bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple Hormone Resistance in Short Children Born with Intrauterine Growth Retardation?
Authors: Chatelain Pierre G. , Nicolino Marc , Claris Olivier , Salle Bernard , Chaussain Jean-Louis
Published: April 2003

Intrauterine growth retardation (IUGR) is encountered in 2.5% (–2 SD) of newborns. Lack of postnatal catch-up growth is found in 8–20%. If GH secretion is increased early postnatally in IUGR, then some persistently short IUGR children may present with GH insufficiency. However, the mechanism of postnatal catch-up growth is heterogenous. The response to GH treatment with regard to plasma IGF-1, GH dose and growth velocity was analyzed in persistently short idiopathic IUGR children and compared to GH-deficient (GHD) and familial short stature (FSS) children of similar age and degree of short stature. IUGR children require both a greater basal and GH-induced plasma IGF-1 in order to achieve a growth velocity of similar magnitude to that of FSS and GHD children. These data suggest a different sensitivity to GH in IUGR compared to FSS or GHD children, sustaining the hypothesis that these idiopathic IUGR children may be partially IGF-1 resistant. The recent report of partial insulin resistance in IUGR subjects raises the possibility of an IGF-1 receptor- or post-receptor-mediated defect.
Growth Hormone in the Treatment of Short Stature in Young Children with Intrauterine Growth Retardation
Authors: Czernichow P. , Fjellestad-Paulsen A.
Published: April 2003

Growth acceleration and bone maturation were studied in children with severe short stature and a history of intrauterine growth retardation (IUGR) to determine the effect of growth hormone (GH)-treatment. Patients were enrolled in an open randomized, multicenter trial and allocated to either the treated group (group 1, n = 38) or the control group (group 2, n = 31). Both groups were treated daily with 0.2 IU/kg/body weight during 3 years. The children in group 2 started the study with a 1-year observation period followed by a 3-year treatment period. At baseline, the mean age was 4.5 years, bone age was 3.3 years, height standard deviation score (SDS) was –3.4, height velocity (HV) SDS was –1.6. Auxologic data were measured every 3 months and bone age was assessed at the start of the study (baseline) and then every 12 months thereafter. After 1 year of treatment, linear HV in group 1 increased significantly in comparison with the pretreatment period (from 5.7 ± 2.0 to 10.1 ± 1.7 cm/year; p < 0.001). Increased HV was sustained during the 2nd and 3rd year of treatment and was significantly higher than at baseline. A similar growth pattern was seen during the 3 years of growth hormone (GH) treatment in group 2. The mean height SDS for chronological age increased by 2.0 ± 0.7 in the 2 groups after 3 years of treatment. Bone age remained retarded but increased with a mean of almost 4 years after 3 years of treatment in both groups. Even at a dose that is three times the replacement dose, treatment with recombinant human GH was well tolerated. From these results, we conclude that recombinant human GH treatment over 3 years can induce sustained catch-up growth in young children with severe short stature and a history of IUGR.
Molecular Mechanisms of Diabetic Angiopathy – Clues for Innovative Therapeutic Interventions
Authors: Bierhaus Angelika , Ziegler Reinhard , Nawroth Peter P.
Published: April 2003

Advanced glycation end products (AGEs), known to accumulate during aging and at accelerated rate during the course of diabetes, have been demonstrated to induce changes in endothelial properties that might contribute to the pathogenesis of micro- and macroangiopathy. Since AGE-formation not only changes the physicochemical properties of proteins, but also induces cellular signalling, activation of transcription factors and subsequent gene expression, AGEs are now regarded as important mediators of diabetic vascular disease. The growing knowledge on the molecular mechanisms underlying the AGE-dependent activation of vascular endothelial cells implicates possible new therapeutic interventions in the therapy of diabetic angiopathy.
Diabetic Glomerulopathy in Young IDDM Patients
Authors: Rudberg S. , Osterby R.
Published: April 2003

The clinical course of diabetic nephropathy may be described in stages; the normo-, micro- and macroalbuminuric stage. The basis for its development is the diabetic glomerulopathy in which accumulation of basement membrane (BM) material is pivotal. Normoalbuminuric patients have normal or slightly increased BM thickness; microalbuminuric patients show further BM thickening and mesangial expansion, formation of new capillaries, arteriolar and interstitial changes. The degree of diabetic glomerulopathy may be predicted by long-term glycemic control, diabetes duration and glomerular filtration rate (GFR). A slight decline in GFR in microalbuminuric patients is associated with increases in BM thickness, capillary diameter and interstitial volume fraction. In turn, the degree of early diabetic glomerulopathy may predict the level of microalbuminuria several years later. Improved metabolic control, even to not normal levels, retards the increase of BM thickness and matrix volume in microalbuminuric adolescents. If matrix accumulation may be prevented diabetic nephropathy will not develop. Morphometric analyses may thus be useful in evaluating the effect of intervention, also during shorter periods and at early stages.
Predictive Value of Tubular Markers for the Development of Microalbuminuria in Adolescents with Diabetes
Authors: Kordonouri Olga , Hartmann Reinhard , Müller Christian , Danne Thomas , Weber Bruno
Published: April 2003

The predictive value of tubular proteinuria and/or enzyme excretion for the development of microalbuminuria in patients with diabetes mellitus was investigated over a period of 7.5 years in 64 children and adolescents without microalbuminuria at baseline. An abnormal urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) preceded the increase of albumin excretion in all 8 patients (12.5%) developing microalbuminuria during this period (positive/negative predictive value 0.2 and 1.0, respectively). Also both, the actual as well as the long-term glycemic control (HbA1c) up to the onset of abnormal NAG excretion were predictive for the development of microalbuminuria. Fifty percent of those patients with both an elevated NAG excretion and an HbA1c ≧9% developed micro-albuminuria within the next 5 years. Therefore, periodic monitoring of urinary NAG excretion should be incorporated into the follow-up of patients with type 1 diabetes mellitus.
Non-Evidence-Based Concepts Are Still Established in the Treatment of IDDM
Authors: Heise Tim , Berger Michael , Sawicki Peter T.
Published: April 2003

Medicine is and always has been full of unproven concepts. However, when they are frequently used in clinical practice, they seem established and are therefore seldom questioned. In his book ‘Follies and fallacies in medicine’ (Glasgow, The Tarragon Press, 1989) Peter Skrabanek clearly proposed a way to improve the quality of medicine by being chronically sceptical towards all ‘established’ concepts. By cyting Bertold Brecht he proposed ‘scepticemia’ as a major tool to speed up the progress in medicine: ‘The chief cause of poverty in science is imaginary wealth. The chief aim of science is not to open a door to infinite wisdom but to set a limit to infinite error.’ In this article we will try to analyze the evidence of the three so-called cornerstones of diabetes therapy – diet, exercise and insulin – with regard to their efficacy in reaching the goals of treatment in type 1 (insulin-dependent) diabetes.
Global Situation of Growth Hormone Treatment in Growth Hormone- Deficient Children
Authors: Tanaka Toshiaki
Published: April 2003

Diagnostic criteria and treatment modalities were investigated through questionnaires from eleven countries and compared with those in Japan. All countries but Australia, where the patients can be treated with GH judged by only auxological data, use the combination of auxological data and peak GH value in provocation tests. GH value is still gold standard, but the cut off value differs among countries. Apart from the differences in cut off value, since it is well-known that GH concentrations vary according to the assay methods and measurement kits, standardization of the measurement kits is mandatory. GH dose ranges between 0.5 and 0.7 IU/kg/week in most countries. The lowest dose (fixed dose of 0.5 IU/kg/week) is used in Japan and the heightest dose (1.05 IU/kg/week) is used in the USA. The costs for GH treatment are most expensive in Japan.
The Clinical Usefulness of Liquid Human Growth Hormone (hGH) (Norditropin® SimpleXxTM) in the Treatment of GH Deficiency
Authors: Iyoda Kuniaki , Moriwake Tadashi , Seino Yoshiki , Niimi Hiroo
Published: April 2003

Human growth hormone (hGH) is an essential therapeutic drug for the treatment of GH deficiency. The development of recombinant GH using a pen injection system has enabled easy and safe treatment of GH-deficient patients; however, the process of dissolving hGH in the powder form is complicated and dangerous. In this study, we investigated the usefulness of a newly developed liquid form of hGH (Norditropin® SimpleXxTM) in the treatment of 51 patients with GH deficiency. Fifteen previously untreated patients with GH deficiency were treated with liquid hGH (group A), and 36 patients who had previously used hGH in the powder form were changed to the liquid form (group B). Both groups were treated with liquid hGH 0.5 IU/kg per week for 6 months. The growth rate of patients in group A increased from 4.0 ± 2.4 cm/year to 9.2 ± 2.9 cm/year. The patients in group B continued to grow at the same rate as before using the liquid hGH therapy. Questionnaires to the patients in group B demonstrated that 85% preferred the convenience of using the new liquid form of hGH. Our results indicate that liquid hGH has similar efficacy to that of powder hGH, but its improved convenience may have a beneficial effect on patient compliance.
Growth Hormone and Fluid Retention
Authors: Møller Jens , Nielsen Sten , Hansen Troels Krarup
Published: April 2003

A major side effect of growth hormone (GH) administration is fluid retention. Most data indicate that adult GH-deficient patients are dehydrated, i.e. they have low total body water, low extracellular water and low plasma volume. When GH substitution is initiated in these patients their body fluid compartments are restored to normal. The fluid retaining capacity of GH should therefore be regarded as a desirable physiological normalization of fluid homeostasis rather than an unpleasant side effect.
Impact of Growth Hormone Administration on Other Hormonal Axes
Authors: Jørgensen J.O.L. , Ovesen P. , Juul A. , Hansen T.K. , Skakkebæk N.E. , Christiansen J.S.
Published: April 2003

Growth hormone regulates several other hormonal systems and vice versa. The present review focusses on the effect of GH administration in adults on selected hormonal systems. Growth hormone treatment has been linked to development of central hypothyroidism in hypopituitary children. We now know that GH enhances the extra-thyroidal conversion of T4 to T3. Lowering of T4 during GH treatment therefore reflects biochemical unmasking of subclinical central hypothyroidism. In normal adults GH administration does not affect the pituitary-gonadal axis. There is, however, evidence to suggest that GH substitution in hypopituitary adults enhances peripheral actions of sex steroids (males) and stimulates gonadal function (females). Both increased, unchanged and reduced basal and ACTH stimulated glucocorticoid levels have been reported during GH treatment. Several groups have recorded reduced levels of cortisol binding globulin with unchanged free cortisol concentrations. Regular assessment of thyroid and glucocorticoid status during GH substitution in GH-deficient patients is recommended.
Body Composition as a Clinical Endpoint in the Treatment of Growth Hormone Deficiency
Authors: Haymond Morey W. , Sunehag Agneta L. , Ellis Kenneth J.
Published: April 2003

Endpoints in the treatment and management of adults with growth hormone (GH) deficiency (GHD) can be problematic. Changes in body composition with recombinant human GH (rhGH) treatment may be one of the most objective measures that could be applied in judging the effectiveness and long-term efficacy. The relative strengths and weaknesses of measures of body composition and their potential for clinical utility in the setting of rhGH replacement in GHD in adults are discussed. Measurement of changes in body fat, regardless of the method employed, from pretreatment baseline through 2–6 months of treatment may be quite useful in demonstrating the efficacy of rhGH in each patient. Other changes in body composition are compromised by the imprecision of the measurements, shifts in extracellular water, and the small real changes which occur in bone and muscle in the GHD subject. Use of body composition measures of change in fat content as an endpoint in determining the efficacy of rhGH treatment in adults with GHD cannot be implemented on the basis of current data and would require a carefully designed prospective, controlled study. Until such criteria are established and accepted, endocrinologists must continue to manage these patients purely on the basis of their clinical judgment.
CYP11B2 Expression in Rat Liver and the Effect of Spironolactone on Hepatic Fibrogenesis
Authors: Yang Xishan , Li Xu , Wu Pingsheng , Meng Ying , Li Sumei , Lai Wenyan
Published: April 2003

Objective: In consideration of the hypothetical possibility that locally produced aldosterone is likely to take an active part in fibrogenesis of the liver, we undertook the present study to investigate the expression of aldosterone synthase gene CYP11B2 in rat liver and the curative effect of spironolactone on fibrosis of the liver. Methods and Materials: 160 Wistar rats weighing about 250 g were divided into four groups as follows: model group, spironolactone group, malotilate group and control group. After 2, 4, 6, 8 and 10 weeks, the animals were sacrificed. Morphological examination was based on microscopic and electron microscopic findings. The area of collagen was examined by an Image Analyse System (Leica). By means of reverse transcriptase-polymerase chain reaction and in situ hybridization, the expression of CYP11B2 was detected. Results: The expression of CYP11B2 mRNA, which was localized in the endoplasm of fat-storing cells, was upregulated when fibrogenesis occurred. The grade of fibrosis and the area of collagen in the spironolactone group were less than those in the model group before the 6th week (p < 0.05). After the 6th week, there was no significant difference between the spironolactone group and the model group (p > 0.05). Conclusions: The expression of CYP11B2 mRNA is upregulated in fibrotic liver. Spironolactone can partly have a fibrogenesis-inhibiting effect in the early stage of CCl4-induced hepatic fibrogenesis.
Human Endometrial Stromal Interleukin-1 Beta: Autocrine Secretion and Inhibition by Interleukin-1 Receptor Antagonist
Authors: Tanaka Tetsuji , Sakamoto Tomoko , Mizuno Kuniko , Umesaki Naohiko , Ogita Sachio
Published: April 2003

Decidualization of human endometrial stromal cells is suppressed by endometrial IL-1 in an autocrine or paracrine manner, indicating that constant suppression of stromal decidualization by IL-1 requires a neutralizing mechanism for IL-1 action to accept embryo implantation. Since production of IL-1ra in human endometrium is reported to be 10- to 30-fold higher than that of IL-1α/β, we investigated whether endogenous IL-1β secreted from human endometrial stromal cells can be inhibited by IL-1ra by using an in vitro decidualization culture. Human stromal cells were cultured with 8-Br-cAMP to induce decidualization, and concentrations of IL-1β, IL-8, and prolactin in the culture supernatants were assayed before and after decidualization. There was no significant difference in mean IL-1β concentrations measured before and after decidualization. Addition of IL-1ra to endometrial stromal cell cultures strongly inhibited endogenous IL-8 secretion from the cells. Although IL-1β showed a biphasic effect on cell proliferation and a suppressive effect on decidualization of stromal cells, these effects were completely inhibited by IL-1ra. The results imply that a high in vivo concentration of IL-1ra in human endometrial tissues may regulate IL-1 effects on decidualization and cell proliferation of human endometrial stromal cells.
Treatment of Juvenile Rheumatoid Arthritis with Growth Hormone
Authors: Simon Dominique , Prieur Anne-Marie , Czernichow Paul
Published: April 2003

Severe growth retardation and profoundly altered body composition are observed in children with juvenile chronic arthritis receiving glucocorticoids. This study assessed the effects of growth hormone (GH) on height velocity, body composition and bone density. Fourteen patients were treated with GH (1.4 U/kg/week) for 1 year and then studied for a 2nd year off GH. The treatment increased insulin-like growth factor 1 and insulin-like growth factor binding protein 3 plasma levels. All patients showed an increase in height velocity. Lean body mass increased by 12%. After the cessation of GH therapy, height velocity fell to pretreatment values, and weight and fat mass increased markedly. Bone formation and resorption markers significantly increased during treatment and returned to pretreatment values after discontinuation of GH treatment. These results suggest that GH may partially counteract the adverse effects of glucocorticoids on growth and metabolism in patients with chronic inflammatory disease.
Low Areal Bone Mineral Density Values in Adolescents and Young Adult Turner Syndrome Patients Increase after Long-Term Transdermal Estradiol Therapy
Authors: Gussinyé M. , Terrades P. , Yeste D. , Vicens-Calvet E. , Carrascosa A.
Published: April 2003

Objective: To study the effects of long-term estradiol therapy on areal bone mineral density (aBMD) values in young adult Turner syndrome patients. Methods: The effects of 2-year transdermal estradiol administration on lumbar, L2–L4, aBMD values were evaluated in 12 Turner syndrome patients, 15.41–21.85 years old, who had reached adult height and had low aBMD values. Puberty was induced in all at a chronological age above 12 years and menarche appeared between 13.82 and 15.40 years. The patients were on oral estrogen/gestagen therapy from then until the start of the study. Adhesive patches of 17-β-estradiol designed to be worn for 72 h and deliver 100 µg of estradiol per day, which results in a steady mean serum estradiol level of 75 pg/ml, were used for 21 days. From day 11 to day 21, 10 mg of oral didrogesterone were also added. Nutritional and physical activity habits were evaluated at the beginning, after 1 year and at the end of the study. Results: aBMD values significantly increased from 0.910 ± 0.065 to 1.005 ± 0.086 g/cm2 (10.06 ± 3.37%) and the z-score from –2.38 ± 0.63 to –1.54 ± 0.71 (0.81 ± 0.30 z-score). No significant differences were observed in body mass index, calcium intake and physical activity habits at the start, during and at the end of the study. Conclusion: In summary, our results underline the importance of estrogens for bone mass peaking and suggest that this therapeutic protocol may be useful in the therapy of Turner syndrome patients with low bone mass.
Transient Pseudohypoaldosteronism with Complex Malformation of Internal Genitalia
Authors: Iliev D.I. , Petruch U.R. , Ranke M.B. , Binder G. , Leriche C. , Strotbek G. , Wollmann H.A.
Published: April 2003

At the age of 3 weeks, a girl presenting with acute dehydration was admitted to our hospital. Clinical and laboratory findings revealed malformations of the genitourinary tract, an acute urinary infection and electrolyte disturbances (severe hyponatremia at 115 mmol/l and mild hyperkalemia at 5.6 mmol/l). According to anamnestic data, the child was born to healthy, nonconsanguineous parents. Vaccum extraction was done in the 38th gestational week due to pathological cardiotocography (CTG) findings. Auxological parameters were within the normal range for gestational age. Normal values for 17-OH progesterone and ACTH ruled out congenital adrenal hyperplasia (CAH). Pathologically high aldosterone and plasma renin activity (PRA) confirmed the diagnosis of pseudohypoaldosteronism with salt-wasting crisis which proved to be transient.
Effect of Human Chorionic Gonadotropin Derivatives on Leydig Cell Function
Authors: Ronco Ana María , Llanos Miguel N.
Published: April 2003

Background: Several human chorionic gonadotropin (hCG) derivatives have been detected in healthy human subjects, indicating that they may play a role in cell function. These hCG derivatives include deglycosylated hCG, proteolytic digestion products of hCG and free α and β subunits of the hormone. It is well documented that testicular Leydig cells are responsive to luteinising hormone (LH) or its analogue hCG. These hormones have high affinity for LH/hCG receptors on the plasma membrane. Methods: We designed functional and binding studies to compare the effects of native hCG and several hCG derivatives on a rat Leydig cell system. The molecular weight of the hCG derivatives was determined by SDS-PAGE and the binding affinity to LH/hCG receptors was measured by a radioligand assay. In addition, their ability to produce testosterone, cyclic AMP and arachidonic acid release was also studied. Results: These hCG derivatives, with the exception of the free β subunit, were able to bind to LH/hCG plasma membrane receptors with different affinities than that of native hCG. In addition, hCG derivatives did not increase intracellular cAMP levels or arachidonic acid release. However, they did increase testosterone production. Conclusion: Taken together, the results of this study lead us to suggest that these hCG derivatives may regulate the action of the native hormone in Leydig cells and are, thus, molecules of physiological relevance.
Height, Bone Mineral Density and Bone Markers in Congenital Adrenal Hyperplasia
Authors: Paganini C. , Radetti G. , Livieri C. , Braga V. , Migliavacca D. , Adami S.
Published: April 2003

Aim: To evaluate height, bone growth, areal bone mineral density (aBMD), volumetric bone mineral density (vBMD) and markers of bone turnover in a group of patients affected by congenital adrenal hyperplasia (CAH). Patients: There were 50 patients (23 males, 27 females), aged 1–28 years, affected by CAH due to 21-hydroxylase deficiency: 27 with the salt-wasting (SW); 14 with the simple virilizing (SV), and 9 with the nonclassical (NC) forms. Methods: Bone morphometry was evaluated with the metacarpal index (MI) and lumbar aBMD and vBMD (L2–L4) by dual energy X-ray absorptiometry. Serum osteocalcin was used as a marker of bone formation, while urinary cross-linked N-telopeptides of type-I collagen and free deoxypyridinoline levels were evaluated as indexes of bone resorption. Results: The height standard deviation score (SDS) was –0.41 ± 1.4 in SW patients, –0.01 ± 1.9 in SV patients, and –0.01 ± 2.3 in NC patients. There was no significant difference among groups and against zero. The MI SDS was also not different between groups and against zero.aBMD was significantly lower in the pubertal patients compared with normal values, but only when patients with the SW and SV forms were considered together (p < 0.05). vBMD was significantly reduced in all patients with the classical form. Bone markers were not different in patients and controls. Conclusion: Our study shows that normal height can be attained in CAH patients; however, an impairment in bone growth and mineralization may be found in adolescents and young adults affected by the classical form.
The SAHA Syndrome
Authors: Orfanos Constantin E. , Adler YaeI D. , Zouboulis Christos C.
Published: April 2003

The presence of seborrhoea, acne, hirsutism and alopecia in women has first been summarized as SAHA syndrome in 1982 and can be associated with polycystic ovary syndrome, cystic mastitis, obesity and infertility. In 1994, the association of these androgen-dependent cutaneous signs, was classified according to their etiology into four types: (1) idiopathic, (2) ovarian, (3) adrenal, and (4) hyperprolactinemic SAHA. The HAIRAN syndrome has been currently described as a fifth variant with polyendocrinopathy. The SAHA syndrome generally occurs in young to middle-aged women and involves either the presence of elevated blood levels of androgens or increased androgen-driven peripheral response with normal circulating androgen levels. Peripheral metabolism of androgens takes place in various areas within the pilosebaceous unit, as indicated by local differences in the activities of aromatase, 5α-reductase as well as of the presence of the androgen receptors. In cases of SAHA syndrome, careful diagnostic and clinical evaluation has to be performed in order to identify the cause for peripheral hyperandrogenism and to exclude androgen-producing tumors. Treatment will target the etiology, whereas the management in idiopathic cases will aim to improve the clinical features of SAHA.
To Screen or Not to Screen for Pre-Type 1 Diabetes?
Authors: Schatz Desmond , Krischer Jeffrey , She Jin-Xiong
Published: April 2003

The incidence of type 1 diabetes is increasing worldwide and the disease is an onerous burden both to the individual and to society. There are thus important reasons to screen for the disease before it becomes manifest: (1) to improve understanding of the natural history of the prediabetic period; (2) to gain further insights into the immunopathogenesis of the disease; (3) to identify individuals for prevention trials; (4) to make an earlier diagnosis in order to reduce morbidity and mortality. Great strides have been made, yet there is still a great deal to be learned. Opponents of screening argue that screening tests for the disease have a low positive predictive value and that predicting the disease without a primary prevention capability raises ethical considerations because of induced stress, lifestyle changes, cost and potential effects on insurability. The greatest single barrier against large-scale population screening and prevention of the disease remains the lack of an effective intervention. However, screening in the context of well-designed research studies must continue – ultimately the benefit to the individual and to society will be immense.
Children with Type 2 Diabetes: The Risks of Complications
Authors: Matthews D.R. , Wallace T.M.
Published: April 2003

Type 2 diabetes is an increasing problem in children. Two decades ago it had been described only in selected groups, e.g. the Pima Indians. Childhood type 2 diabetes appears to be similar to the metabolic syndrome in adults and is characterized by obesity, hyperglycaemia and insulin resistance. It can present a diagnostic challenge in children, as they can present with diabetic ketoacidosis; the measurement of autoantibodies and C-peptide levels may be helpful. The logarithmic association between the risk of complications with increasing glycaemia which has been established for adults with type 2 diabetes is likely to hold true for children but the conclusions of trials in adults must be extrapolated with caution. Little is known about the onset and progression of macrovascular disease in affected children but it is almost certain that they will develop an excess of premature cardiovascular disease. However, the importance of reducing glycaemia in younger adults with diabetes, in order to minimize the incidence of microvascular complications, has been unequivocally demonstrated in the Diabetes Control and Complications Trial (DCCT). Diet and exercise have a major role to play in the treatment and prevention of type 2 diabetes in children as well as adults – the escalation of type 2 diabetes throughout the developed world is a major public health problem. Extrapolating data from adults, metformin appears to be the logical first-line treatment in children with type 2 diabetes; sulphonylureas are also used but neither of these agents have been evaluated in trials in children and are not licensed for such use. With regard to other newer agents, it seems wise to use well-established drugs with a long track record and for which the long-term safety data are available.
Islet Cell Transplantation and Other New Technologies for Treating Type 1 Diabetes: A Paediatric View
Authors: Daneman Denis
Published: April 2003

Recent advances in diabetes care have facilitated the achievement and maintenance of excellent metabolic control. New insulin pumps and continuous glucose monitoring systems provide cause for optimism that an artificial pancreas may soon be developed. In addition, transplantation biology has advanced to the point where pancreas and islet transplants are being performed with increasing frequency. Recent reports suggest that improved techniques for isolation of islets and immune suppression may allow these procedures to become more commonplace. However, serious questions regarding long-term safety and efficacy need to be answered in older individuals before consideration is given to their more routine use in children and adolescents with diabetes.
How Do We Educate Young People to Balance Carbohydrate Intake with Adjustments of Insulin?
Authors: Waldron Sheridan , Hanas Ragnar , Palmvig Birthe
Published: April 2003

The dietary management of childhood diabetes is complex. Is it possible to educate young people to balance carbohydrate with their insulin? Can dietary knowledge be translated into lasting behaviour change? Do present teaching methods provide the skills necessary for children and parents to adjust their insulin therapy adequately? Evidence shows great variation in glycaemic control between centres and countries but the impact of dietary education methods is poorly evaluated and its links with clinical and psychosocial outcomes is virtually unknown. There is also little evidence to suggest cohesive teamworking with clear dietary targets for glycaemic control, lipids, incidence of hypoglycaemia, compliance, effect on peer and sibling relationships, and evaluation of individual dietary components, e.g. fibre, fat, antioxidants. There is wide variation in methods of dietary education, which are often based on historic practice. They include rigid counting of grams of carbohydrate, carbohydrate portion assessments, qualitative diets, low glycaemic index diets and the more recent ‘intensified’ carbohydrate measures with daily adjustments of insulin (the basis also of pump management). This last method has many benefits although it requires extensive nutrition education, it allows greater flexibility and variety of food intake, is sensitive to the varying daily energy expenditure of childhood and it addresses postprandial glycaemic excursions, all of which are inadequately managed by conventional therapy. However, one of the problems of overemphasizing carbohydrate measurement is that total carbohydrate intake may be suppressed, with a resulting increase in fat, this may contribute to an increase in cardiovascular risk. The ISPAD Consensus Guidelines 2000 contain dietary recommendations but scientific evidence is often lacking. Limited dietary studies show that some countries can meet guidelines more successfully than others. There are many reasons for this, such as food availability, types of food eaten, food preferences and family/cultural/religious influences. Educational methods must be adapted to local customs. Is there enough evidence to recommend a particular dietary education method? What outcomes do we hope to achieve? The workshop explored these issues in order to develop a deeper understanding of the complexity of dietary modification in childhood diabetes.
Hypoglycaemia and Counterregulation during Childhood
Authors: Matyka K. , Ford-Adams M. , Dunger D.B.
Published: April 2003

Hypoglycaemia is particularly common in young children with type 1 diabetes mellitus yet the normal protective counterregulatory responses have been little studied in this age group. The studies reported have shown conflicting results, in part related to prior glycaemic control and also to the method of investigation used. Counterregulatory hormone responses during both spontaneous and experimentally induced episodes of nocturnal hypoglycaemia do appear to be blunted, which may be a function of sleep itself. Although studies of cognitive function have consistently shown defects in certain areas of neurocognitive performance, particularly in those children with early-onset diabetes or a prior history of severe hypoglycaemia, the contribution of nocturnal hypoglycaemia to the development of these impairments has not been evaluated. In young adults and adolescents, nocturnal hypoglycaemia has been linked to cardiac arrhythmia and the risk of sudden death. The development of new techniques for continuous subcutaneous glucose monitoring may allow detailed study of counterregulatory responses and symptom recognition in young children. Effective intensification of insulin therapy without an increased risk of hypoglycaemia may be possible using new insulin analogues or continued subcutaneous intravenous infusion (CSII), thus improving patient compliance and overall quality of clinical care.
Selection for and Initiation of Continuous Subcutaneous Insulin Infusion
Authors: Hanas Ragnar
Published: April 2003

Continuous subcutaneous insulin infusion (CSII) has been used in the paediatric age group for more than 20 years. The technique is not yet widely used in most countries but there has recently been increasing interest in pump therapy for young children and adolescents. In 1999, 7.5% of Swedish children and adolescents with diabetes used pumps, now the figure is approaching 12%. The indication for starting pump therapy has usually been a medical problem, but today quality of life issues are becoming increasingly important. One technique sometimes used is to start CSII by wearing the pump only at night. Daily insulin requirements are usually decreased compared with injection therapy. Studies have shown that it is possible to lower HbA1c when using an insulin pump and that the risk of severe hypoglycaemia can be lowered. The use of CSII has also been successful in preventing recurrent admission for diabetic ketoacidosis. While starting pump therapy does take an extra effort from both the diabetes team and the family, routine visits are generally no more time-consuming than for patients on multiple injection therapy. CSII can be initiated during admission to hospital but most pumps are started on an outpatient basis. Our department has the patients on the day care ward for 3–4 days of ‘pump school’. Parents wear a saline pump for practice. The total daily insulin dose is usually lowered 15–20% compared with multiple injections; on average 40–50% (sometimes up to 60%) of the daily dose is given as basal rate. We start all pumps on rapid-acting analogues and use 40 IU/ml if the basal rate is <0.3 IU/h. In conclusion, the use of CSII in children and adolescents is well accepted and can be managed safely.
On Estimating the Proportion of Variance in a Phenotypic Trait Attributable to a Measured Locus
Authors: Wijsman Ellen M. , Nur Nadav
Published: April 2003

The measured genotype approach can be used to estimate the variance contributions of specific candidate loci to quantitative traits of interest. We show here that both the naive estimate of measured-locus heritability, obtained by invoking infinite-sample theory, and an estimate obtained from a bias-corrected variance estimate based on finite-sample theory, produce biased estimates of heritability. We identify the sources of bias, and quantify their effects. The two sources of bias are: (1) the estimation of heritability from population samples as the ratio of two variances, and (2) the existence of sampling error. We show that neither heritability estimator is less biased (in absolute value) than the other in all situations, and the choice of an ideal estimator is therefore a function of the sample size and magnitude of the locus-specific contribution to the overall phenotypic variance. In most cases the bias is small, so that the practical implications of using either estimator are expected to be minimal.
Optimal Sibship Selection for Genotyping in Quantitative Trait Locus Linkage Analysis
Authors: Purcell S. , Cherny S.S. , Hewitt J.K. , Sham P.C.
Published: April 2003

In this paper we present a novel method for selecting optimally informative sibships of any size for quantitative trait locus (QTL) linkage analysis. The method allocates a quantitative index of potential informativeness to each sibship on the basis of observed trait scores and an assumed true QTL model. Any sample of phenotypically screened sibships can therefore be easily rank-ordered for selective genotyping. The quantitative index is the sibship’s expected contribution to the non-centrality parameter. This expectation represents the weighted sum of χ2 test statistics that would be obtained given the observed trait values over all possible sibship genotypic configurations; each configuration is weighted by the likelihood of it occurring given the assumed true genetic model. The properties of this procedure are explored in relation to the accuracy of the assumed true genetic model and sibship size. In comparison to previous methods of selecting phenotypically extreme sibships for genotyping, the proposed method is considerably more efficient and is robust with regard to the specification of the genetic model.
Weighting Improves the ‘New Haseman-Elston’ Method
Authors: Forrest William F.
Published: April 2003

Elston et al. [Genet Epidemiol, in press] apply the results of Wright [Am J Hum Genet 1997;60:740–742] and Drigalenko [Am J Hum Genet 1998;63:1242–1245] to extend the traditional Haseman-Elston regression scheme [Haseman and Elston, Behav Genet 1972;2:3–19] to include not only linkage information contained in the sib pair’s squared difference, but also information in their mean-corrected squared sum. The new algorithm detects linkage to a quantitative trait locus by modelling sib pair trait covariance as a function of identity-by-descent status. We demonstrate why this new estimator is suboptimal and can in some cases be inferior to the original Haseman-Elston method. We also describe a simple approach to estimation which improves on this new Haseman-Elston method by incorporating variance-based weights into the test statistic while staying within the linear modelling framework. In support of our theoretical claim, we conduct both a sib pair simulation and an application to GAW 10 sib pair data showing that our new estimator is superior to both the old and new Haseman-Elston schemes currently implemented in the analysis package S.A.G.E. 4.0.
Mutation Analysis of a Mauritian Hereditary Breast Cancer Family Reveals the BRCA2 6503delTT Mutation Previously Found to Recur in Different Ethnic Populations
Authors: Khittoo G. , Manning Andrew , Mustun Hassen , Appadoo Jayshree , Venkatasamy Shadila , Fagoonee Indurlall , Ghadirian Parviz , Tonin Patricia N.
Published: April 2003

Mauritius, a small island some 855 km off the east coast of Madagascar, has a multiethnic population of about 1.2 million with a high population density of about 611 per km2. The recent industrialization of the island seems to have been accompanied, in less than 10 years, by an increase of at least 30% in breast cancer incidence. We have detected the BRCA2 6503delTT mutation in two sisters of the same family of Indian origin but living in Mauritius for at least five generations. This mutation has been found to recur in geographically diverse populations and haplotype analysis has shown a common ancestry. The haplotype of the mutation found in the Mauritian family differs from that found in other populations harbouring the same mutation, suggesting that the BRCA2 6503delTT mutation most likely arose independently.
Improved Power of Sib-Pair Linkage Analysis Using Measures of Complex Trait Dynamics
Authors: Moore Jason H.
Published: April 2003

The influence of epistasis on a quantitative trait can reduce the power of linkage analysis to identify the underlying loci. In the present study, we simulated a complex trait derived from a dynamic one-locus gene expression system with epistasis arising from feedback regulation and tested the power of sib-pair linkage analysis methods for detecting the underlying quantitative trait locus (QTL). Using this simple genetic architecture, we demonstrate that the power of sib-pair linkage analysis can be greatly improved if measures of complex trait dynamics are considered.
Y Chromosome Binary Markers to Study the High Prevalence of Males in Sardinian Centenarians and the Genetic Structure of the Sardinian Population
Authors: Passarino Giuseppe , Underhill Peter A. , Cavalli-Sforza L. Luca , Semino Ornella , Pes Giovanni M. , Carru Ciriaco , Ferrucci Luigi , Bonafè Massimiliano , Franceschi Claudio , Deiana Luca , Baggio Giovannella , De Benedictis Giovanna
Published: April 2003

We have analyzed a sample of 40 centenarians and 116 young controls from Sardinia, with a set of new Y chromosome binary markers, to evaluate if Y chromosome genes are involved in the high prevalence of males among centenarian Sardinians (1/2 vs. 1/4 in other populations studied). The results indicate that none of the seven lineages that account for >97% of the Y chromosome diversity in Sardinia provide an advantage with respect to the extreme longevity. However, our results, although based on the male-specific Y chromosome polymorphisms, give a clear profile of the pattern of genetic variability in Sardinia. Indeed they indicate that the Sardinian population had two main founder populations that have evolved in isolation for at least the last 5,000 years. These findings set the stage for future studies on longevity and other complex traits in Sardinia.
A Tournament of Linkage Tests in Complex Inheritance
Authors: Zhang W. , Tapper W. , Collins A. , Jacobs K.B. , Elston R.C. , Morton N.E.
Published: April 2003

The performance of some weakly parametric linkage tests in common use was compared on 200 replicates of oligogenic inheritance from Genetic Analysis Workshop 10. Each random sample for the quantitative trait was dichotomized at different thresholds and also selected through 2 affected sibs, generating 8 combinations of sample and variable. The variance component program SOLAR performed best with a continuous trait, even in selected samples, when the population mean was used. The sib-pair program SIBPAL2 was best in most other cases when the phenotype product, population mean, and empirical estimates of pair correlations were used. The BETA program that introduced phenotype products was slightly more powerful than maximum likelihood scores under the null hypothesis and approached but did not exceed SIBPAL2 under its optimal conditions. Type I errors generally exceeded expectations from a χ2 test, but were conservative with respect to bounds on lods. All methods can be improved by use of the population mean, empirical correlations, logistic representation for affection status, and correct lods for samples that favour the null hypothesis. It remains uncertain whether all information can be extracted by weakly parametric methods and whether correction for ascertainment bias demands a strongly parametric model. Performance on a standard set of simulated data is indispensable for recognising optimal methods.
Case-Control Studies of Genetic Markers: Power and Sample Size Approximations for Armitage’s Test for Trend
Authors: Slager S.L. , Schaid D.J.
Published: April 2003

The association of a candidate gene with disease can be efficiently evaluated by a case-control study in which allele frequencies are compared for diseased cases and unaffected controls. However, when the distribution of genotypes in the population deviates from Hardy-Weinberg proportions, the frequency of genotypes – rather than alleles – should be compared by the Armitage test for trend. We present formulas for power and sample size for studies that use Armitage’s trend test. The formulas make no assumptions about Hardy-Weinberg equilibrium, but do assume random ascertainment of cases and controls, all of whom are independent of one another. We demonstrate the accuracy of the formulas by simulations.
Genetic Heterogeneity in Five Italian Regions: Analysis of PAH Mutations and Minihaplotypes
Authors: Giannattasio Sergio , Dianzani Irma , Lattanzio Paolo , Spada Marco , Romano Valentino , Calì Francesco , Andria Generoso , Ponzone Alberto , Marra Ersilia , Piazza Alberto
Published: April 2003

Molecular analysis of 289 chromosomes has been performed in a cohort of phenylketonuria (PKU) patients whose ancestors lived in five Italian regions, Calabria, Campania, Piemonte, Puglia/Basilicata and Sicilia. Phenylalaninehydroxylase (PAH) gene mutations and minihaplotypes (combinations of PAH gene STR and VNTR systems) have been determined for 78.5 and 64%, respectively, of the chromosomes studied. 21 different minihaplotypes and 24 PKU mutations were found. Heterogeneity tests carried out for the frequencies of mutations and minihaplotypes show that the distribution of eight mutations and four minihaplotypes is statistically heterogeneous in the five Italian regions. Although the evolutionary rate of microsatellites or the age of these mutations is difficult to estimate with accuracy, our findings taken together show a genetic stratification of the Italian population. These results rule out allelic homogeneity of PKU at the molecular level between regions of Italy, yet minihaplotype data may be of practical use for a multistep approach to PAH gene genotyping.
Preferential Inactivation of a dupX(q23 → q27–28) Chromosome in a Girl with Mental Retardation and Dysmorphy
Authors: Volleth M. , Stumm M. , Mohnike K. , Kalscheuer V.M. , Jakubiczka S. , Wieacker P.
Published: April 2003

We report on an 18-year-old female with de novo tandem duplication Xq23→Xq27–28. The breakpoints of the duplication segment have been mapped by FISH using a panel of locus specific YACs. Despite selective inactivation of the aberrant X chromosome, proven by a combination of molecular and cytogenetic studies, the patient exhibits mental retardation, dysmorphic features and short stature. Possible mechanisms explaining this unexpected finding are discussed.