
Published: April 2003

Treatment modalities for growth hormone (GH) substitution in GH-deficient children at puberty is still a matter of debate. Although circulating GH levels increase during puberty, it has not been proven that the increase of exogenous GH is necessary for a normal pubertal growth spurt. Increasing GH levels may thus well be the consequence and not the cause of the pubertal growth spurt. A permissive role of GH for pubertal growth has been hypothesized. Some effects of exogenous GH may even be detrimental to pubertal growth; specifically, puberty seems to be shortened by GH administration. Further aspects of the physiology of GH secretion and the poor imitation by current replacement schemes are discussed. Only randomized, prospective studies will allow to define the optimal dose of GH at puberty. As long as these studies are missing, a pragmatic approach is an individualized, minimalistic GH substitution scheme under close surveillance. GH dose at puberty should be kept at prepubertal levels, but must be increased once height velocity drops below the 50th percentile. This widely used approach ensures unnecessary, costly and potentially harmful overdosages of GH.
Biochemical Markers of Diabetic Microangiopathy
Authors: Dahl-Jørgensen Knut
Published: April 2003

The first signs of diabetic microvascular complications in the eyes and kidney, and early signs of neuropathy, may develop in children and adolescents. The development and progression of such complications are clearly related to blood glucose control. The mechanisms by which microangiopathy develops are not exactly known, and there are no excellent biochemical markers with high predictive value for future microangiopathy. The best available markers today are HbA1c and the urinary albumin excretion. New biochemical markers related to advanced glycation end products (AGEs), and recently possible genetic markers, have been described. The predictive value of single markers and the combination of such markers has to be tested in long term clinical studies.
Factors Modifying the Effect of Hyperglycemia on the Development of Retinopathy in Adolescents with Diabetes
Authors: Danne Thomas , Kordonouri Olga , Enders Ingo , Hövener Gerd , Weber Bruno
Published: April 2003

The Berlin Retinopathy Study follows children from the onset of diabetes with serial retinal examinations by fluorescein angiography. It confirmed that long-term poor glycemic control, both before and after puberty, is the major risk factor for the development of retinal changes. The relationship between long-term HbA1c and background retinopathy follows an exponential, non-linear function. Apart from glycemia, several other factors (age at onset, puberty, lipids, blood pressure, genetic factors, smoking) may be of varying relevance in the individual patient. Nevertheless, best glycemic control from the onset of diabetes appears to be of outstanding importance as the HbA1c levels already during the first year of diabetes are related to the later development of background retinopathy.
Process Quality Management in Pediatric Diabetes Care
Authors: Schoenle Eugen J.
Published: April 2003

The description of a functioning pediatric diabetes center continuously reaching an acceptable metabolic control for the average diabetic patient cannot be done on a substantial scientific basis. Such an approach obviously relies on empirical observations and personal opinion. In this article, it is first demonstrated that the outpatient clinic of the center for pediatric diabetology in Zurich can be compared with the general population of this region of Switzerland and, in addition, that the average HbA1c is not representing a selected cohort or a privileged population. In the following, the long-term strategy of our diabetes staff is described on the example of insulin-dependent diabetes during adolescence.
Outcome of Quality Management in Pediatric Diabetes Care
Authors: Bindesbøl Mortensen Henrik
Published: April 2003

In 1988 and 1990 screening for HbA1c and albumin excretion rate (AER) in diabetic children was carried out throughout Denmark. Each study included about 1,000 diabetic patients and found HbA1c and insulin requirements increased during maturation in both sexes. No significant differences in HbA1c were seen among adolescents treated with two, three or more daily insulin injections. The prevalence of persistent microalbuminuria was 4.3% which was associated only with age and diastolic blood pressure. An international survey on HbA1c and insulin treatment, involving 2,873 children, showed HbA1c to vary significantly between centers. Severe hypoglycemia was related to younger age (0–8 years) and lower HbA1c. Of the children on twice and three times daily injections, 37% used a premixed form of insulin. Very young children were treated with a higher proportion of long-acting insulin. Among adolescent boys, lower HbA1c was related to the use of more short-acting insulin. The data confirm that current treatment of childhood diabetes is inadequate.
Computer Programs and Datasheets
Authors: Holl Reinhard W.
Published: April 2003

Despite modern treatment regimens, late complications in IDDM patients are still prevalent. Even in developed countries, a significant number of patients do not get the treatment which would be considered optimal based on the present state of medical knowledge. Quality documentation provides a successful approach to unmask deficits and to improve the outcome of care. Structural aspects as well as process and outcome indicators are different in pediatric diabetology compared to the care of adult patients. The German Working Group on Pediatric Diabetology has discussed and finalized a Statement on Quality Control, including specific parameters to be recorded prospectively in all patients. Under the auspices of the German Ministry of Health, a Computer Program designed for inpatient and outpatient care in pediatric diabetology was developed. Among many other features, internal and external quality control according to the guidelines of the German Working Group are facilitated by this approach, as no separate data entry is required. This program is now widely used among pediatric – as well as some adult – diabetes centers in Germany. Regular external comparisons of quality indicators are organized by the Working Group.
Physiological Roles of Integrin α6β1 in Ovarian Functions
Authors: Fujiwara Hiroshi , Kataoka Nobuhiko , Honda Tetsuro , Ueda Masamichi , Yamada Shigetoshi , Nakamura Kimihiko , Suginami Hiroshi , Mori Takahide , Maeda Michiyuki
Published: April 2003

We previously reported that human ovarian cells express integrin β1 families. The physiological role(s) of integrins was investigated using in vitro human granulosa cell culture and in vivo mouse ovulation model. In human luteinizing granulosa cell culture obtained from the patients undergoing in vitro fertilization treatment, laminin, which is a ligand for integrin α6β1, suppressed the production of progesterone by granulosa cells. On the other hand, the anti-α6 monoclonal antibody (mAb) GoH3, which partially inhibits the interaction between integrin α6β1 and laminin, enhanced production of progesterone by 2-fold of the control under the culture with laminin, indicating that integrin α6β1 regulates the luteinization of human granulosa cell during the periovulatory phase. In an immature superovulated 13-day-old ICR (CD-1) mice model, intraperitoneal administration of GoH3 induced successful ovulation, whereas no ovulation was observed in the GoH3-nontreated groups, showing that integrin α6β1 is related to gonadotropin-induced follicular growth. These findings suggest that the interaction between integrin α6β1 and laminin plays an important role in the corpus luteum formation and follicular growth.
Significance of Sex Steroids in Roles of Cadherin Subfamily and Its Related Proteins in the Uterine Endometrium and Placenta
Authors: Fujimoto Jiro , Sakaguchi Hideki , Hirose Reiko , Tamaya Teruhiko
Published: April 2003

To know the biological functions of the adherens junction in uterine endometrium, mRNA expressions of E-cadherin and α- and β-catenin, which mainly comprise the adherens junction, were determined. Furthermore, to understand various functions related to V-cadherin in the placenta, vessel permeability was determined by assessing V-cadherin mRNA expression in HUV-EC-C cells, derived from the endothelial cells in human umbilical cord. The levels of E-cadherin and α- and β-catenin mRNAs in the endometria of the proliferative phase were significantly less than those of the secretory phase. Treatment with estradiol dipropionate significantly reduced their levels in the endometria of the secretory phase. These suggest that the functions of the adherens junction in endometrial epithelial cell are controlled by sex steroids. On the other hand, estradiol decreased the endothelial cell barrier properties in HUV-EC-C cells, whereas progesterone partly reversed the changes induced by estradiol. While estradiol decreased the level of V-cadherin mRNA in HUV-EC-C cells, progesterone partly reversed the level decreased by estradiol. Therefore, sex steroids play a role in placental development and function related to cadherins on the endothelial cells, probably via placental vessel permeability.
Role of β1 Integrins in Human Endometrium and Decidua during Implantation
Authors: Yoshimura Yasunori , Miyakoshi Kei , Hamatani Toshio , Iwahashi Kazuhiro , Takahashi Jun , Kobayashi Noriko , Sueoka Kou , Miyazaki Toyohiko , Kuji Naoaki , Tanaka Mamoru
Published: April 2003

The present study was undertaken to investigate the expression and function of β1 integrins in human endometrium and decidua. Fluorescence-activated flow cytometry demonstrated the greater expression of the β1, α1, α2, and α5 subunits of the β1 integrin family in cultured stromal cells from the midsecretory phase than in those of the early proliferative phase. The addition of estradiol (E2) and progesterone (P) to cultured stromal cells in the early proliferative phase increased the expression of β1 integrins in vitro. The immunohistochemical distribution of β1 integrins demonstrated predominantly glandular epithelial staining in the proliferative phase, and stromal and glandular staining in the midsecretory phase. Flow cytometry also demonstrated the expression of β1, α1, α2, α3, α5, and α6 subunits of β1 integrin family in cultured decidual cells. Immunohistochemistry confirmed the β1 integrin cell surface phenotypes in cultured decidual cells observed by flow cytometry. In the subsequent experiment, the effects of antibodies against specific β1 integrin heterodimers on mouse embryo attachment and spreading were tested to identify the role of β1 integrins in early implantation. We developed assays for the attachment of mouse embryos and for trophoblastic spreading on cultured human decidual cells. The addition of antibodies directed against β1 and α integrin subunits to cultured decidual cells did not affect the rates of hatching or attachment of the blastocysts, whereas the outgrowth of embryos on the decidual cells was inhibited by their antibodies in a dose-dependent manner. Thus, β1 integrin in human endometrium and decidua may be important in mediating the organization of extracellular matrix proteins derived from embryos during the early stage of implantation.
Serum Growth Hormone Measurements in Clinical Practice: An Audit of Performance from the UK National External Quality Assessment Scheme
Authors: Seth John , Ellis Andy , Al-Sadie Ruth
Published: April 2003

The replacement of growth hormone (GH) radioimmunoassays with a variety of more specific immunometric methods in diagnostic service laboratories has led to a worsening of between-laboratory agreement, reflecting differences in method bias. Incorrect calibration and differences in specificity are important causes of method bias, but the impact of this on interpretation is not clear. In order to maximize the diagnostic reliability of GH testing for small stature, manufacturers should carefully calibrate their methods against the appropriate GH International Standard, and should use antibodies of broadly agreed specificity. Laboratories performing GH tests should participate in a reliable External Quality Assessment (EQA) scheme and guidelines for investigation that incorporate normal GH responses should be agreed.
Variety in Growth Hormone Determinations due to Use of Different Immunoassays and to the Interference of Growth Hormone-Binding Protein
Authors: Ebdrup Lotte , Fisker Sanne , Sørensen Hans Holmegaard , Ranke Michael B. , Ørskov Hans
Published: April 2003

More than 30 years after their introduction, growth hormone (GH) immunoassays showed the poorest inter-laboratory agreement of the various hormone assays evaluated in 1998 by the UK National External Quality Assessment Scheme, in which different laboratories using different assays reported that analyses of identical samples differed two- to threefold in value. There is therefore an urgent requirement and desire within the scientific community, particularly within centres diagnosing and treating GH deficiency and acromegaly, to resolve this problem and to develop a GH assay(s) that measures solely all of the relevant components of circulating GH immunoreactivity. The main confounders in the estimation of GH levels (now that the use of GH standards other than that recommended by the World Health Organization has largely been eliminated) are GH heterogeneity, anti-GH antiserum binding site specificity and interference from circulating high-affinity GH-binding protein (GHBP). The effects of these factors are closely related. The present study investigates these factors, focussing on the influence of GHBP and antibody binding site specificity on various assays for GH. The findings lead the authors to suggest that a solution to the problem may be to develop a GH assay that measures specifically and solely all serum 22 kDa GH, as this is the major circulating fraction and carries the dominant GH bioactivity.
What Randomized Trials and Systematic Reviews Can Offer Decision Makers
Authors: Altman Douglas G.
Published: April 2003

It is important to recognize the studies that yield the most reliable evidence upon which to base treatment decisions. Randomized trials have a particular place in providing high-quality unbiased comparisons of different treatments, when carried out to a high methodological standard. Empirical evidence shows that such trials are not always done well, and also that poor methodology is associated with biased findings. Consumers of the published literature need to be able to recognize which trials can be trusted. Systematic reviews and meta-analyses offer an organized approach to assessing all the relevant literature on a topic, particularly when several randomized trials address the same treatment comparison. Like trials, systematic reviews and meta-analyses need to be carried out to a high standard. They offer particular potential for providing the most useful information for clinical decision making. Critical aspects of these types of study are considered in this paper.
What Observational Studies Can Offer Decision Makers
Authors: Black Nick
Published: April 2003

Observational studies, for example cohort and case-control studies in which patients are allocated treatment on a non-random basis, are thought by some investigators to be flawed. This view results from the fact that, unlike experimental methods (randomized controlled trials; RCTs), the results of such observational studies are vulnerable to confounding. However, this view assumes that satisfactory adjustment of differences in risk or prognosis between treatment groups is impossible and it ignores some of the limitations of RCTs. While many of the problems involved in conducting RCTs could be overcome, the practical implications for researchers and funding bodies mean this is often not possible. In such circumstances, observational studies offer an alternative to an absence of any scientific evidence. While making use of observational methods, researchers must acknowledge the associated limitations: the inevitable inability to take unknown confounders into account, non-blinding of practitioners and patients, and the inclusion of practitioners’ and patients’ treatment preferences.
Clinical Research Databases and Clinical Decision Making in Chronic Diseases
Authors: Kahn Michael G.
Published: April 2003

Chronic diseases are the major source of morbidity, mortality, and resource utilization. Large-scale longitudinal databases are rapidly proliferating in both single- and multi-institutional settings, providing clinical data on a broad range of patients who receive ‘real world’ management. Although bias and changing medical management may limit the types of questions that can be addressed using the data contained in longitudinal clinical databases, many initial hypotheses can be generated from the data. Because chronic diseases persist over long periods of time, understanding the impact of temporal relationships, and of concurrent clinical events and contexts is critical to meaningful interpretation of clinical data. Adapting techniques initially developed for the physical sciences and for statistical process control can produce visual displays of clinical data that capture complex temporal and contextual information. With these tools, investigators can quickly explore vast quantities of clinical data, and discover new temporal relationships and emerging trends.
Growth Hormone Secretagogues: The Clinical Future
Authors: Micic Dragan , Casabiell Xesus , Gualillo Oreste , Pombo Manuel , Dieguez Carlos , Casanueva Felipe F.
Published: April 2003

Growth hormone (GH) releasing hexapeptide (GHRP)-6 and other peptidergic and non-peptidergic compounds collectively designated GH secretagogues (GHS) are potent releasers of GH in man. Their clinical future may be envisioned in three areas: therapy of GH-deficient (GHD) states, diagnosis of GHD, and non-endocrinological actions. As therapeutic agents and compared with GH itself, GHS have the disadvantage of lower potency but have a more physiological and safer profile of GH secretion. GHS administration could be indicated for states in which medium GH doses have been shown to be effective. As a diagnostic tool, the combined administration of GH releasing hormone plus GHRP-6, both at saturating doses, is currently the most powerful releaser of GH, devoid of side effects and convenient for the patient; it may also be an alternative to the insulin tolerance test for the diagnosis of GHD in adult patients. Their potential action at cardiovascular level is highly promising. Although the clinical future of GH releasing substances is appealing, probably the most relevant contribution has yet to be discovered. Once the endogenous ligand of the GHS receptor is identified, we will have an insight into the real hypothalamic control of GH secretion in man. With this knowledge it is likely that some diagnostic and therapeutic actions that are commonly undertaken will significantly change.
Insulin-Like Growth Factor-I and Binding Protein-3 and Risk of Cancer
Authors: Giovannucci Edward
Published: April 2003

Insulin-like growth factor (IGF)-I is an important mitogen required by some cell types to progress from the G1 phase to the S phase of the cell cycle. IGF binding proteins (IGFBPs) can have opposing actions, in part by binding IGF-I, but also by direct inhibitory effects on target cells. As mitogens and anti-apoptotic agents, IGFs may be important in carcinogenesis, possibly by increasing the risk of cellular transformation by enhancing cell turnover. Indeed, many types of neoplastic cells express or overexpress IGF-I receptors, which stimulate mitogenesis when activated by IGF-I in vitro. In vivo, tissue IGF bioactivity is determined not only by circulating IGF-I and IGFBP levels, but also by local production of IGFs, IGFBPs, and possibly IGFBP proteases that enhance IGF-I availability by cleaving IGFBPs. Because determinants of tissue IGF bioactivity appear to be regulated in parallel with circulating IGF-I level, it is reasonable to hypothesize that the substantial intraindividual variability in circulating levels of IGF-I and IGFBP-3 may be important in determining risk of some cancers. In recent epidemiologic studies, relatively high plasma IGF-I and low IGFBP-3 levels have been independently associated with greater risk of prostate cancer in men, breast cancer among premenopausal women, and colorectal adenoma and cancer in men and women and possibly lung cancer. These include prospective data from the Physicians’ Health Study and the Nurses’ Health Study. In general, two- to fourfold elevated risks have been observed for prostate cancer in men in the top quartile of IGF-I relative to those in the bottom quartile, and low levels of IGFBP-3 were associated with an approximate doubling of risk. For breast cancer, an association with IGF-I for postmenopausal women was not apparent, but strong associations were observed for premenopausal cases in the Nurses’ Health Study. Further study is needed to confirm this subgroup finding in women. Recent data also indicate that high IGF-I and low IGFBP-3 increase risk of colorectal cancer and large or villous adenomas. Of note, for colorectal neoplasia, fourfold elevated risks were observed in men and women with low IGFBP-3, whereas high IGF-I was associated with a doubling of risk. These emerging epidemiologic data indicate that high levels of IGF-I and low levels of IGFBP-3 are associated with an increased risk of at least several types of carcinoma that are common in economically developed countries. Further study is required to determine the clinical relevance of these findings.
Diagnosis of Late Puberty
Authors: Argente J.
Published: April 2003

Late puberty is defined as the lack of pubertal development at two standard deviations above the mean age for the general population of the geographical area. In practical terms, this is a chronological age of 14 years for males (testicular volume <4 ml) and 13 years for girls (lack of thelarche). The goal of the assessment is to determine whether the delay or lack of development is due to a lag in normal pubertal maturation or represents an abnormality that must be investigated. Etiologies of pubertal delay and pubertal failure include: a) Constitutional delay of puberty (healthy patients with a clinical history of delayed growth and development; b) Hypogonadotropic states (congenital abnormalities, tumours, endocrinopathies); c) Hypergonadotropic states (chromosomal alterations, syndromes, genetic disorders, radiotherapy/chemotherapy); d) Secondary to chronic illness (organic abnormalities, oncological diseases, malnutrition, eating disorders and endocrinopathies). Diagnostic evaluation must include: a detailed physical examination, including auxological parameters (height and bone maturation), personal and familial antecedents, measurements of general hematological and biochemical parameters, gonadotropins, prolactin, thyroid hormones, sex steroids, growth hormone and growth factors. When necessary, an MRI must be performed. A karyotype is indicated in girls with delayed puberty and short stature and in boys who have small testes and hypergonadotropism.
Norditropin® SimpleXxTM: A Liquid Human Growth Hormone Formulation, a Pen System and an Auto-Insertion Device
Authors: Müller J. , Skakkebæk N.E. , Jacobsen B.B. , Keller E. , Heinrich U. , Hartmann K. , Hokken-Koelega A.C.S. , Delemarre-van de Waal H.A.
Published: April 2003

Patient compliance is of vital importance for the outcome of any medical therapy. Compliance is especially a problem in long-term treatment of non-life threatening diseases, such as growth retardation in children. Until recently, all human growth hormone (hGH) products required a reconstitution process. Norditropin® SimpleXxTM is a liquid formulation of the biosynthetic hGH product Norditropin®, and, together with an improved NovoPen® 1.5, NordiPenTM, and an auto-insertion device, PenMateTM/NordiPenMateTM, it has been developed in order to ease the injection process for patients. A randomized, open, multicentre, crossover trial compared Norditropin® SimpleXxTM/improved NovoPen® 1.5 with freeze-dried Norditropin® PenSet®/Nordiject®. A total of 67 children with GH deficiency, aged 5–18 years, were treated with either Norditropin® SimpleXxTM for 6 weeks followed by Norditropin® for 6 weeks or the opposite (sequences I and II, respectively). Acceptability/convenience and pain perception were evaluated by questionnaire after each period. The function and handling of the PenMateTM were evaluated in a Dutch trial by 27 GH-treated children with intrauterine growth retardation, aged 4–16 years, and their parents. All children were accustomed to using the Nordiject® pen. The evaluation of the PenMateTM was based on a questionnaire. A similar trial was conducted in England, in which the NordiPenTM and the NordiPenMateTM were evaluated by 25 GH-treated children and their parents. Norditropin® SimpleXxTM was found to be easier to inject by 64% of the children, and 98% of the children found the system easier to use overall. There was no difference in pain perception between the two administration systems, as judged by questionnaires and visual analogue scale score. Three out of four patients preferred to continue treatment with Norditropin® SimpleXxTM. The safety profiles of the two systems were similar. In the Dutch trial, the PenMateTM was found to be easy and safe to handle, even for very young children (aged 4–5 years). Of patients who took a long time to get used to the injections, 73% found that the new pen would help. A total of 88% of the children would prefer to use the PenMateTM in the future. Positive results of the handling tests were also reported in the British trial. The use of Norditropin® SimpleXxTM and the auto-insertion device may improve patient compliance.
Metabolic Studies of a Synthetic Lipolytic Domain (AOD9604) of Human Growth Hormone
Authors: Ng F.M. , Sun J. , Sharma L. , Libinaka R. , Jiang W.J. , Gianello R.
Published: April 2003

A synthetic analogue (AOD9604) of the lipolytic domain of human growth hormone (hGH) has been studied for its metabolic actions in obese Zucker rats. Daily treatment with an oral dose of AOD9604 of 500 µg/kg body weight for 19 days reduced over 50% (15.8 ± 0.6 vs. 35.6 ± 0.8 g) body weight gain of the animals in comparison with the control. The adipose tissues of the AOD9604–treated animals were found to have an increase in lipolytic activity. In contrast to chronic treatment with intact hGH, chronic treatment with AOD9604 showed no adverse effect on insulin sensitivity of the animals, as demonstrated with euglycemic clamp techniques. The results in the present study suggest that the analogue of the hGH lipolytic domain may have the potential to be developed into an orally usable and safe therapeutic agent for obesity.
Auxological and Endocrine Evolution of 28 Children with Prader-Willi Syndrome: Effect of GH Therapy in 14 Children
Authors: Tauber M. , Barbeau C. , Jouret B. , Pienkowski C. , Malzac P. , Moncla A. , Rochiccioli P.
Published: April 2003

We report on the auxological and endocrine evolution of 28 patients presenting with Prader-Willi syndrome. Half of them received growth hormone (GH) therapy (group 2). The spontaneous auxological evolution was analyzed in the two groups from 2 to 8 years; the mean SDS for height remained stable (–0.6 ± 0.6) in group 1 and decreased (from –2.0 ± 0.9 to –2.7 ± 0.6) in group 2. Magnetic resonance imaging showed marked pituitary hypoplasia in the two groups. In group 2, the mean GH peak after two provocative tests was 3.8 ± 2.4 µg/l, the mean SDS values for insulin-like growth factor I levels were –2.0 ± 1.5 (range from –0.5 to –5.0). The mean duration of GH treatment was 3.6 ± 2.9 (range 1–9.3) years. 14 children completed 1 year of treatment. The two groups had opposite evolutions in ΔSDS for height (–0.8 ± 0.8 vs. +1.1 ± 0.8), for growth velocity (–1.9 ± 2.2 vs. +2.9 ± 2.7), and for Z score of the body mass index (+0.37 ± 1.3 vs. –0.14 ± 0.76; group 1 vs. group 2). This retrospective study shows that, in children with Prader-Willi syndrome and true GH deficiency, long-term GH therapy is effective in increasing growth velocity and in maintaining body mass index.
Epidermal Growth Factor Inhibits 8-Br-cAMP-Induced Decidualization of Human Endometrial Stromal Cells
Authors: Sakamoto Tomoko , Tanaka Tetsuji , Umesaki Naohiko , Ogita Sachio
Published: April 2003

The effects of epidermal growth factor (EGF) on human endometrial stromal cells have not been characterized well, although production of EGF in endometrial epithelial and stromal cells and expression of EGF receptors in endometrial stromal cells have been reported. We investigated the effects of EGF on endometrial cell viability, 8-Br-cAMP-induced stromal decidualization, and prolactin secretion from decidualized endometrial stromal cells using an in vitro decidualization activity assay of human endometrial stromal cells. EGF did not show any significant effects on viable cell numbers of nondecidualized and 8-Br-cAMP-induced decidualized cells. Prolactin release from the 8-Br-cAMP-induced decidualized cells was not affected by EGF. However, EGF dose-dependently inhibited prolactin release from the stromal cells that were in the process of decidualization by co-stimulation with 8-Br-cAMP and EGF, though there was no significant change in viable cell numbers of the 8-Br-cAMP-stimulated decidualizing cells. Flow cytometric analysis revealed that 8-Br-cAMP enhanced EGF receptor expression on the endometrial stromal cells. These results indicate that endometrial EGF inhibits decidualization through autocrine/paracrine mechanisms.
Loss of Imprinted Genes and Paternal SUR1 Mutations Lead to Focal Form of Congenital Hyperinsulinism
Authors: Fournet Jean-Christophe , Mayaud Christine , de Lonlay Pascale , Verkarre Virginie , Rahier Jacques , Brunelle Francis , Robert Jean-Jacques , Nihoul-Fékété Claire , Saudubray Jean-Marie , Junien Claudine
Published: April 2003

Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a heterogeneous disorder characterized by profound hypoglycaemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI), because the management differs significantly. The intriguing similarity between islet cell hyperplasia and tumourigenesis prompted us to investigate whether the imprinted genes in the 11p15 region are involved. Results showed that diffuse forms are caused by constitutional homozygous or compound heterozygous mutations of the SUR1 gene. In contrast, focal forms are caused by loss of the maternally inherited 11p15 region, resulting in both loss of the maternally expressed tumour suppressor genes accounting for hyperplasia and somatic reduction to hemizygosity or homozygosity of the paternally inherited SUR1, limited to the lesion. Thus, this somatic disorder, which leads both to β-cell proliferation and to hyperinsulinism, can be considered the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation.
Neonatal Diabetes: New Insights into Aetiology and Implications
Authors: Shield Julian P.H.
Published: April 2003

Neonatal diabetes mellitus (NDM) is defined as hyperglycaemia occurring in the first few weeks of life. It can be either transient (TNDM) or permanent (PNDM), and until recently, little was known about the condition. A cohort of 30 infants with a history of TNDM has been studied, and findings have suggested that NDM does not have the same aetiology as classical type 1 childhood diabetes. Uniparental isodisomy of chromosome 6 and an unbalanced duplication of paternal chromosome 6 have both been described as a genetic basis for TNDM in over 75% of the cases. In addition, cerebellar hypoplasia and Walcott-Rallison syndrome have been associated with PNDM, suggesting an autosomal recessive inheritance pattern; furthermore, a mutation in the gene insulin promoter factor 1 has been identified as a cause of pancreatic agenesis in PNDM. In the long term, TNDM may reduce beta cell functional capacity and present a predisposition to type 2 diabetes mellitus.
Molecular Pathogenesis of Neonatal Hypothyroidism
Authors: Krude Heiko , Biebermann Heike , Schnabel Dirk , Ambrugger Petra , Grüters Annette
Published: April 2003

In patients with congenital hypothyroidism (CH), the autosomal recessive inheritance of mutations of thyroid peroxidase, thyroglobulin and the NIS and pendrin genes encoding for sodium iodide transporters has been identified. CH due to thyroid dysgenesis was considered to be a sporadic disease, but recently, inheritable defects of thyroid development have been described. The autosomal recessive inheritance of mutations of the thyroid-stimulating hormone receptor gene was recognized in patients with CH and thyroid hypoplasia, while autosomal dominant mutations of the Pax-8 gene were described in patients with thyroid dysgenesis. In addition, analysis of mutations of the β-thyrotropin gene has resulted in a new understanding of the pathogenesis of central CH. Molecular genetic studies in patients with CH detected by newborn screening will provide the information necessary for genetic counselling and may help to explain the less favourable outcome present in 5–10% of the patients.
Neonatal Endocrinology of Abnormal Male Sexual Differentiation: Molecular Aspects
Authors: Hiort Olaf
Published: April 2003

Normal male sexual differentiation is a complex mechanism, depending on genetic and hormonal control. The bipotent gonad arises at the genital ridge under the control of autosomal genes which are also involved in the formation of other organs. Progression towards testicular differentiation is mediated through both autosomal and gonosomal genes, leading to alignment of Sertoli cells and Leydig cells. Within the latter, androgen formation is induced by human chorionic gonadotrophin and luteinizing hormone. The influence of testosterone and dihydrotestosterone leads to differentiation of epidydimis, vasa deferentia, prostate and external genitalia. Androgens mediate their action through the androgen receptor, a nuclear transcription factor controlling the regulation of so far unknown target genes. Genetic variations within this pathway interrupt normal male development and will lead to malformation of external and/or internal genitalia.