bluuebunny/crossref_metadata_2025 huggingface dataset:
Fetal Cell Isolation from Maternal Blood Cultures by Flow Cytometric Hemoglobin Profiles
Authors: Bohmer Ralph M. , Stroh Helene P. , Johnson Kirby L. , LeShane Erik S. , Bianchi Diana W.
Published: April 2003

Objective: We conducted a trial to test if the blood of pregnant women contains fetal clonogenic erythroid cells the progeny of which can be identified and isolated by a newly developed flow-sorting procedure. Methods: We have previously demonstrated the identification of fetal nucleated red cells in cocultures of fetal and adult blood. The procedure is based on profiles of the correlated contents of fetal and adult hemoglobin (HbF and HbA, respectively), using antibodies specific for the different hemoglobin chains. In such profiles, fetal cells contain only HbF, while the vast majority of adult cells contain either only HbA or a combination of HbA and HbF. HbF+ HbA– cells are flow sorted and fetal cells identified by fluorescence in situ hybridization, using chromosome-specific probes. This technique provides a yield that approaches 100%, meaning that fetal cells will be found even if the culture contains only a single fetal erythroid colony among thousands of maternal colonies. Peripheral blood samples were obtained from 11 women carrying chromosomally normal male fetuses, from 5 women carrying trisomy 21 fetuses, and from 2 women carrying trisomy 18 fetuses. A further six samples came from women with an unknown fetal karyotype. As positive controls, we used blood samples drawn after termination procedures that tended to induce some fetomaternal hemorrhage. In parallel to the method being tested, we employed alternative techniques of fetal cell detection: one third of the mononuclear cell preparations from each maternal blood sample was not cultured but labeled with anti-HbF antibodies for flow sorting of F+ cells. Ten percent of the total harvested cell population of each culture was subjected to quantitative polymerase chain reaction analysis targeting a Y-chromosome-specific sequence. Results: Most posttermination blood samples yielded fetal cells with high purity which demonstrates the validity of the method. However, no fetal cells were found in any of the maternal blood samples with normal or abnormal pregnancies, neither before nor after culture. Conclusion: We conclude that a cell culture approach targeting clonogenic erythroid cells offers no advantage over established methods of direct isolation.
Evaluation of a Culture System for Enrichment of CD34+ Hematopoietic Progenitor Cells Present in Maternal Blood
Authors: Manotaya Saknan , Elias Sherman , Lewis Dorothy E. , Simpson Joe Leigh , Bischoff Farideh Z.
Published: April 2003

Background: Clonogenic expansion of fetal cells in maternal blood is one approach to overcome the very low number of target cells available for prenatal genetic analysis. However, efficient methods of enrichment, culturing conditions and subsequent analysis of fetal cells are lacking. Optimization of this technique requires more detailed evaluation of the composition and distribution of fetal cells that cross the placenta into the maternal circulation. Previous studies by others have shown that fetal blood is rich in CD34+ progenitor cells capable of expansion in cultures supplemented with hematopoeitic growth factors. Moreover, CD34+ fetal cells have been recovered from maternal blood following enrichment. Objective: In this study, we examine the type and frequency of hematopoietic progenitor cells detected in maternal (n = 13) and non-pregnant control (n = 4) peripheral blood specimens. Methods: A methylcellulose-based culture system was used to perform colony assays on CD34+-enriched or non-enriched cells. Overall, a total of 2,249 colonies were scored for colony type among the 17 samples. To determine whether fetal cells were present and expanded, all colonies present in each of the 10 confirmed male-cases (n = 1,525 colonies) were examined either by PCR or FISH. Results: With CD34+-enriched maternal samples, we observed a significantly higher number of burst-forming unit-erythroid (BFU-E) and a reduced number of colony-forming unit-granulocyte, macrophage (CFU-GM) colonies compared to the non-enriched samples. Of 1,067 colonies analyzed by PCR for the amelogenin locus on X and Y, none were found positive for the 250-bp Y-specific sequences. Of 458 colonies tested by FISH for presence of X and Y probe signals, no XY-male cells were detected. Conclusion: We conclude that hematopoiesis is enhanced during pregnancy, but the number of fetal progenitor cells is either very low or fail to expand using the enrichment techniques and culturing conditions described in this study. Further development of methods is warranted before considering this approach for prenatal diagnosis.
In vitro Studies of Haematopoietic Colony-Forming Capacity of Human Fetal Liver Cells at Exposure to Cytotoxic and Immunomodulatory Drugs
Authors: Lindton Bim , Markling Lola , Ringdén Olle , Westgren Magnus
Published: April 2003

Objective: Intrauterine transplantation with haematopoietic stem cells (SC) as a treatment for immunological, haematological and metabolic inherited disorders has not been effective in fetuses with a normal immunological status. Inhibition of the fetal haematopoiesis or immunosuppression might therefore be a therapeutic alternative in fetal SC transplantation. The aim of the present study was to evaluate the effects of drugs that might be considered as therapeutic options in fetal transplantations on the colony-forming capacity of fetal haematopoietic SC. Methods: Fetal liver cells were incubated with doxorubicin, daunorubicin, antithymocyte-globulin (ATG), OKT-3 (Orthoclone) and betamethasone. The effects of these drugs on colony formation by fetal hematopoietic SC were evaluated. Colony-forming capacity assays were cultured during 10 days after drug incubation on day 1 and evaluated for differences in number of colonies compared to unexposed cells. For betamethasone, similar studies were performed with adult bone marrow. Results: A significant reduction in fetal liver haematopoietic colony formation of BFU-E, CFU-GM and CFU- GEMM was detected when 0.1 M doxorubicin (p < 0.05) and 0.5 µM daunorubicin (p < 0.05) were added. OKT-3 (5 µg/ml) and ATG (4 µg/ml) significantly reduced BFU-E, CFU-GM and CFU-GEMM (p < 0.05). A concentration of 0.2 µg/ml betamethasone caused a significant reduction of BFU-E, CFU-GM and CFU-GEMM (p < 0.05). Conclusions: The drugs investigated in this in vitro study were capable to different degrees to decrease the colony-forming capacity of fetal haematopoietic progenitor cells. Whether this strategy will become an alternative in fetal SC transplantations is an open question and further studies are required to elucidate the potential use of these drugs in fetal transplantation.
Effect of Pathological Perinatal Conditions on the Maternofetal Transfer of Mononuclear Cells
Authors: Brune Thomas , Koch Hans Georg , Plümpe Ulrike , Coenen-Worch Verena , Harms Erik , Louwen Frank
Published: April 2003

Objective: It is known that mononuclear cells can cross the placenta in both directions: from mother to fetus and the other way. In addition, it has been shown that perinatal pathological conditions can affect the fetomaternal cell transfer. This study has focused on the question whether perinatal conditions will also support the transfer of maternal cells in the fetus. Methods: Minisatellite polymerase chain reaction (PCR) with a sensitivity of 1:100 was used to examine blood samples of 36 mother-child pairs for transplacental mononuclear cell transfer (group 1). Furthermore, 28 blood samples of mother-child pairs were examined by allele-specific PCR (sensitivity 1:1,000) for maternofetal mononuclear cell transfer; only 9 of these mother-child pairs were informative (group 2). Results: Three cases of maternofetal and 2 additional cases of fetomaternal mononuclear cell transfer could be documented in group 1; 2 of the 9 informative samples in group 2 showed a maternofetal mononuclear cell transfer. In conclusion, 9 of 40 cases lacking maternofetal cell transfer and 4 of 5 cases with maternofetal cell transfer were high-risk deliveries (p < 0.01). Conclusion: The current study shows that certain ante-partum conditions like placental insufficiency or chorioamnionitis increase significantly the chance that maternal cells enter the fetus.
Early Amniocentesis and Congenital Foot Deformities
Authors: Nikkilä A. , Valentin L. , Thelin A. , Jörgensen C.
Published: April 2003

Objective: Several studies have shown an increased risk of congenital foot derformities after early amniocentesis. These studies have comprised amniocenteses performed before 13 completed gestational weeks. In this study, the risk of foot deformities after amniocentesis performed at 12–14 completed gestational weeks was determined. Methods: 3,469 genetic amniocenteses in singleton pregnancies performed before 15 completed gestational weeks were studied. The intention was to perform the amniocenteses at 12–14 weeks of gestation, but 32 amniocenteses were performed at the gestational age 11 weeks + 5 days or 11 weeks + 6 days. The pregnancies were followed up with regard to fetal loss and leakage of amniotic fluid. After birth, newborns with a diagnosis of foot deformity were identified from the Swedish Medical Birth Registry. The observed number of foot deformities was then compared with the expected number which was calculated stratified for delivery hospital, year of birth, and maternal age. Results: The observed number of foot deformities was significantly higher than the expected: exact odds ratio 1.74 (exact 95% confidence interval 1.06–2.69). The rate of spontaneous abortions after the procedure was 1.8%, and the rate of leakage of amniotic fluid was 1.9%. There was a significant trend for all complications to decrease with increasing gestational age at amniocentesis. Conclusion: Women undergoing amniocentesis at 11+5 to 14+6 gestational weeks have an increased risk of giving birth to a child with a congenital foot deformity.
Does Amniotic Fluid Alpha-Fetoprotein Have Diagnostic or Prognostic Value at the Time of Second Midtrimester Genetic Amniocentesis?
Authors: Mandruzzato G.P. , Fischer-Tamaro L. , De Seta F. , D’Ottavio G. , Rustico M.A. , Conoscenti G. , Meir Y.L. , Pinzano R. , Maso G. , Grasso A. , Gigli C.
Published: April 2003

In order to assess the usefulness of amniotic fluid α-fetoprotein (AFP) levels at the time of midtrimester genetic amniocentesis, 4,430 cases were retrospectively studied to compare the high, normal or low AFP values with the karyotype characteristics and fetal anatomy using ultrasound (US) scanning and confirmed by postnatal evaluation or necroscopy in the case of termination of pregnancy. All the cases presenting malformations were correctly diagnosed by US examinations. AFP levels over the 2nd standard deviation (SD) were found in 112 cases (2.52%) and below the 2nd SD in 11 cases (0.24%). The characteristics of these cases are presented and discussed. According to our results, it is concluded that routine assessment of AFP at the time of midtrimester genetic amniocentesis, if coupled with optimal US scanning, is no longer justified.
Arthrogryposis multiplex congenita and Cerebellopontine Ischemic Lesions in Sibs: Recurrence of Prenatal Disruptive Brain Lesions with Different Patterns of Expression?
Authors: Mahieu-Caputo D. , Salomon L.J. , Dommergues M. , Aubry M.C. , Sonigo P. , Martinovic Y. , Le Merrer M. , Dumez Y. , Encha-Razavi F.
Published: April 2003

Arthrogryposis multiplex congenita (AMC) is a heterogeneous group of disorders in which prolonged decrease or absence of fetal movements results in a series of deformational anomalies. The rate of recurrence ranges from 25% in some recessive forms of myogenic arthrogryposis or of primary anterior horn cell loss, to less than 1% in anoxic-ischaemic damage. Cerebral clastic processes are considered as sporadic. We report on a non-consanguineous family in which the first child was affected by AMC and the following pregnancy was terminated because cerebellum hypoplasia was suspected at ultrasound and confirmed by fetal magnetic resonance imaging. Post-mortem findings demonstrated pontocerebellar ischaemic-haemorrhagic injuries. The occurrence of these neurologic abnormalities in the same family suggests a common mechanism, which might correspond to a same genetic defect with different patterns of expression. This is the first prenatal report suggesting that an ‘ischaemic’ process, usually recognised as sporadic could in fact be due to an inherited abnormality. Careful prenatal follow-up of third-trimester fetal brain development may be required in pregnant women with a family history of AMC.
Soluble Intercellular Adhesion Molecule 1 in Umbilical Cord Serum: Potential for the Diagnosis of Neonatal Infections
Authors: Daraï Emile , Poncelet Christophe , Soriano David , Lejeune Veronique , Bringuier Annie-France , Madelenat Patrick , Feldmann Gerard , Scoazec Jean-Yves
Published: April 2003

Objective: To evaluate the diagnostic relevance to neonatal infections of the soluble intercellular adhesion molecule 1 (sICAM-1) cord serum level. Methods: The case-control study included 66 term newborn infants with and without risk factors for neonatal infections. Cord blood serum determinations of white blood cell count, C-reactive protein, fibrinogen, and sICAM-1 were systematically performed associated with bacterial cultures from placenta, ears, and gastric fluids. Results: 6 of 33 infants (18.2%) with risk factors were infected, and 13 (39.4%) were colonized. Two infants included in the group without infection risk factors (n = 33) were colonized. No difference in sICAM-1 cord serum levels was found according to the presence of premature rupture of membrane, fetal tachycardia >160 bpm, meconial amniotic fluid, and duration of labour >10 h. No difference in sICAM-1 was noted between infected and non-infected infants. The cord serum levels of sICAM-1 were significantly higher in infants after forceps extraction (p = 0.01). A correlation was observed between sICAM-1 and C-reactive protein cord serum levels (p = 0.004, r = 0.371) and between sICAM-1 level and neutrophil count (p = 0.01, r = 0.489). Conclusions: Our results suggest that cord serum sICAM-1 determinations have no diagnostic relevance to neonatal infection. The increase of sICAM-1 cord serum levels in infants after forceps extraction suggests its potential to evaluate cerebral trauma or hypoxia.
Effect of Ob/Gyn Residents’ Fatigue and Training Level on the Accuracy of Fetal Weight Estimation
Authors: Ben-Aroya Zahi , Segal David , Hadar Amnon , Hallak Mordechai , Friger Michael , Katz Miriam , Mazor Moshe
Published: April 2003

Objective: To determine the effect of Ob/Gyn residents’ fatigue and training level on the accuracy of their clinical and ultrasonographical estimation of fetal weight (EFW). Methods: In this study, clinical and ultrasonographical EFWs were performed by various residents. Actual birth weight, gravidity, parity, gestational age, body mass index, presence or absence of diabetes and hypertensive diseases, presentation and amniotic fluid index were recorded. All EFWs were divided into 3 groups according to the hour they were performed. All residents were divided into 4 groups according to their training level. The accuracy of EFW as compared with actual birth weight was then analyzed according to the shift and to the residents’ seniority by using the ANOVA test. Multivariate analysis was performed to evaluate the factors that significantly and independently affected the weight evaluation. Results: Statistically significant differences were found between the clinical EFW and the birth weight among the working shifts for birth weights of 2,500 g and more (p = 0.032 and p = 0.035). For clinical EFW, night shifts were the most inaccurate (9.27, 8.05 and 9.78% of error for day, evening and night shift, respectively; p = 0.03). The accuracy of ultrasonographical EFW was not affected by the residents’ fatigue level. The residents’ training level did not alter the accuracy of either clinical or sonographical EFW. The accuracy of clinical EFW was affected independently by the work shift (p = 0.01), whereas no factor was found to independently effect the accuracy of ultrasonographic EFW. Conclusions: Ob/Gyn residents’ fatigue affects the accuracy of clinical but not ultrasonographical EFWs. Residents’ training level does not alter either the clinical or sonographical EFW.
Pathogenesis of Acardiac Twinning: Clues from an Almost Acardiac Twin
Authors: Driggers R.W. , Blakemore K.J. , Bird C. , Ackerman K.E. , Hutchins G.M.
Published: April 2003

Objective: To search for clues to the pathogenesis of acardiac twinning. Methods: We examined a case of monoamniotic twins in which twin A’s only sonographic abnormality was a dilated, tortuous ductus venosus. Twin B also had this abnormality as well as multiple other anomalies that included enormous hydrops and a severely hypoplastic heart. Following termination of pregnancy, autopsy was performed. Results: Postmortem examination of the placenta confirmed monochorionic, monoamniotic placentation with two adjacent trivascular cords. Autopsy confirmed the sonographic findings of enormous hydrops in twin B with a severely malformed, almost nonexistent heart. In addition, the liver was small and was represented by a cyst-like structure with thin rims of congested parenchyma surrounding large vascular spaces. Conclusion: We believe the sequence of events in this case was early twin-to-twin transfusion resulting in a dysfunctional heart in twin B. This enabled a twin reversal arterial perfusion sequence with further deterioration of twin B’s heart and extreme congestion of deoxygenated blood exiting the heart into the inferior vena cava and ductus venosus. This case supports the concept that circulatory reversal in the face of an initially functioning heart may lead to congestion, tissue hypoxia and secondary organ atrophy.
Inverse Relationship between Platelet Density and Reactivity Alterations at Coronary Angiography
Authors: Järemo P. , Lindahl T.L. , Fransson S.G. , Milovanovic M. , Logander E. , Richter A.
Published: April 2003

This work investigates relationships between platelet density and reactivity. 21 individuals subject to coronary angiography were studied. Peak platelet density was analyzed using a newly developed electronic device. The apparatus measures light transmission through test tubes containing density-separated platelets, thus allowing an estimation of the platelet distribution in the gradient. A flow cytometry technique was used for determining platelet reactivity after stimulating with ADP. Platelet counts, mean platelet volumes, peak platelet density and platelet reactivity were determined immediately before (day 1) and 24 h after cardiac catheterization (day 2). For all parameters changes during the day of angiography were compared with platelet density alterations. The subjects were divided into two groups according to density changes at angiography. Group 1 individuals showed density alterations (i.e. day 2 – day 1 value) ≧–8 × 10–5 kg/l. In contrast, group 2 subjects either displayed density changes <–8 × 10–5 kg/l or grossly disturbed platelet density patterns on day 2. Before angiography both groups had similar platelet counts and volumes. Then platelet reactivity when stimulating with ADP did not differ significantly between the two groups. After angiography, the number of fibrinogen-positive cells when stimulating with ADP rose by 6 ± 8% for group 2 patients. The corresponding figure for group 1 was –1 ± 6%. The difference was significant (p = 0.01). No such relationships were found when comparing density alterations and changes of platelet counts and volumes. We conclude that in this study platelet density alterations at coronary angiography are inversely related to variations of platelet reactivity.
Evaluation of an Optimal Dose of Low-Molecular-Weight Heparin for Thromboprophylaxis in Pregnant Women at Risk of Thrombosis Using Coagulation Activation Markers
Authors: Bombeli T. , Raddatz Mueller P. , Fehr J.
Published: April 2003

There is no consensus on the dose of low-molecular-weight (LMW) heparin for thromboprophylaxis in pregnant women at increased risk of thrombosis. Based upon monitoring with anti-factor Xa activity, the studies showed conflicting results suggesting either fixed dosages throughout the pregnancy or dosages adapted to the gestational age. We tested whether monitoring thromboprophylaxis with D-dimers and thrombin-antithrombin complexes (TAT) would provide additional information on the optimal dose of LMW heparin. Women (165 women and 202 pregnancies) with hereditary or acquired thrombophilia or a history of thrombosis were considered to receive prophylactic LMW heparin therapy. All women received initially 5,000 IU/day of dalteparin s.c. All further dosages were determined solely on the basis of TAT and/or D-dimer values which were determined every 2–3 weeks. As soon as one of these values increased above the normal range, the dose of LMW heparin was adjusted. In 84.6% of all pregnancies, TAT and/or D-dimer values increased above the normal range once or more during the pregnancy. Consequently, the dose of LMW heparin had to be adjusted at least once over the course of the pregnancy. The mean daily dose of LMW heparin increased from 5,000 to 11,200 U between the 6th and 40th week of gestation. Adverse effects included one major bleeding and six local complications, but no thromboembolic event. In conclusion, increasing doses of LMW heparin are needed to keep TAT and D-dimers within the normal range during pregnancy. Hence, to suppress thrombin generation, apparently, the dosage of LMW heparin should be adjusted to the gestational age rather than using fixed doses throughout the pregnancy. However, it remains to be further established whether elevated TAT and D-dimers truly reflect a prothrombotic state during pregnancy.
Coexistence of Factor V G1691A and Factor II G20210A Gene Mutations in a Thrombotic Family Is Associated with Recurrence and Early Onset of Venous Thrombosis
Authors: Gemmati D. , Serino M.L. , Moratelli S. , Tognazzo S. , Ongaro A. , Scapoli G.L.
Published: April 2003

Two G-to-A mutations at positions 1691 of the factor V (FV) gene and 20210 of the prothrombin (FII) gene have been associated with an increased risk of venous thromboembolism. We report a thrombosis-prone family in which one subject – the propositus who exhibited combined heterozygous FV G1691A and FII G20210A mutations – showed spontaneous and early clinical onset (at 23 years), recurrences of deep-vein thrombosis and pulmonary embolism. His asymptomatic father carried the FII G20210A substitution and his mother, characterized by an isolated thrombotic episode on occasion of surgery (at 48 years), carried the FV G1691A substitution. In the maternal lineage, one of the propositus’ uncles had thrombosis on occasion of a bone fracture (at 65 years) despite the absence of known prothrombotic defects. A sister of the propositus carried the FII G20210A and the brother the FV G1691A mutation. They have been asymptomatic until now. The propositus’ two children, 20 and 16 years old, both carry the FV G1691A substitution and have been asymptomatic until now. The plasma levels of FII were higher in carriers of the FII G20210A allele if compared with noncarriers, and the activated protein C resistance phenotype, associated with the FV Leiden mutation, showed a complete correlation with the FV G1691A mutation. Despite the very limited number of thrombotic cases involved in this survey, which does not allow statistically sound conclusions, the data obtained from this family suggest that the synergy of inherited factors and transient risk conditions could play a key role in the occurrence of thrombotic accidents.
Comparison of Stimulated Growth Hormone Levels in Primed versus Unprimed Provocative Tests
Authors: Gönç E. Nazlı , Yordam Nurşen , Kandemir Nurgün , Alikasifoglu Ayfer
Published: April 2003

Objective: To show the importance of priming prior to growth hormone (GH) stimulation tests in the diagnosis of GH deficiency, the effect of different doses and schedules of testosterone (T) on GH levels. Patients and Methods: Eighty-four prepubertal and early pubertal boys whose heights were 2 SD below the mean and height velocities <4 cm per year and who failed in GH stimulation tests were included in the study. The boys were divided into two groups: the first group consisting of 41 boys was primed with 62.5 mg/m2 (low dose testosterone – LDT) and the second group consisting of 43 boys with 125 mg/m2 depot testosterone (conventional dose testosterone – CDT) intramuscularly 1 week before the stimulation test. Twenty-one boys out of 36 who failed in GH stimulation tests after one dose T injection were treated with three doses of 62.5 mg/m2 T (multiple dose testosterone – MDT) injections monthly and retested. Results: The GH levels increased from 4.80 ± 2.78 to 11.50 ± 8.84 ng/ml and from 4.76 ± 2.46 to 12.98 ± 8.30 ng/ml by priming with LDT and CDT respectively. The increment of mean GH levels by both LDT and CDT were found to be similar (p = 0.443). The peak GH levels were found to be elevated >10 ng/ml in 22/41 (54%) and 26/43 (60%) who received LDT and CDT respectively (p = 0.528). The mean GH level of 21 boys who received MDT was increased from 5.38 ± 2.50 ng/ml (by priming with one dose T) to 10.19 ± 6.13 ng/ml (p = 0.004). Twelve (57%) of 21 boys who received MDT responded to GH stimulation test >10 ng/ml. The T level increased from 0.71 ± 0.97 to 4.54 ± 2.80 ng/ml by LDT (p < 0.001) and from 0.65 ± 0.71 to 7.18 ± 3.18 ng/ml by CDT (p < 0.001). The increment of T level was higher by CDT than LDT (p = 0.001). There was no correlation between T and peak GH levels after priming. Conclusion: LDT is as effective as CDT in priming of GH stimulation tests. The ones who failed in GH stimulation tests after one dose T injection can be primed with MDT. The stimulated GH level after priming was related neither to the plasma level of T nor the dose of T.
Hormones and Handedness
Authors: Mulligan J. , Stratford R.J. , Bailey B.J.R. , McCaughey E.S. , Betts P.R.
Published: April 2003

Background: The Wessex Growth Study has monitored the growth and psychological development of short normal (SN) and average height control subjects since they entered school in 1985/1986. During psychometric testing, we found that 25% SN compared to 9% control subjects wrote with their left hand. The short group also attained significantly lower scores on measures of IQ and attainment and displayed less internalisation of control. Laterality, however, is thought to be influenced by the intrauterine environment and has been associated with pubertal delay. At recruitment, short children had a relatively low birth weight, delayed bone age and were more likely than controls to be short for family. Objectives: To determine if birth conditions were associated with lateral preference and whether laterality could account for the differences found during the psychometric assessment or predict pubertal timing of SN children. Methods: Subjects were classified as right- (RH) or left-handed (LH) according to the writing hand and the data were investigated examining the effect of handedness and stature. Results: RH and LH SN children were no more likely to suffer birth complications than those of average height. Psychometric testing did not reveal any significant differences between RH and LH SN children and their patterns of growth appeared to be similar. However, both RH and LH SN children scored less well on tests of cognitive ability and analyses of covariance revealed significant gender/handedness effects for both the timing of puberty and final height. Conclusions: The increase in left-handedness among SN children did not appear to be related to adverse birth conditions, but it may be that the hormones responsible for growth and development also play some part in brain laterality and cognitive development.
Thyroid C-Cell Hyperplasia in an Adolescent with Neurofibromatosis Type 1
Authors: Segni Maria , Massa Rita , Bonifacio Vincenzo , Tartaglia Francesco , Pucarelli Ida , Marzullo Antonella , Pasquino Anna Maria
Published: April 2003

Background: Subjects with neurofibromatosis type 1 (NF1) show an increased risk of endocrine tumors, especially pheochromocytoma, whereas thyroid C-cell hyperplasia (CCH) and medullary thyroid carcinoma (MTC) are very rare events described only in adult patients. Method: A case of CCH diagnosed in a 14-year-old girl affected with NF1 is reported. Calcitonin serum level after pentagastin was elevated (286 pg/ml). Genetic testing was performed in order to rule out mutations in the RET proto-oncogene. Result: No germline mutation previously reported in MEN2 was detected. Multifocal and bilateral CCH was demonstrated by immunohistochemistry. Conclusion: It is suggested that in such a genetic background of high risk for malignancy, CCH could be considered as an extremely rare condition likely preceding MTC.
Prevalence of Macroprolactin Detected by Elecsys® 2010
Authors: Sánchez-Eixerés M. Rosa , Mauri Montserrat , Alfayate Rocío , Graells M. Luisa , Miralles Carmen , López Alicia , Picó Antonio
Published: April 2003

Background: Macroprolactin or big-big PRL is, usually, a complex of little prolactin (PRL) with anti-PRL autoantibody. There are some patients with hyperprolactinemia showing a high proportion of serum macroprolactin. However, its clinical significance is not clear. Immunoassays used to determine PRL differ in their ability to detect macroprolactin. Moreover, in recent years, PRL assays have changed from isotopic methods (radioimmunoassays and immunoradiometric assays) to non-isotopic automated immunoassays. The effect of macroprolactin on currently used methods is often unknown. The aim of this work was to study the different reactivity of macroprolactin in two immunoassays systems, Elecsys 2010 and ACS Centaur, and to assess the clinical repercussion of this condition. Methods: We studied retrospectively 956 consecutive routine patients. Samples with a PRL value >636 mIU/l (211 samples) were subjected to the polyethylene glycol (PEG) precipitation test to detect macroprolactin, and 2 of them also to gel filtration chromatography for further confirmation. PRL was measured by Elecsys 2010 and, alternatively, by ACS Centaur. Results: By Elecsys 2010, macroprolactin was detected in 19 patients (9%). After removing macroprolactin, PRL levels were within the normal range in every case but one. When original sera from patients with macroprolactin were processed with ACS Centaur. PRL levels were normal or only marginally elevated. The correlation of PRL values in samples with and without macroprolactin assayed by both systems was 0.64 and 0.98, respectively. Conclusions: Nearly 9% of hyperprolactinemic patients detected by Elecsys 2010 may have macroprolactin, but the detection rate obtained using ACS Centaur is much lower. As macroprolactin seems to have minimal clinical relevance, it would be important that the users of PRL assays be aware to what extent macroprolactin interferes with their assays, and have available a validated method, such as the PEG precipitation test, to confirm the presence of macroprolactin.
Effects of Estrogen on Serum Leptin Levels and Leptin mRNA Expression in Adipose Tissue in Rats
Authors: Tanaka Masami , Nakaya Sachiko , Kumai Toshio , Watanabe Minoru , Tateishi Tomonori , Shimizu Hiromi , Kobayashi Shinichi
Published: April 2003

Objective: In this study, we examined changes in serum leptin levels during the estrus cycle and the role of estrogen in these changes. Methods: We measured serum leptin levels during normal estrus cycles in intact rats and estradiol-17β (E2)-induced artificial estrus cycles in ovariectomized rats. Results: Serum leptin levels increased 1.6-fold from 4.2 ± 0.2 ng/ml during diestrus stage 2 to 6.7 ± 0.9 ng/ml during proestrus stage during the 4-day estrus cycle. During the E2-induced estrus cycle, serum leptin levels increased 2.3-fold from 2.3 ± 0.1 ng/ml at estrus to 5.4 ± 1.2 ng/ml at proestrus. E2 also increased serum leptin concentrations and leptin mRNA expression in adipose tissue of immature rats. Discussion: These findings suggest that increased serum leptin induced by estrogen during proestrus may trigger the preovulatory release of luteinizing hormone. Furthermore, our findings indicate that estrogen has a positive effect on leptin production in adipose tissue.
Effects of Growth Hormone Treatment on Left Ventricular Dimensions in Children with Noonan’s Syndrome
Authors: Noordam C. , Draaisma J.M.T. , van den Nieuwenhof J. , van der Burgt I. , Otten B.J. , Daniels O.
Published: April 2003

Objective: To study the effects of long-term growth hormone (GH) treatment on left ventricular (LV) dimensions in children with Noonan’s syndrome (NS). Methods: Echocardiographic measurements of LV dimensions were performed before and during GH treatment in 27 participants (21 boys, 6 girls) in a partly controlled 3-year trial of high-dose GH treatment (0.15 IU/kg/day). Nineteen children had a congenital heart defect, 1 of them had hypertrophic obstructive cardiomyopathy. In the first 3 years, the children were assigned to 1 of 2 groups: group A with discontinuation of GH treatment in the 3rd year, or group B without GH treatment in the 1st year. After the 3rd year, 12 of the 27 children were followed up for 2 additional years to evaluate the long-term effects of GH treatment on the heart. Results: At baseline, LV internal diameters were smaller, while posterior wall thickness were thicker than normal. Over the 1st year, changes in LV dimensions were comparable between the 2 groups. No significant differences were found in LV dimensions between the situation at baseline and after 4 years of GH treatment. Conclusion: Long-term high-dose GH treatment does not have clinically significant adverse effects on LV dimensions in children with NS.
Growth Hormone Treatment Does Not Alter Lower Limb Asymmetry in Children with Russell-Silver Syndrome
Authors: Rizzo V. , Traggiai C. , Stanhope R.
Published: April 2003

Background: Growth hormone (GH) treatment has been proven to have a beneficial effect on growth in children with Russell-Silver syndrome (RSS). Methods: We describe 7 prepubertal children with RSS and lower limb asymmetry treated with GH for 3 years. Results: There was a significant increase in height without any significant change in the asymmetry. Conclusions: We conclude that the rapid growth acceleration to GH treatment does not alter the lower limb asymmetry in children with RSS.
Unusual Association of Adrenal Angiosarcoma and Cushing’s Disease
Authors: Invitti Cecilia , Pecori Giraldi Francesca , Cavagnini Francesco , Sonzogni Angelica
Published: April 2003

The occurrence of an angiosarcoma in the adrenal gland is exceedingly rare as only 21 patients have been reported in the literature since its first description 30 years ago. We report the clinicopathological features of a 34-year-old patient presenting with overt Cushing’s syndrome due to a ACTH-secreting pituitary adenoma and an adrenal spindle cell angiosarcoma. This association made the diagnosis of Cushing’s disease particularly puzzling in view of the results of biochemical tests which were compatible in part with adrenal and in part with paraneoplastic hypercortisolism and the negative pituitary imaging. The unique appearance of this tumor and its diagnostic implications are discussed.
A Case of Pheochromocytoma with Renal Artery Stenosis and Post-Surgical Watery Diarrhea
Authors: Blasi Claudio , D’Amore Francesco , Delle Fave Gianfranco , Massa Rita , Reale Maria Gabriella , Caliumi Chiara , Letizia Claudio
Published: April 2003

A 35-year-old woman was admitted to our hospital with the following complaints, headache, sweating, anxiety, dizziness, nausea, vomiting and severe hypertension. The technical images (abdominal CT, scintigraphic octreotide scan and renal arteriography) revealed the presence of a left adrenal pheochromocytoma and stenosis of the renal artery. Ten days following adrenalectomy, watery diarrhea appeared. The long-acting somatostatin analogue octreotide (LAR, 30 mg/month, i.m.), was started, and after 2 weeks diarrhea decreased and gradually disappeared. In conclusion, we were confronted with an unusual case of pheochromocytoma associated with renal artery stenosis and the appearance of watery diarrhea some days after surgical treatment. Treatment with octreotide brought about the remission of diarrhea in this patient.
Kinetics and Effect of Percutaneous Administration of Dihydrotestosterone in Children
Authors: Charmandari Evangelia , Dattani Mehul T. , Perry Leslie A. , Hindmarsh Peter C. , Brook Charles G.D.
Published: April 2003

Background: Percutaneous administration of dihydrotestosterone (DHT) has been successful in promoting phallic growth in infants and children with 5α-reductase deficiency raised as males. We investigated whether percutaneous administration of DHT is similarly effective in patients with micropenis due to alternative diagnoses. Methods: Six patients (age range 1.9–8.3 years) with micropenis of variable etiology were studied prospectively. 2.5% DHT gel was applied to the phallus once daily at a dose of 0.15–0.33 mg/kg body weight. Serum DHT concentrations were measured at 0, 2, 4, 8, 12 and 24 h following application of DHT gel. Results: Peak DHT concentrations were attained within 2–8 h after application of the gel and subsequently remained within the normal adult range in all but 1 patient, who had received the lowest dose of 0.15 mg/kg. An increase in phallic growth, ranging from 0.5–2.0 cm, was achieved after 3–4 months of treatment in all patients whose DHT concentrations were maintained within adult range. Conclusion: Percutaneous administration of DHT in a dose of 0.2–0.3 mg/kg once daily for a period of 3–4 months may be useful in the management of patients with testosterone biosynthetic defects, who have sufficient masculinization to warrant male sex assignment, or in patients with micropenis prior to reconstructive surgery.
Growth Abnormalities Associated with Adrenal Disorders and Their Management
Authors: Savage M.O. , Lebrethon M.-C. , Blair J.C. , Ho J.T.F. , Johnston L.B. , Lienhardt A. , Clark A.J.L. , Chaussain J.-L.
Published: April 2003

Linear growth can be disturbed in paediatric adrenal disease associated with endocrine hypo- or hyperfunction. Tall stature is a feature in some patients with adrenocorticotropic hormone resistance syndromes and short stature is recognized in the IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) association. In autoimmune Addison’s disease, growth is usually normal. In congenital adrenal hyperplasia, height may be compromised by advanced skeletal maturation or by suppressed growth, particularly in the neonatal period due to excess glucocorticoid treatment. In virilizing adrenal tumours, height is increased at diagnosis, but after surgical cure final height is usually in the normal range. In Cushing’s disease, height was abnormally short in 50% of patients at presentation. After successful treatment, spontaneous catch-up growth was not seen. This led to a diagnosis of growth hormone (GH) deficiency in 80% of patients. With GH replacement, catch-up growth and long-term benefit occurred. Disturbance of linear growth is an important feature of many patients with adrenal disorders in childhood. Assessment of its pathogenesis and careful management are necessary to ensure optimal final adult height.
Turner’s Syndrome: A Paediatric Perspective
Authors: Sas Theo C.J. , de Muinck Keizer-Schrama Sabine M.P.F.
Published: April 2003

In childhood the symptoms with the greatest impact on girls with Turner’s syndrome are: (1) congenital cardiac abnormalities (which can be corrected by surgical intervention); (2) short stature (mean adult height between 142 and 147 cm); and (3) ovarian failure (absent spontaneous puberty). Recent studies have shown that growth hormone (GH) treatment in young girls (8 years of age or younger) with Turner’s syndrome results in normalization of adult height in most of the girls when using the ‘standard’ GH dose of about 4 IU/m2 per day (≈0.045 mg/kg per day). Higher GH doses (6 or 8 IU/m2 per day) or the use of oxandrolone may be more effective, but their efficacy on adult height and safety in the very long term still have to be proven. If GH treatment is started early, low-dose oestrogens for induction of puberty can be given at 12 years of age without interfering with the capability of the GH treatment to normalize adult height. GH does not seem to have negative side effects on body proportions, cardiac dimensions, blood pressure, carbohydrate metabolism or bone mineral density.
Medical Problems of Adult Turner’s Syndrome
Authors: Gravholt Claus Højbjerg
Published: April 2003

Several issues should be addressed when managing women with Turner’s syndrome. Female sex hormone substitution should be offered to help prevent the increased morbidity seen in Turner’s women, which consists of an increased risk of fractures and osteoporosis, and a clustering of diseases such as ischaemic heart disease, hypertension, stroke and type 2 diabetes, the latter entities being part of the insulin resistance syndrome. Furthermore, hypothyroidism is often seen, and the risk of type 1 diabetes may also be increased. Congenital malformations of the heart are frequently seen in Turner’s syndrome, possibly increasing the risk of dissecting aorta aneurism. Liver enzymes are often elevated and there may be an increased risk of liver cirrhosis. Mortality seems to be increased in Turner’s syndrome, women with the ‘pure’ 45,X karyotype being the most severely affected. In clinical practice, careful monitoring of glucose and bone metabolism, weight, thyroid function and blood pressure should be carried out. A cardiovascular risk profile should be determined and the patient informed of the risks and benefits of sex hormone replacement therapy. Sex hormone replacement therapy is highly recommended, although at present there are no longitudinal data documenting the long-term positive effect of sex steroid substitution. However, hypogonadism is expected to explain at least part of the decreased lifespan found in Turner’s syndrome. Since general physicians only encounter these patients infrequently, it is recommended that the care and treatment of Turner’s syndrome be centralized.
Health-Related Quality of Life: Methods of Assessment
Authors: Barofsky Ivan
Published: April 2003

Developing a health-related quality of life (HRQOL) assessment requires both a conceptual model and an extended plan whereby the assessment can continue to be developed with repeated applications. While generic HRQOL assessments exist and can be readily applied, it is when the assessment is integrated into the treatment development process that it is of most value, and to do this optimally requires either disease or study-specific assessments. Investigators were encouraged to view the assessment task as an information processing activity, and to be as concerned about how a person generates an HRQOL assessment as much as what they state their HRQOL to be. The added value of doing an HRQOL assessment is also discussed.
Purification and Distribution of Ghrelin: The Natural Endogenous Ligand for the Growth Hormone Secretagogue Receptor
Authors: Kojima Masayasu , Hosoda Hiroshi , Kangawa Kenji
Published: April 2003

Growth hormone secretagogues (GHS) are small synthetic molecules that act through a specific G-protein coupled receptor (GPCR) termed GHS-R, which is a distinct receptor from that of growth hormone releasing hormone (GHRH). This receptor was one of the orphan GPCR, i.e. a GPCR with no known natural ligand, until we purified its endogenous ligand from rat stomach and named it ‘ghrelin’. Ghrelin is a 28-amino-acid peptide, in which the serine 3 is modified by an n-octanoic acid and this modification is essential for ghrelin’s activity. The discovery of ghrelin indicates that the release of GH from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelin from the stomach and hypothalamus.
Toward the Future Schooling of Girls: Global Status, Issues, and Prospects
Authors: Slaughter-Defoe Diana T. , Addae Wendy Akua , Bell Candace
Published: April 2003

This paper evaluates the role that formal schooling has played in the lives of girls and women in 20th century developing and developed nations. Studies of the literacy rates of girls and women around the world are considered together with studies of maternal schooling, and its effects on a variety of female behaviors. The paper is designed to provoke critical discussion about the future of public schooling worldwide, using the complex relationship between schooling and females’ development as a metaphor for this process. The experiences of girls and women within schools are especially informative and suggestive of the potential contributions of public schooling to the general well-being of a nation. However, there have been, and continue to be, many challenges to access and equity within schools and classrooms around the world. The United States of America is the nation used as a case study example for the developed world. We conclude that flexibility and choice are crucial features if useful future options for formal schooling are to be enhanced for girls and women worldwide.
cDNA Cloning, Biological and Immunological Characterization of the Alkaline Serine Protease Major Allergen from Penicillium chrysogenum
Authors: Chou Hong , Lai Hsiu-Yu , Tam Ming F. , Chou Ming-Yuan , Wang Soo-Ray , Han Shou-Hwa , Shen Horng-Der
Published: April 2003

Background:Penicillium chrysogenum (Penicillium notatum) is a prevalent airborne Penicillium species. A 34-kD major IgE-reacting component from P. chrysogenum has been identified as an alkaline serine protease (Pen ch 13, also known as Pen n 13 before) by immunoblot and N-terminal amino acid sequence analysis. Methods: In the present study, Pen ch 13 was further characterized in terms of cDNA cloning, protein purification, enzymatic activity, histamine release and IgE cross-reactivity with alkaline serine protease allergens from two other prevalent fungal species – P. citrinum (Pen c 13) and Aspergillus flavus (Asp fl 13). Results: A 1,478-bp cDNA (Pen ch 13) that encodes a 398-amino-acid alkaline serine protease from P. chrysogenum was isolated. This fungal protease has pre- and pro-enzyme sequences. The previously determined N-terminal amino acid sequence of the P. chrysogenum 34-kD major allergen is identical to that of residues 116–125 of the cDNA. Starting from Ala116, the deduced amino acid sequence (283 residues) of the mature alkaline serine protease has a calculated molecular mass of 28.105 kD with two cysteines and two putative N-glycosylation sites. It has 83 and 49% sequence identity with the alkaline serine proteases from P. citrinum and A. fumigatus, respectively. The recombinant Pen ch 13 was recovered from inclusion bodies and isolated under denaturing condition. This recombinant protein reacted with IgE antibodies in serum from an asthmatic patient and with monoclonal antibodies (PCM8, PCM10, PCM39) that reacted with the 34-kD component from P. chrysogenum. The N-terminal amino acid sequence of the purified native Pen ch 13 is identical to that determined previously for the 34-kD major allergen in crude P. chrysogenum extracts. The purified native Pen ch 13 has proteolytic activity with casein as the substrate at pH 8.0. This enzymatic activity was inhibited by phenylmethylsulfonyl fluoride or diethylpyrocarbonate. Pen ch 13 was also able to degrade gelatin and collagen but not elastin. Basophils from 5 asthmatic patients released histamine (12–73%) when exposed to the purified Pen ch 13. In ELISA (enzyme-linked immunosorbent assay) experiments, IgE for Pen ch 13 was able to compete with purified Pen ch 13, Pen c 13 or Asp fl 13 in a dose-related manner. Conclusions: These results demonstrated that the 34-kD major allergen of P. chrysogenum is an alkaline serine protease. These results also indicated that atopic patients primarily sensitized by either of these prevalent fungal species may develop allergic symptoms by exposure to other environmental fungi due to cross-reacting IgE antibodies against this protease.