bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of Circulating 17β-Oestradiol with Haemostatic Factors in Healthy Postmenopausal Women
Authors: Mukherjee Manjari , DeLorenzo Ferruccio , Kadziola Zbigniew , Rutlin Accabre , Ranlall Nancy , Sembhi Kuldip , Dawson Gloria , Kakkar Vijay V.
Published: April 2003

The aim of the study was to evaluate any correlation between the circulating oestrogenic hormone 17β-oestradiol and haemostatic factors in healthy postmenopausal women. In keeping with this objective, the correlations were evaluated irrespective of whether the source of the hormone was purely endogenous or exogenous as well. Accordingly, a univariate correlation adjusted for age, body mass index, and duration of menopause was determined in 42 healthy postmenopausal women aged 47–78 years, 19 of whom were self-reported users of hormone replacement therapy. The rest were self- reported never users. Serum 17β-oestradiol exhibited a direct correlation with endogenous thrombin potential extrinsic pathway (R = 0.42, p = 0.01) and prothrombin fragments 1 and 2 (R = 0.37, p = 0.03) and an inverse correlation with antithrombin III (R = –0.36, p = 0.03) and α2-antiplasmin (R = –0.45, p = 0.005). The observations suggest an association of this hormone with net thrombin generation on the one hand and improved fibrinolysis on the other.
Influence of Fibrinogen Degradation Products on Thrombin Time, Activated Partial Thromboplastin Time and Prothrombin Time of Canine Plasma
Authors: Mischke R. , Wolling H.
Published: April 2003

To investigate how thrombin time, activated partial thromboplastin time (APTT) and prothrombin time are influenced by fibrinogen degradation products (FDP), different concentrations (0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.8 and 1.0 mg/ml) of the purified FDP X, Y, D and E were added to the plasma of healthy dogs. If fragment Y was added to the plasma a considerable inhibitory effect could be demonstrated for all three test systems. A significant prolongation (p < 0.05) was found for concentrations of ≥0.1 mg/ml (thrombin time, APTT) and ≥0.2 mg/ml (prothrombin time). With FDP Y concentrations from >0.185 mg/ml (prothrombin time) to >0.24 mg/ml (APTT) coagulation time was prolonged beyond the respective reference range. As regards the other fragments, a comparable inhibitory effect could only be shown for fragment X added to the thrombin time test system. This effect can most probably be explained by the competition of the FDP X and fibrinogen for the fibrinogen binding sites of thrombin, rather than by a fibrin polymerization disorder. The results demonstrate that for plasma with normal fibrinogen concentration the group tests are only prolonged beyond the reference range at FDP concentrations very rarely found in spontaneous hyperfibrinolysis.
Characterization of Murine Anti-Glycoprotein Ib Monoclonal Antibodies That Differentiate between Shear-Induced and Ristocetin/Botrocetin-Induced Glycoprotein Ib-von Willebrand Factor Interaction
Authors: Cauwenberghs N. , Ajzenberg N. , Vauterin S. , Hoylaerts M.F. , Declerck P.J. , Baruch D. , Deckmyn H.
Published: April 2003

Platelet adhesion to vascular subendothelium under conditions of high shear stress is mediated by the platelet glycoprotein (GP) Ib-von Willebrand Factor (vWF) interaction. The aim of this study was to characterize the murine monoclonal antibodies (MoAbs) 27A10 and 28E6, both raised against purified GPIb. The MoAb 27A10 is a potent inhibitor of shear-induced platelet adhesion to collagen type I in a flow chamber at shear rates of 1,300 and 2,700 s–1. 20 μg/ml of MoAb 27A10, furthermore, could completely block shear-induced aggregation in a modified Couette viscometer at shear rates of 1,000 and 4,000 s–1. On the other hand, MoAb 27A10 had a negligible effect on botrocetin-induced GPIb-vWF binding and is only a poor inhibitor of the ristocetin-dependent interaction. In contrast, MoAb 28E6 did abolish both the ristocetin- and botrocetin-induced GPIb-vWF binding, whereas it did not block the shear-induced interaction. Thus, we identify here two anti-GPIb MoAbs 27A10 and 28E6 that either preferentially inhibit the shear-induced or the ristocetin/botrocetin-induced platelet-vWF interaction. With these tools it should be possible to more clearly define the mechanisms by which platelets bind to vWF in vivo.
Culturally Mediated Learning and the Development of Self-Regulation by Survivors of Child Abuse: A Vygotskian Approach to the Support of Survivors of Child Abuse
Authors: Miltenburg Ruth , Singer Elly
Published: April 2003

In his studies of handicapped and ‘difficult’ children, Vygotsky applied one of his basic assumptions in the domain of affective development: that human individuals try to master themselves from the ‘outside’ through the development of higher mental functions. His theoretical accounts provide both a conceptualization of the unique methods employed by abused children to compensate and a conceptual framework to study the way new psychological tools can assist the further development of abused children’s methods of compensation. In this respect, a Vygotskian therapeutic approach, together with current constructivist theories of the development of abused children, provides an alternative to psychodynamic and cognitive therapies that focus on the cause of ‘original’ traumatic experiences and the (cathartic) re-living of affective reactions to them. Clinical examples are discussed to illustrate this Vygotskian therapeutic approach.
The Quality of Cultural Tools and Cognitive Development: Gal’perin’s Perspective and Its Implications1
Authors: Arievitch Igor M. , Stetsenko Anna
Published: April 2003

Vygotsky theorized that instruction plays a key part in cognitive development by providing culturally evolved cognitive tools which, once internalized by the child, mediate and advance the child’s cognitive functioning. Gal’perin further elaborated this approach arguing that it is the quality (specific character) of cognitive tools (such as concepts, criteria, schemas) acquired by the child that to a large extent defines the specifics of cognitive development. He theoretically explicated and empirically tested an alternative type of instruction which, unlike traditional instruction, directly generated cognitive development by providing cognitive tools of a higher quality (based on theoretical concepts as opposed to empirical concepts). The often overlooked yet important implications of Gal’perinian perspective are: 1) that there is a need for the theory of development to conceptualize and integrate the processes related to learning, and 2) that most existing theories of development capture just one possible version of development – the version that is bound to deficient cognitive tools employed in the currently dominating type of instruction.
The Potential of Argument in Knowledge Building
Authors: Leitão Selma
Published: April 2003

It is a matter of quasi-consensus among argumentation researchers that engaging in argumentation sets the scene for changes in people’s views. However, the actual process by which such changes occur has not yet been entirely understood. This article represents an effort towards understanding how processes of knowledge building and transformation evolve in argumentation. To achieve this goal, it outlines a unit of analysis designed to capture the process by means of which knowledge is continuously updated through argumentation. Then, the analysis of fragments of people’s argumentation illustrates how this unit of analysis can be utilized. It also provides an account of some of the ways in which reasoning is organized in face-to-face argumentation as well as in the speaker’s own discourse.
Long-Term Treatment with Angiotensin-Converting Enzyme Inhibitors, Beta-Blockers or a Combination of Angiotensin-Converting Enzyme Inhibitors and Beta-Blockers in Low-Risk Patients after Acute Myocardial Infarction: The ABC Study
Authors: Theres Heinz , Binkau Jana , Fotuhi Parwis , Flieger Robert , Schneider Tino , Wernecke Klaus-Dieter , Baumann Gert
Published: April 2003

Background: Therapy with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers improves the prognosis of patients with impaired ventricular function, and of patients with symptoms of heart failure after acute myocardial infarction. Long-term treatment strategies for low-risk patients after acute myocardial infarction have not as yet been elucidated by clinical studies. Objective: The objective of this study is to deliver evidence of a possible additional, long-term effect from the combination of ACE inhibitors and beta-blockers, as compared with monotherapy with ACE inhibitors or beta-blockers, for patients after acute myocardial infarction but with only slightly restricted left ventricular function, and without symptoms of heart failure. Methods: In 160 patients who have suffered myocardial infarction, but do not have appreciable impairment of left ventricular ejection fraction, i.e. ejection fraction ≥40%, or symptoms of heart failure, we shall administer either monotherapy with ramipril or metoprolol, or combination therapy in the form of ramipril and metoprolol. The primary end point will be the left ventricular ejection fraction after 18 months. Secondary end points will be mortality, arrhythmia, cardiac stress tolerance, development of heart failure and the need for revascularization.
Which Stent Should Be Regarded as the Gold Standard for Treatment of Coronary Artery Stenoses?
Authors: Kelbæk H. , Jørgensen E.
Published: April 2003

Coronary stenting using the first-generation Palmaz-Schatz stent in patients with ischaemic heart disease has proved efficient compared with balloon angioplasty. The objective of the DANSTENT study is to evaluate the clinical and angiographic outcome of implantation of a second-generation slotted-tube stent in coronary artery lesions. The DANSTENT study is a randomised multicentre trial comparing procedural success, clinical outcome and angiographic determination of the minimal lumen diameter and frequency of restenosis in the target vessel 6 months after implantation of a 15-mm Palmaz-Schatz or a 16-mm second-generation rigid-flex NIR stent. Both stents are hand-crimped onto balloons and deployed at high pressure. All angiograms will be evaluated by a core laboratory. The relationship between polymorphism of the angiotensin-converting enzyme gene and the occurrence of coronary restenosis will also be investigated. More than 450 patients will be included in the study, which will determine the level of coronary restenosis at 6-month follow-up and the clinical outcome 6 and 12 months after implantation of the stents. Sub-study analyses will evaluate possible differences between the two groups with regard to the size of the target vessel and total number of coronary occlusions.
Variable Interindividual Responses to Antiplatelet Therapies – Do They Exist, Can We Measure Them, and Are They Clinically Relevant?
Authors: van de Graaff Eric , Steinhubl Steven R.
Published: April 2003

Many patients suffer thrombotic events such as myocardial infarction, stroke and peripheral embolism despite therapy with recommended doses of all currently approved antiplatelet agents. Researchers have suggested that a subset of patients may be resistant to the antiplatelet effects of aspirin, and have developed substantial evidence to support this theory. The thienopyridines ticlopidine and clopidogrel and the glycoprotein IIb/IIIa inhibitors also exhibit substantial interpatient variability in the level of platelet inhibition they achieve. There are several biochemical factors that may contribute to the etiology of individual resistance to antiplatelet medications. Some studies suggest that the variability in patient responsiveness to these drugs may have clinical consequences, and data from trials evaluating clinical end points are needed to further elucidate this correlation.
Mapping Genes through the Use of Linkage Disequilibrium Generated by Genetic Drift: ‘Drift Mapping’ in Small Populations with No Demographic Expansion
Authors: Terwilliger Joseph D. , Zöllner Sebastian , Laan Maris , Pääbo Svante
Published: April 2003

Linkage disequilibrium has been a powerful tool in identifying rare disease alleles in human populations. To date, most research has been directed to isolated populations which have undergone a bottleneck followed by rapid exponential expansion. While this strategy works well for rare diseases in which all disease alleles in the population today are clonal copies of some common ancestral allele, for common disease genes with substantial allelic heterogeneity, this approach is not predicted to work. In this paper, we describe the dynamics of linkage disequilibrium in populations which have not undergone a demographic expansion. In these populations, it is shown that genetic drift creates disequilibrium over time, while in expanded populations, the disequilibrium decays with time. We propose that common disease alleles might be more efficiently identified by drift mapping – linkage disequilibrium mapping in small, old populations of constant size where the disequilibrium is the result of genetic drift, not founder effect. Theoretical models, empirical data, and simulated population models are presented as evidence for the utility of this approach.
α1-Antitrypsin (PI) Alleles as Markers of Westeuropean Influence in the Baltic Sea Region
Authors: Beckman L. , Sikström C. , Mikelsaar A.-V. , Krumina A. , Kučinskas V. , Beckman G.
Published: April 2003

The distribution of α1-antitrypsin (PI) alleles was studied in an attempt to elucidate migrations and admixture between populations in the Baltic Sea region. The frequency of the PI Z allele, a typically Northwesteuropean marker gene, showed a highly significant regional variation in the Baltic Sea region. The highest frequency (4.5%) was found in the western part of Latvia (Courland). The PI S allele, another marker of Westeuropean influence, also showed an increased frequency in the Courland population. These results indicate that among the populations east of the Baltic Sea the Curonian population has the most pronounced Westeuropean influence. Archaeological data have shown that from the 7th century and for several hundreds of years Courland received immigrations from mainland Sweden and the island of Gotland. We speculate that the increased frequencies of the PI Z alleles and S alleles in Courland may have been caused by these migrations.
Allele Frequency of D17S855 Microsatellite Locus in Japanese People
Authors: Yokozaki Hiroshi , Tahara Eiichi
Published: April 2003

Allele frequency of D17S855 microsatellite locus, an intragenic polymorphic cytosine-adenine repeat located in the BRCA1 gene, was analyzed in 456 normal tissues of Japanese adults. The frequency of D17S855 microsatellite polymorphism was 77.9% (335/456). The size of D17S855 PCR fragments ranged from 137 to 157 bp. The most frequent allele was 151 bp (29.9%) followed by 149-bp (19.3%), 145-bp (17.5%), and 147-bp (17.0%) fragments. The observed allele distribution of this microsatellite was similar to that of Southern Swedes, while it was quite different from that of European Caucasian specimens deposited in the Genome Database.
Localization of the Gene Responsible for Familial Benign Polycythemia to Chromosome 11q23
Authors: Vasserman Natalia N. , Karzakova Luisa M. , Tverskaya Svetlana M. , Saperov Vladimir N. , Muchukova Olga M. , Pavlova Galina P. , Efimova Nadejda K. , Vankina Natalia N. , Evgrafov Oleg V.
Published: April 2003

Familial benign polycythemia (FBP) (OMIM 263400) is a rare autosomal recessive condition characterized by erythrocytosis, normal leukocyte and platelet counts, normal uric acid level, and usually increased erythropoietin production. There is a high incidence of this disorder in Chuvashia (Russian Federation), probably due to a founder effect. In an attempt to locate the gene responsible for this disorder, we have carried out linkage studies in 12 Chuvash families, with 35 affected and 32 unaffected members. Linkage to the erythropoietin and erythropoietin receptor loci was excluded, and the FBP gene was assigned to the region of chromosome 11q23 between D11S4142 and D11S1356, with a maximal lod score of 6.61.
Some Ethical Issues at the Population Level Raised by ‘Soft’ Eugenics, Euphenics, and Isogenics1
Authors: Neel James V.
Published: April 2003

It is argued that at the population level there are three central genetic developments raising ethical issues. The first is the emergence of ‘soft’ eugenics, due primarily to the increasing ability to detect carriers of genetic diseases, to monitor their pregnancies, and to provide the option to abort a fetus predisposed to major genetic disease. The second development is the recognition of the extent to which many serious diseases of adult life are due to a disturbance of ancient genetic homeostatic mechanisms due to changing life style, raising the question of whether a society that increasingly pays the medical bills should attempt to impose healthier standards of living on its members. Such an attempt at ‘euphenics’ may be thought of as the antithesis to eugenics. The third development relates to recognition of the need to regulate the size of the earth’s population to numbers that can be indefinitely sustained; this regulation in a fashion (isogenic) that will preserve existing genetic diversity.
Effects of Misspecification of Allele Frequencies on the Type I Error Rate of Model-Free Linkage Analysis
Authors: Mandal Diptasri M. , Wilson Alexander F. , Elston Robert C. , Weissbecker Karen , Keats Bronya J. , Bailey-Wilson Joan E.
Published: April 2003

Linkage analyses of simulated quantitative trait data were performed using the Haseman-Elston (H-E) sib pair regression test to investigate the effects of inaccurate allele frequency estimates on the type I error rates of this test. Computer simulations generating a quantitative trait in nuclear families were performed using GASP [1]. Assuming no linkage, several data sets were simulated; they differed in marker allele numbers and frequencies, number of sib pairs and number of sibships. Each set of simulated data was analyzed using (1) all parental marker data, (2) half of the parental marker data, and (3) no parental marker data, using both correct and incorrect allele frequencies in the latter 2 cases. The H-E sib pair linkage method was found to be robust to misspecification of marker allele frequencies regardless of the number of alleles.
Estimation of Transmission Probabilities in Families Ascertained through a Proband with Variable Age-at-Onset Disease: Application to the HLA A, B and DR Loci in Finnish Families with Type 1 Diabetes
Authors: Pitkäniemi Janne , Onkamo Päivi , Arjas Elja , Tuomilehto-Wolf Eva , Tuomilehto Jaakko
Published: April 2003

An open problem of some interest in the study of HLA has been the possible existence of transmission distortion in the human HLA complex. In this paper, transmission probabilities are estimated and tested using data on HLA A, B and DR loci genotypes of parents and offspring ascertained from the entire population of Finland (Childhood Diabetes in Finland Study) through one or more offspring diagnosed with insulin-dependent diabetes mellitus (IDDM) during the recruitment period from September 1986 to July 1989. First, we show how to get unbiased estimates of transmission probabilities from the family data collected in the disease registry of incident cases. This is accomplished by assuming that transmission of HLA genes to children in the general population is conditionally independent given the parents’ genotypes, and the birth dates of all offspring. Based on the sampling (ascertainment) process in the study on Childhood Diabetes in Finland, younger siblings of the index child (the oldest proband) are independent of the ascertainment and therefore give rise to unbiased inference regarding allele transmission. The hypothesis of Mendelian transmission of alleles at each locus was tested using the standard χ2 test. Goodness-of-fit of the Mendelian inheritance model to the individual locus data is calculated by maximizing the likelihood function over allele transmission intensities at each locus. The existence of a strong transmission distortion is not supported by this study at the loci considered.
Dose-Dependent Effect of Octreotide on Insulin Secretion after OGTT in Obesity
Authors: Bertoli A. , Magnaterra R. , Borboni P. , Marini M.A. , Barini A. , Fusco A. , Bollea M.R.
Published: April 2003

Objective: The present study aimed at evaluating the acute effect of increasing doses of octreotide (OCT), a long-acting somatostatin analogue, on glucose tolerance and insulin secretion. Methods: A standard and two other oral glucose tolerance tests 30 min after subcutaneous administration of OCT were performed in randomized order in each subject. Obese subjects received 10, 25, or 50 µg of OCT; control subjects received only 10 and 25 µg. Fifteen obese and 10 control subjects were studied; all of them had a normal glucose tolerance. Plasma glucose and insulin levels were measured at times –30, 0, 30, 60, 90, 120, 150, and 180 min after the glucose tolerance test. Results: The results demonstrated that, following OCT administration, both control and obese subjects developed a reduced glucose tolerance, a delayed glycemic peak, and an increase of late plasma glucose values. Fasting as well as stimulated insulin secretions were higher in obese subjects as compared with controls, and insulin secretion was inhibited in a dose-dependent manner by OCT. Conclusions: These data indicate that the action of OCT might be due to at least two different cooperative mechanisms: (1) a delayed glucose absorption, as suggested by the delay of glycemic peak, and (2) a direct or vagal-mediated effect on β-cells, as suggested by the reduction of the area under the curve values in spite of the elevated late glycemic levels. It is noteworthy that doses of OCT as low as 10 and 25 µg are sufficient to inhibit insulin secretion both in normal and obese subjects.
Long-Term Treatment in Children with Hypopituitarism: Pubertal Development and Final Height
Authors: Birnbacher R. , Riedl S. , Frisch H.
Published: April 2003

Auxological data, pubertal development and final height were analyzed in 25 patients with growth hormone (GH) deficiency who were treated only with pituitary GH in 3 doses/week. 15 patients had a spontaneous onset of puberty and in 10 puberty was induced. The duration of therapy was 7.5 years, the dosage was about 11 U/m2/week and was not changed during puberty. 80% of the patients with induced puberty, but only 33% of the children with spontaneous puberty reached final heights within the 2 SD range. Final height was correlated with height at the start of treatment only in patients with spontaneous puberty, which shows the necessity of early treatment initiation in this group. The lack of this correlation in patients with induced puberty might be attributed to gonadotropin deficiency. Height at the onset of puberty was related to final height only in the group with gonadotropin deficiency. A prediction model for calculation of the first year height velocity which was derived from present treatment procedures showed a too favorable prediction for our patients. The reasons for the insufficient final results may be due to impure GH preparations, suboptimal dosage, low frequency of injections and late onset of therapy.
Changes in Urinary Excretion of Type-I Collagen Cross-Linked C-Telopeptide and N-Telopeptide in Perimenopausal Women
Authors: Taga Michiyoshi , Shirashu Kazuhiro , Minaguchi Hiroshi
Published: April 2003

In order to assess the dynamics of bone turnover during menopausal transition, we measured the urinary excretion of C-telopeptide (CTX) and N-telopeptide (NTX) of type-I collagen, new markers of bone resorption, using two ELISAs which recognize the corresponding cross-linked peptide of type-I collagen. CTX and NTX levels in postmenopausal women were significantly higher than those in premenopausal women, confirming the enhancement of bone resorption after menopause. The measurement of CTX and NTX, which is convenient and specific for bone resorption compared with conventional bone resorption markers, pyridinoline and deoxypyridinoline, might be useful in the management of postmenopausal women.
Efficacy and Safety of Growth Hormone Treatment in Children with Prior Craniopharyngioma: An Analysis of the Pharmacia and Upjohn International Growth Database (KIGS) from 1988 to 1996
Authors: Price D.A. , Wilton P. , Jönsson P. , Albertsson-Wikland K. , Chatelain P. , Cutfield W. , Ranke M.B.
Published: April 2003

We studied short- and long-term responses to growth hormone (GH) treatment and adverse medical events (AE) in 488 patients with craniopharyngioma who were entered into the Kabi International Growth Study (KIGS). First-year growth response and responsiveness (n = 394) were similar to those seen in children with idiopathic GH deficiency. The growth response over 5 years (n = 152) was unaffected by the recurrence of tumour and prior tumour management, but was greater in those receiving thyroxine. Mean height standard deviation scores (SDS) at the end of GH treatment (n = 129) was –0.7 ± 1.2, and 79% achieved a height over –2 SD of target height, with evidence of further growth potential. Final height SDS correlated positively with height SDS at the start of treatment and with target height SDS, whereas gain in height SDS was inversely correlated with height SDS and bone age at the start of GH treatment. The rate of recurrence of tumour, 0.045/treatment year, was greater in those who had been treated with surgery alone compared to surgery and cranial irradiation. Other AE included headaches, fluid retention and convulsions occurring at rates of 0.025, 0.005 and 0.004/treatment year, respectively. We concluded that GH treatment is safe and effective in children with craniopharyngioma and provide data for counselling of parents about outcome during GH treatment.
Circadian Rhythms
Authors: Turek Fred W.
Published: April 2003

1997 marks the 25th anniversary of the discovery of the master circadian pacemaker in mammals in the hypothalamic suprachiasmatic nucleus. Remarkable progress has been made over the last 25 years in elucidating the physiological mechanisms involved in the entrainment, generation and expression of circadian rhythms at the cellular and systems levels. The recent discovery and cloning of the first mammalian clock gene is expected to lead to rapid advances in the understanding of the genetic and molecular mechanisms underlying circadian rhythmicity in mammals. Indeed, the impressive and extensive database on circadian rhythms in mammals obtained over the past 25 years provides a foundation for making rapid progress in utilizing future genetic and molecular findings for discovering the fundamental mechanisms controlling 24-hour temporal organization.
Processes Underlying Sleep Regulation
Authors: Borbély Alexander A.
Published: April 2003

Sleep is regulated by homeostatic, circadian and ultradian processes. Slow waves and sleep spindles are EEG markers of sleep processes which have counterparts at the cellular level. The interaction of homeostatic and circadian sleep regulation has been formalized in the two-process model and validated in experiments. Sleep is not only a global brain phenomenon but also a regional cerebral process whose intensity may be influenced by prior activity during waking.
Endocrine Secretions under Abnormal Light-Dark Cycles and in the Blind
Authors: Bellastella Antonio , Pisano Gustavo , Iorio Sergio , Pasquali Daniela , Orio Francesco , Venditto Teresa , Sinisi Antonio Agostino
Published: April 2003

Both endogenous and exogenous factors are involved in regulation of endocrine secretions. Among the exogenous ones, light plays an important role both in animals and in humans. Pineal gland mediates light action on the endocrine system, by means of variations of melatonin (MT) secretion. Here we discuss about the influence of abnormal light-dark cycles and in particular of blindness on pineal and pituitary secretions and on those of correlated glands. MT secretion is usually inhibited by light: thus it reaches the highest levels at night. Exposure to short or long photoperiod causes variations in circadian or infradian MT rhythmicity. Blind patients can show higher daytime levels with a phase-advanced or phase-delayed circadian rhythm. Lack of light stimulus affects cortisol rhythm shifting the zenith of secretion and inducing a free-running rhythm. Blindness can abolish nocturnal growth hormone (GH) peak and impair the GH response to some stimuli; moreover it impairs the growth of affected patients. Light stimulus influences favorably gonadal function both in animals and in man. In animals, sexual activity and gonadal function decline during the seasons with reduced luminosity. A similar finding has been described in women living in a region with a strong seasonal contrast in luminosity. Blindness can impair luteinizing hormone, follicle-stimulating hormone, prolactin and testosterone secretion in prepubertal boys causing pubertal delay or more severe hypogonadism; it can affect pubertal development and fertility in women. Light can influence thyroid function in animals. Lack of light stimulus in blind man seems to cause different effects on thyroid function before and after puberty. Increase of free thyroid hormone levels has been found in prepubertal but not in adult blind patients, probably due to a resetting of the treshold for thyrotropin feedback suppression after puberty in these patients.
Temporal Profiles and Clinical Significance of Pulsatile Insulin Secretion
Authors: Polonsky Kenneth S. , Sturis Jeppe , van Cauter Eve
Published: April 2003

In this article, recent experiments are reviewed which have addressed the role of oscillatory insulin secretion in the pathophysiology of glucose intolerance and diabetes. The ultradian oscillations of insulin secretion appear to be an integral part of the feedback loop between glucose and insulin secretion and as a result are abnormal in states of glucose intolerance. Treatment of impaired glucose tolerance with troglitazone, a thiazolidinedione that improves insulin sensitivity, leads to an improvement in the ability of the β-cell to sense and respond to a glucose stimulus restoring the ability of glucose to entrain the ultradian oscillations. The rapid oscillations of insulin secretion appear to be an inherent feature of the cellular mechanisms of insulin secretion since they persist in the isolated perfused pancreas and in perifused islets. These oscillations are paralleled by changes in intracellular Ca2+ and are also abnormal in states of glucose intolerance and diabetes. Available evidence indicates that these alterations are due to decreased expression of voltage-dependent Ca2+ channels on the β-cell membrane.
Growth Failure in Prader-Willi Syndrome Is Secondary to Growth Hormone Deficiency
Authors: Thacker Margaret J. , Hainline Bryan , Dennis-Feezle Lori St. , Johnson Nancy B. , Pescovitz Ora Hirsch
Published: April 2003

Growth failure is a recognized feature of the Prader-Willi syndrome (PWS). Despite evidence that hypothalamic dysfunction accompanies the syndrome, the etiology of this growth failure remains controversial because most patients with PWS are obese. In order to contribute to resolution of this controversy, we performed a retrospective analysis of 16 obese and non-obese PWS children. GH deficiency was diagnosed in 12 of the 16 subjects and occurred independently of weight status. All of the non-obese subjects were GH deficient. Of the 4 GH-sufficient children, 2 were moderately obese and 2 were morbidly obese. One of these children had clinical evidence of GH deficiency including a low IGF-1 level. Only one of the children had evidence of GH deficiency and a normal IGF-1 level, a pattern that could be attributable to obesity. We conclude that most short children with PWS have growth hormone deficiency and that this deficiency probably results from hypothalamic dysfunction.
Effects of Glucagon-Like Peptide 1 (7–36 Amide) on Glucose Kinetics during Somatostatin-Induced Suppression of Insulin Secretion in Healthy Men
Authors: Shalev Anath , Ninnis Ronald , Keller Ulrich
Published: April 2003

Glucagon-like peptide 1 (GLP-1) is known to stimulate insulin secretion and biosynthesis, but has also been shown to decrease insulin requirements in type 1 diabetic subjects suggesting insulin-independent effects. To assess whether GLP-1 exerts also direct effects on whole-body glucose metabolism, 6,6-D2-glucose kinetics were measured in 8 healthy volunteers receiving once GLP-1, once saline during hyperglycemic glucose clamping, while somatostatin with replacement amounts of insulin, glucagon and growth hormone was infused. Even though endogenous insulin secretion could not be blocked completely (increased plasma concentrations of C-peptide and proinsulin), somatostatin infusion resulted in stable insulin and glucagon plasma levels in both protocols (GLP-1 vs. placebo: NS). After 3 h of GLP-1 infusion, peripheral glucose disappearance significantly increased compared to placebo (p < 0.03) despite of somatostatin-induced suppression of insulin and glucagon secretion. Thus, GLP-1 infusion seems to have direct stimulatory effects on peripheral glucose metabolism in man.
Apparent Functionality But Impractical Quantification of Neurotensin Receptors on Human Peripheral Lymphocytes
Authors: Lhiaubet Anne-Marie , Avard Claire , Schimpff Rose-Marie
Published: April 2003

Neurotensin (NT), a neuromodulator, is also thought to play an immunomodulatory role. We sought to confirm the effects of NT on proliferation in human peripheral blood lymphocytes (PBLs; n = 10), to characterize the binding properties of the NT receptor using Scatchard analysis, and to measure NT receptors using blood volumes (50 ml) applicable to clinical investigation. Incubation of phytohemagglutinin-stimulated PBLs with NT (10–10 to 10–13 M) in the presence of 0.07% normal human serum (72 h at 37°C) significantly enhanced proliferation (p < 0.001), which is consistent with PBLs possessing functional NT receptors. However, the various experimental conditions tested constantly yielded low specific NT binding to human PBLs, and hence Scatchard analysis was impossible for 50-ml blood samples. Our data confirm the existence of a link between NT and the immune system and support a physiological significance for this link. However, measurement of NT receptor binding in readily available cells proved unsuitable for clinical investigation.
Isolated ACTH Deficiency
Authors: de Luis D.A. , Aller R. , Romero E.
Published: April 2003

Isolated ACTH is a rare cause of secondary adrenocortical insufficiency. The diagnosis is made by the demonstration of low cortisol production with low plasma ACTH, absent adrenal responses to stimulation for pituitary or hypothalamus with intact adrenal response to exogenous ACTH, and normal secretory indices of other pituitary hormones. We conclude that the diagnosis of this condition may be difficult due to the varied clinical presentation and etiologies.
Late Development of Resistance to Bromocriptine in a Patient with Macroprolactinoma
Authors: Delgrange E. , Crabbé J. , Donckier J.
Published: April 2003

We report the case of a man with an invasive macroprolactinoma who developed resistance to bromocriptine to which he had previously responded satisfactorily for 5 years. Subsequently, hyperprolactinemia was controlled equally well with 600 µg quinagolide daily and later with 4.5 mg cabergoline weekly. This observation suggests that a loss of dopamine receptors at the tumoral cell surface might be the mechanism underlying acquired resistance to bromocriptine. In addition, no tumor growth was observed over a 10-year follow-up, which virtually excludes a malignant transformation of the prolactinoma. This case emphasizes the need for close supervision of patients with macroprolactinoma, even after the serum prolactin concentration has been normalized by bromocriptine. It furthermore illustrates the usefulness of quinagolide and cabergoline when resistance to bromocriptine develops after a prolonged period of adequate response to this drug.
Opioid Blockade Effect on Insulin β-Cells Secretory Patterns in Polycystic Ovary Syndrome
Authors: Ciampelli Mario , Fulghesu Anna Maria , Guido Maurizio , Murgia Francesca , Muzj Giuseppe , Belosi Chiara , Fortini Antonio , Cento Rosa , Lanzone Antonio
Published: April 2003

In order to evaluate the involvement of endogenous opiates in the insulin disorders of polycystic ovary syndrome (PCOs) a total of 25 PCOs women and 11 normo-ovulatory controls were studied by comparing the effect of a chronic opioid blockade on β-cells responsiveness to oral glucose load and to intravenous glucagon bolus. Each patient, studied on follicular phase, underwent to oral glucose tolerance test (OGTT), and, 2 days later, to a glucagon intravenous bolus (1 mg); these tests were then repeated after 6 weeks of naltrexone treatment (50 mg orally). Naltrexone treatment did not modify the insulin secretory patterns of control subjects, whereas the same therapy significantly reduced, in hyperinsulinemic PCOs women, the β-cell hyperresponsiveness both to oral glucose load and to intravenous glucagon (p < 0.05 and p < 0.01, respectively), even if with different mean percent decrease (32% OGTT vs. 45% glucagon, p < 0.05). Moreover, normoinsulinemic PCOs patients showed a slight, but not significantly increase in the β-cells response to OGTT after opioid blockade, whereas, in the same situation, the insulin release after glucagon bolus was significantly reduced (p < 0.01). Chronic opioid blockade did not modify gonadotropins, steroids and SHBG levels in either group. Our data show that naltrexone treatment is able to reduce the β-cell response to a direct intravenous secretagogue stimulus in all PCOs patients, while only in hyperinsulinemic PCOs subjects the same treatment is effective in reducing the exaggerated insulin secretion after oral glucose load. The reason for such a discrepancy could be ascribed to a different effect of opioids on first- and second-phase insulin secretion, or, alternatively, to an involvement of other secretagogue factors, such as glucoincretins.
Predictive Value of Serum Follicle-Stimulating Hormone Levels in the Differentiation between Hypogonadotropic Hypogonadism and Constitutional Delay of Puberty
Authors: Odink Roelof J. , Schoemaker Joop , Schoute Erik , Herdes Erik , Delemarre-van de Waal Henriette A.
Published: April 2003

Objective: Gonadotropin secretion was evaluated to predict hypogonadotropic hypogonadism (HH) in 36 children suspected of having HH. Methods: LH was measured for 24 h at 10-min intervals, and FSH and estradiol or testosterone at 1-hour intervals. Twenty boys (age 15.7, range 13.2–19.3 years) and 16 girls (age 16.1, range 13.0–20.6 years) were studied. Results: LH pulses were detected in 9 boys and 5 girls. HH was confirmed in all 11 LH apulsatile boys and in 8 of 11 LH apulsatile girls. Random FSH values of ≤1.11 and ≤2.86 IU/l in boys and girls, respectively, discriminated patients with LH pulses from patients without (sensitivity for lack of LH pulses 97 and 100%, respectively). In boys testicular volume was not discriminatory. In 1 girl LH pulses were observed without estradiol production, suggesting LH neurosecretory dysfunction. Conclusions: Low FSH levels in adolescence are strongly related to a lack of LH pulses. Lack of LH pulses is highly suspect for HH. FSH may be a tool in the differentiation between HH and delayed puberty.
Hypercalcemia due to Parathyroid Hormone-Related Protein Secretion by Melanoma
Authors: Yeung Sai-Ching Jim , Eton Omar , Burton Douglas W. , Deftos Leonard J. , Vassilopoulou-Sellin Rena , Gagel Robert F.
Published: April 2003

About 1–2% of melanoma patients develop hypercalcemia. We report hypercalcemia without bone metastasis in a 46-year-old woman with advanced melanoma. The hypercalcemia was associated with elevated serum parathyroid hormone-related protein (PTHrP) levels. An even higher concentration (10 times the serum level) in pleural effusion caused by pleural metastases implied that the source of the increased circulating PTHrP was the melanoma. Immunohistochemical staining of paraffin sections, performed using a monoclonal antibody (9H7) against the peptide sequence 109–141 of human PTHrP, detected PTHrP in the cytoplasm and nucleoli of melanoma cells in an autopsy specimen but not in specimens from this patient prior to onset of hypercalcemia. Considering the evidence, it is very likely that PTHrP production by melanoma caused hypercalcemia in this patient.
Growth and Growth Hormone Status following Treatment for Childhood Leukaemia
Authors: Shalet S.M. , Brennan B.M.D.
Published: April 2003

The exact contribution of growth hormone (GH) deficiency to the adverse growth outcome, in those receiving cranial irradiation (18–24 Gy) or total-body irradiation for haematological malignancies in childhood, remains difficult to disentangle as nearly always the cause of the growth disturbance is multifactorial: chemotherapy, graft-versus-host disease, hypothyroidism, and skeletal dysplasia may all impact on growth. There are few published data from which one can assess the efficacy of GH replacement on final height in those children who received cranial irradiation (18–24 Gy) and/or total-body irradiation; there is no evidence, however, of an increased risk of leukaemic relapse. Endocrine reassessment in the teenagers, who received cranial irradiation (18–24 Gy) for acute lymphoblastic leukaemia many years earlier, revealed a significant incidence of GH deficiency with the additional suggestion that many had been GH deficient for several years. This raises a number of important questions: What is the best way to organize long-term endocrine follow-up? How often should GH status be reassessed? What are the specific benefits of GH replacement in adult life for such individuals? These and other questions require further study.
Expression of Pit-1 mRNA and Activin/Inhibin Subunits in Clinically Nonfunctioning Pituitary Adenomas
Authors: Sanno Naoko , Teramoto Akira , Sugiyama Makoto , Matsuno Akira , Takumi Ichiro , Tahara Shigeyuki , Osamura R.Yoshiyuki
Published: April 2003

The pituitary-specific transcriptional factor Pit-1 is known to play a role in the development and differentiation of pituitary cells. Recent investigations have suggested a role for this transcriptional factor in pituitary adenomas, especially growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas. In this study we analyzed the expression of Pit-1 mRNA and its protein in 24 clinically nonfunctioning pituitary adenomas in comparison with normal pituitary glands using in situ hybridization (ISH) and immunohistochemistry (IHC). The interaction between inhibin/activin, a member of the transforming growth factor-β family, and Pit-1 was also studied. Immunohistochemically, Pit-1 protein was detected in 9 of 24 adenomas (37.5%), and 8 of these 9 were also positive for the α subunit of glycoprotein (αSU). The expression of Pit-1 mRNA was detected in 14 of 24 (58.3%) clinically nonfunctioning adenomas, and it was found in all cases which expressed the Pit-1 protein. By the combined ISH and IHC method, Pit-1 mRNA was frequently observed in αSU-immunopositive cells in adenomas. The inhibin/activin α subunit was detected in all 24 adenomas and the βA subunit was detected in 13 of 24 adenomas. The inhibin/activin βA subunit was detected frequently with Pit-1 mRNA. From our observations, the inhibin/activin βA subunit in nonfunctioning adenomas may have related the expression of Pit-1 mRNA in these adenomas.
Growth Hormone Treatment in Growth Hormone-Sufficient and -Insufficient Children with Intrauterine Growth Retardation/Russell-Silver Syndrome
Authors: Azcona C. , Albanese A. , Bareille P. , Stanhope R.
Published: April 2003

Fifty-eight short prepubertal children with IUGR received GH treatment (mean dose: 28 IU/m2/week) for a mean (SEM) period of time of 3.4 (0.13) years (range 1–4 years). They were subdivided according to their GH response to a pharmacological test. Twenty-six were GH insufficient (GHI) (group 1) and 32 were non-GHI (group 2). At the commencement of GH therapy mean chronological age was 6.1 (0.4) years in both groups, mean height SDS (SEM) was –3.5 (0.2) in group 1 and –3.6 (0.2) in group 2, mean growth velocity (GV) SDS (SEM) was –1.9 (0.3) in group 1 and –0.3 (0.2) in group 2. GH therapy induced significant growth acceleration throughout the follow-up period without any significant differences between the two groups. GV SDS (SEM) increased to +3.0 (0.5) in group 1 and to +3.7 (0.4) in group 2 (p < 0.05 compared to baseline) during the first year of therapy. Subsequently, the growth-promoting effects of GH therapy diminished with time but GV remained significantly higher than baseline. This growth enhancement produced a significant rise in height SDS (SEM) reaching –1.4 (0.2) in group 1 and –1.7 (0.2) in group 2 after 4 years. In conclusion, our data did not show any significant differences in the growth response to GH therapy between GH-sufficient and -insufficient IUGR children who were only distinguishable by their GH secretion. This indicates that the decision to treat a short IUGR child with GH therapy should not be based upon the GH response to a provocative test.
Glucose Tolerance and Insulin Secretion in Children before and during Recombinant Growth Hormone Treatment
Authors: Filler Guido , Amendt Peter , Kohnert Klaus-Dieter , Devaux Siegmar , Ehrich Jochen H.H.
Published: April 2003

This study evaluates glucose metabolism and insulin secretion in children with Ullrich-Turner syndrome (UTS), chronic renal failure (CRF) and kidney transplantation (KTx) with rh GH therapy using an intravenous glucose infusion test. Before treatment, glucose AUC was significantly increased in all patient groups when compared to normal controls. Both the early and second phases of insulin secretion were not altered. During treatment, elevated glucose AUC showed a further increase in patients with KTx but not in patients with CRF or UTS. Both the early and second insulin secretion phases rose significantly in UTS and were transiently elevated after 6 and 12 months of therapy in patients with CRF and KTx. We conclude that growth hormone therapy aggravates alteration of glucose metabolism in patients with KTx and not in children with CRF and UTS. Progressive hyperinsulinemia occurred only in patients with UTS.
Pituitary Apoplexy in an Adolescent with Prolactin-Secreting Adenoma
Authors: Pinto G. , Zerah M. , Trivin C. , Brauner R.
Published: April 2003

A 14.8-year-old girl was treated with bromocriptine for a prolactin-secreting adenoma. She suddenly developed headaches, vomiting, fever and meningeal syndrome. This was associated with corticotropin, thyrotropin and gonadotropin deficiencies. Magnetic resonance imaging showed peripheral enhancement and a central hyposignal suggesting intra-adenoma hemorrhage and then disappearance of the adenoma. Hydrocortisone was initiated in emergency to prevent any risk to life.