bluuebunny/crossref_metadata_2025 huggingface dataset:
46,XY Phenotypic Male with Focal Segmental Glomerulosclerosis Caused by the WT1 Splice Site Mutation
Authors: Tajima Toshihiro , Sasaki Satoshi , Tanaka Yayoi , Kusunoki Hiroyuki , Nagashima Testuro , Nonomura Katsuya , Fujieda Kenji
Published: December 2003

Objective: Frasier syndrome is characterized by progressive glomerulopathy due to nonspecific focal and segmental glomerulosclerosis (FSGS), 46,XY sex reversal and the development of gonadoblastoma from dysgenetic gonads. Donor splice site heterozygous mutations in intron 9 of the Wilms’ tumor gene (WT1) cause this disease. We investigated whether WT1 mutations showed clinical heterogeneity. Patients and Methods: A 6-year-old phenotypic boy was diagnosed as having FSGS. His karyotype was 46,XY. Gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests revealed normal luteinizing hormone, follicle-stimulating hormone and testosterone responses. The other patient was a 7-year-old 46,XY female with FSGS. Prophylactic gonadectomy was performed and gonadoblastoma was found. By polymerase chain reaction and direct sequencing, WT1 was analyzed in these patients. Results and Conclusion: Both patients had IVS9 + 5G→A in intron 9 of the WT1. Our study indicates a normal 46,XY phenotypic male patient with FSGS. The phenotypic variations of the WT1 splice site mutations are further expanded.
Which Stem Cells Should be Used for Transplantation?
Authors: Michejda Maria
Published: December 2003

In view of the ever-increasing demand for human stem cells for transplantation, we initiated in vitro and in vivo studies of human fetal bone marrow stem/progenitor cells derived from lost pregnancies at 16–20 weeks. Utilizing non-human primates as models, we demonstrated that fetal tissue has distinctive biological and therapeutic properties that are optimal for transplantation. Subsequently, we tested and compared the phenotypic and functional characteristics of fetal bone marrow (FBM), adult bone marrow (ABM), and cord blood (CB) and peripheral blood (PB) sources of the most primitive stem/progenitor cells. A striking ontogenic difference in the proportion of CD34+ cells in FBM, ABM, PB and CB was observed (24.6 vs. 2.1 vs. 0.5 vs. 2%). The clonogenic potential, as measured by the CFU-c assay, was also higher in FBM when compared with ABM, PB and CB (202.5 vs. 73.5 vs. 40.8 vs. 65.5 colonies/105 cells). Moreover, there was a significant decrease in proliferative responsiveness in the mixed lymphocyte reaction (MLR) assay of FBM and CB as compared to ABM and PB. The cytokinetic profiles of the cells from the four sources were also analyzed. This study revealed that both FBM and ABM had a higher proportion of S-phase (21.7 and 11.5%, respectively), compared to PB and CB cells (1.2 and 2.8%, respectively). FBM and ABM also showed a higher proportion of cells in the G2-M phase (6.4 and 2.6%, respectively) compared with PB and CB (1.7 and 1.2%, respectively). These data show that FBM has the highest number of proliferating cells. We have also investigated the ontogenic differences in stromal cells derived from FBM, ABM and CB, with a special focus on the expression of selected cytokines, such as CSF, GM-CSF, G-CSF, M-CSF, IL-3, IL-6, IL-10 and IL-11. FBM showed the highest levels of expression of CSF, IL-6 and IL-11 when compared to the other sources. These cytokines may have an important role in engraftment and homing of stem cells. The levels of expression of the other cytokines were similar in all sources of stromal cells, with the exception of G-CSF, which was not detected in CB. Moreover, the number of colonies FBM and ABM cells was higher when inoculated with fetal stromal cells. These results suggested an important regulatory role of cytokines in ontogeny of hematopoiesis. In summary, the foregoing observations indicate that each source of hematopoietic and stromal cells has different intrinsic properties, closely correlated with ontogenetic age, which is a vital determinant for phenotypic characteristics, lineage commitments, immunogenicity as well as proliferative potentials. Our data clearly indicate that FBM is the best source of stem cells for engraftment and therapeutic reconstitution due to its very high proliferative capacity, low immunogenicity and highest number of primitive stem/progenitor cells. It should also be stressed that FBM stem cells retrieved at their optimal stage of hematopoiesis (16–20 weeks) may be the cells of choice for both therapeutic cellular reconstitution and gene targeting.
In utero Hematopoietic Cell Transplantation: What Are the Important Questions?
Authors: Peranteau William H. , Hayashi Satoshi , Kim Heung Bae , Shaaban Aimen F. , Flake Alan W.
Published: December 2003

The treatment of congenital hematologic disorders before birth by in utero hematopoietic stem cell transplantation remains a challenging goal. Although success has been achieved in X-linked severe combined immunodeficiency, the approach has failed in all other disorders attempted thus far. In this review, we examine relevant experimental data from the perspective of an analysis of why failure has occurred. We will also attempt to pose the important questions that will need to be answered prior to further clinical attempts to treat most target disorders by this approach.
The Intracoelomic Route: A New Approach for in utero Human Cord Blood Stem Cell Transplantation
Authors: Noia Giuseppe , Pierelli Luca , Bonanno Giuseppina , Monego Giovanni , Perillo Alessandro , Rutella Sergio , Cavaliere Anna Franca , Straface Gianluca , Fortunato Giuseppe , Cesari Elena , Scambia Giovanni , Terzano Marinella , Iannace Enrico , Zelano Giovanni , Michetti Fabrizio , Leone Giuseppe , Mancuso Salvatore
Published: December 2003

The intracoelomic route for in utero hematopoietic stem cell transplantation has been evaluated in pre-immune fetal sheep and the engraftment characteristics defined. Twelve ovine fetuses (gestational ages: 40–45 days) received intracoelomic transplants of human CD3-depleted (50 × 106 per lamb) or CD34-selected (1–2 × 105 per lamb) cord blood hematopoietic stem cells. Engraftment was evaluated from cell suspension of the liver, spleen, bone marrow and thymus by flow cytometry, cloning assays and polymerase chain reaction (PCR) analysis for human β2-microglobulin gene. The engraftment of liver samples was also evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR), fluorescent in situ hybridization (FISH) and immunohistochemistry. Four fetuses (33%) aborted shortly after intracoelomic transplantation and were not evaluable for engraftment. Engraftment was detected in 4 fetuses obtained from cesarean delivery on day 70 after transplantation of CD3-depleted cord blood cells. The degree of engraftment in these 4 fetuses ranged from 6 to 22% in the different organs (as revealed by antigenic analysis of human CD45 with flow cytometry). Three fetuses obtained after cesarean section at 102 (No. 435184) and 105 (Nos 915293, 037568) days and 1 fetus delivered at term, which received CD34-selected cord blood cells, had human engraftment with 10, 32, 20 and 10% CD45+ cells in bone marrow, respectively. A further check of human chimerism was done at 1 year after birth of the fetus delivered at term and 7.6% of bone marrow chimerism was detected. In 6 out of 8 fetuses evaluable for human engraftment, chimerism was confirmed by PCR analysis for human β2-microglobulin which also identified human cells in brain, spinal cord, heart, lung and skeletal muscle. On liver samples, FISH and RT-PCR confirmed the xenograft of human cells and the immunohistochemical analysis detected human markers of hematopoietic and hepatic lineage of differentiation. This preliminary study indicates that intracoelomic transplantation of human hematopoietic stem cells in fetal lambs is feasible and effective in terms of hematopoietic engraftment.
The Fetal Doppler Mechanical PR Interval: A Validation Study
Authors: Glickstein Julie , Buyon Jill , Kim Mimi , Friedman Deborah
Published: December 2003

Objective: To evaluate the accuracy of pulsed Doppler-derived fetal PR interval measurements obtained by physicians participating in a multicenter prospective fetal echocardiographic study. Methods: Echocardiograms on healthy fetuses were performed and evaluated by 15 pediatric cardiologists/perinatologists across the United States who are participating in a larger clinical trial involving fetuses at risk for autoantibody-associated congenital heart block. Prior to enrolling women in the main trial, each physician was provided with a teaching tape to demonstrate how the pulsed Doppler-derived PR interval is measured. The procedure involves placing a gated pulsed Doppler sample volume in the left ventricle at the junction of the anterior leaflet of the mitral valve and the left ventricular outflow tract in an apical 5-chamber view, and simultaneously obtaining left ventricular filling and emptying. Time intervals are measured from the onset of the mitral A wave (atrial systole) to the onset of the aortic pulsed Doppler tracing (ventricular systole). This represents the mechanical PR interval. Each physician measured the pulsed Doppler-derived fetal PR interval on 5 different subjects recruited from the physician’s specific site. To validate each physician’s technique, the tapes were sent to a central facility and the same intervals were remeasured by an experienced central reader (D.M.F.). A physician was determined to have adequate ability to measure the fetal PR interval if all 5 measurements were within ± 30 ms of the central reader’s measurements, where 30 ms corresponds to 25% of the mean observed in normative PR interval data. This difference was deemed to be the minimum clinically important difference in Doppler PR interval. Results: Fourteen of the 15 physicians were considered to have adequate ability to measure the fetal PR interval according to our established criterion. The overall mean difference between the physicians and the central reader’s measurements was –0.26 ± 11.04 ms (p = 0.84). In addition, 95% of the observed differences were included in the interval (–22.23 to 21.81), which is well within our clinically acceptable range of ± 30 ms. Conclusions: The pulsed Doppler assessment of the mechanical PR interval in the fetus can be accurately performed after minimal training. This technique may be a valuable tool for identification of early and potentially reversible conduction abnormalities in fetuses at risk for more advanced and permanent forms of heart block associated with maternal antibodies to SSA/Ro-SSB/La.
Abnormal Umbilical Cord Doppler Sonograms May Predict Impending Demise in Fetuses with Sacrococcygeal Teratoma
Authors: Olutoye Oluyinka O. , Johnson Mark P. , Coleman Beverly G. , Crombleholme Timothy M. , Adzick N. Scott , Flake Alan W.
Published: December 2003

Objective: To identify factors predictive of fetal demise in fetuses with sacrococcygeal teratoma (SCT). Method: The recent management of monochorionic twins discordant for a large SCT and a singleton with a large SCT was reviewed. Results: Serial fetal echocardiography and ultrasonography with Doppler flow measurements documented rapid growth of the SCT in both cases with a relatively modest increase in combined cardiac output. No placentomegaly or hydrops was observed at any time. In both fetuses with SCT, evolution of abnormal umbilical artery waveforms was observed with the ultimate development of reversed end-diastolic umbilical arterial flow that was followed by sudden fetal demise. Conclusion: Death in these 2 fetuses with large SCTs in the absence of placentomegaly/hydrops or hemodynamic changes suggestive of evolving high-output failure suggests a previously unrecognized mechanism of death in fetuses with large rapidly growing SCTs. In these cases, fetal demise may only be heralded by abnormal umbilical artery waveforms that progress to the premorbid observation of reversed diastolic umbilical artery blood flow. Umbilical artery waveform analysis should be closely monitored with other hemodynamic parameters in fetuses with large SCTs. In such fetuses, depending on the gestational age, abnormalities in umbilical artery waveform should be considered indications for early delivery or in utero intervention to prevent fetal demise.
Fetal Surgery for Congenital Diaphragmatic Hernia and Pulmonary Sequestration Complicated by Postnatal Diagnosis of Transposition of the Great Arteries
Authors: Hamrick Shannon E.G. , Brook Michael M. , Farmer Diana L.
Published: December 2003

This report describes the case of a neonate who underwent fetal surgery for congenital diaphragmatic hernia (CDH) and pulmonary sequestration. His postnatal management was complicated by the additional diagnosis of transposition of the great arteries (TGA). TGA is particularly difficult to diagnose in the fetus. This triad has not previously been documented in the literature. Clinicians should have a high index of suspicion for associated anomalies, especially cardiac, when evaluating and counseling a pregnancy complicated by CDH.
Association of Undetectable Unconjugated Estriol on Multiple Marker Screening with Steroid Sulfatase Deficiency
Authors: Jari Shama D. , Fraer Luanne M. , Hogge W. Allen
Published: December 2003

Objective: To determine whether all patients with undetectable unconjugated estriol (uE3) on multiple marker screening (MMS) are carriers for steroid sulfatase (STS) deficiency. Methods: This is a retrospective review of 65 pregnancies with undetectable uE3 on MMS. Results: Of the 65 pregnancies, there were 21 that continued, 40 spontaneous losses, 2 lost to follow-up and 2 elective terminations. Of the 21 continuing pregnancies, 15 were determined to be carriers of the STS deletion. Twenty-seven of the 40 pregnancy losses were associated with elevated alpha-fetoprotein (AFP); about half of the losses were shown to have occurred prior to sampling. Conclusion: Patients with undetectable uE3 are likely to be carriers of the STS deletion, except those with associated elevated AFP. Elevated AFP with undetectable uE3 on MMS is a marker of preexisting or impending fetal demise.
Prenatal Diagnosis of Congenital Diaphragmatic Hernia in a McFadden Kalousek Type 2 Triploid Fetus
Authors: Bianca S. , Ettore G. , Gullotta G. , Galasso M.G.
Published: December 2003

Triploidy is characterized by an extra haploid set. We report a rare case of a prenatally diagnosed digynic type (McFadden/Kalousek type 2) triploid fetus with congenital diaphragmatic hernia (CDH). Prenatal ultrasonographic examination allows reliable detection of CDH and it is therefore of great importance for proper parental counselling, as well as performing fetal karyotype for associated chromosomal anomalies.
Doppler Measurements in Fetoplacental Vessels after Maternal Betamethasone Administration
Authors: Kähler C. , Schleussner E. , Möller A. , Seewald H.-J.
Published: December 2003

Objective: To observe the influence of maternal betamethasone administration for fetal lung maturation on the arterial, venous and intracardiac blood flow of the fetus and the uterine arteries. Methods: Twenty-seven women with singleton pregnancies were examined before the first, and 30 min and 8, 24, 48 and 72 h after the second of two single doses of 8 mg of betamethasone. We recorded blood flow velocity waveforms of the umbilical artery (UA), the middle cerebral artery, the uterine arteries, the ductus venosus, the inferior vena cava and the right hepatic vein, the pulmonary trunk, the ductus arteriosus and the right and left intraventricular inflow of the heart. Results: The resistance index of the UA showed a significant transient decrease 30 min (p = 0.024) after the second betamethasone dose. The peak systolic velocity of the ductus arteriosus increased significantly 30 min after the 2nd dose (p = 0.009) and then returned to non-significant values. No significant change was observed in any of the other vessels. Conclusion: Betamethasone causes short-term changes in fetal blood flow. However, this effect seems to be mild and reversible and does not appear to contraindicate the use of corticosteroids to promote fetal lung maturation.
Identification of Macrosomic, Normal and Intrauterine Growth Retarded Neonates Using the Modified Neonatal Growth Assessment Score
Authors: Deter Russell L. , Spence Laurel R.
Published: December 2003

Objective: Separation of Macrosomic, normal and intrauterine growth retarded (IUGR) neonates using the modified Neonatal Growth Assessment Score (NGAS). Methods: A sample of 23 neonates with evidence of growth acceleration and 74 neonates classified as normal or IUGR in a previous study was used in this investigation. The prenatal growth of all neonates had been studied longitudinally with ultrasound. From the data collected, Rossavik models describing the growth trajectories of head circumference (HC), abdominal circumference (AC), thigh circumference (ThC), femur diaphysis length, head cube (A) and abdominal cube (B) were specified. These models were used to predict birth weight (WT), crown-heel length (CHL), HC, AC and ThC at birth. Actual birth measurements of WT, CHL, HC, AC and ThC were evaluated using age-specific normal size curves and compared to predicted measurements by means of the growth potential realization index (GPRI). GPRI values were evaluated by comparison to previously established normal ranges and used to calculate Neonatal Growth Assessment Scores (NGAS5). NGAS5 values, together with assessments of anatomical measurements and GPRI values, were used to establish macrosomic, normal and IUGR groups. Principal components analysis was applied to the sets of GPRI values available for each neonate to provide a principal component score for separating macrosomic and normal neonates (m2NGAS51) or one to separate macrosomic, normal and IUGR neonates (m3NGAS51) using linear discriminant analysis. The groups identified by these multivariate methods were compared to the original classification and their characteristics evaluated. Results: The m2NGAS51 and a boundary value of 207.5% separated macrosomic and normal neonates with an accuracy of 97.3%. The m3NGAS51 and boundary values of 210.0 and 182.5% separated macrosomic, normal and IUGR neonates with an accuracy of 96.9%. No single GPRI value or anatomical measurement could achieve these levels of accuracy. All normal infants were AGA but only 45.5% of the IUGR group were SGA and only 60.9% of the macrosomic group were LGA. Thirteen different types of IUGR and eleven different types of macrosomia were identified based on GPRI values. Conclusion: The modified NGAS accurately separates macrosomic, normal and IUGR neonates although growth abnormalities are expressed in different ways in different individuals.
Massive Feto-Maternal Haemorrhage with Good Perinatal Outcome following Failed External Cephalic Version
Authors: Shankar M. , Gough G.W. , Chakravarti S. , Vellacott I.D.
Published: December 2003

Objective: To reinforce the risk of feto-maternal haemorrhage associated with external cephalic version for breech presentation. Method: A single case report with a literature review. Results: Our case report was associated with the largest feto-maternal haemorrhage following external cephalic version reported so far. The perinatal outcome in this case was favourable despite a significant amount of fetal haemorrhage. The literature review did include cases with unfavourable outcomes. No reliable method of monitoring fetuses with feto-maternal haemorrhage has been reported, although middle cerebral artery Doppler studies appear to show promise. Conclusion: External cephalic version is useful in the management of breech presentations at term, but it is not without risks and clinicians need to be aware of this.
Significant Fetal Pulmonary Regurgitation as a Possible Prenatal Sign of Aorto-Pulmonary Window in the Fetus with Intrauterine Growth Retardation
Authors: Respondek-Liberska Maria , Grądecka Małgorzata , Czichos Ewa
Published: December 2003

We report a fetal congenital heart defect – aorto-pulmonary window - found at autopsy, which coexisted with a significant holodiastolic pulmonary regurgitation seen during a routine echocardiography in a fetus with intrauterine growth retardation and multiple anomalies.
Prenatal Paternity Testing Using DNA Extracted from Coelomic Cells
Authors: Makrydimas George , Georgiou Ioannis , Kranas Vasilios , Kaponis Apostolos , Lolis Dimitrios
Published: December 2003

Objective: Prenatal paternity testing can be performed following invasive prenatal diagnosis with amniocentesis or CVS. Coelocentesis is a new technique that could be used as an alternative method early in the first trimester of pregnancy. The aim of this study is to investigate the potential use of the DNA extracted from coelomic cells in the prenatal paternity testing. Methods: Coelocentesis was performed in 20 singleton pregnancies at 7–9 weeks of gestation immediately before surgical termination of pregnancy. Chorionic cells from the placenta and blood cells from the parents were processed by the standard salt extraction method. Two loci, TPO and Apo B, were used for paternity testing in the DNA of coelomic cells, chorionic cells and blood cells. Results: There was concordance in the results obtained from the coelomic cells and chorionic villi. In two cases only the polymorphisms used were not conclusively informative for paternity exclusion. Conclusions: Coelomic cells are potentially useful for early paternity testing.
Intrauterine Myelomeningocele Repair: Effect on Short-Term Complications of Prematurity
Authors: Hamdan A.H. , Walsh W. , Bruner J.P. , Tulipan N.
Published: December 2003

Objective: To determine whether short-term complications of prematurity are affected by intrauterine myelomeningocele repair. Methods: Medical records of the first 100 infants undergoing intrauterine myelomeningocele repair (IUMR) at the Vanderbilt University Medical Center were reviewed. Infants born at <34 weeks’ gestation were identified. Two controls were identified for each IUMR infant. Controls were matched for gestational age, sex, birth weight, antenatal steroids, and mode and month of delivery. Development of respiratory distress syndrome, intraventricular hemorrhage, and chronic lung disease and days on ventilator and length of hospital stay were recorded. The results are expressed as mean values and ranges. Comparison of data between groups was performed using the Mann-Whitney U test. Categorical data were compared using the chi-square test and Fisher’s exact test. p ≤ 0.05 was considered statistically significant. Results: One hundred infants underwent IUMR. Forty-four infants were born at <34 weeks of gestation. Complete data were available on 37 infants. Seventy-four matched controls were studied. Eleven infants from the IUMR group and 23 infants from the control group developed respiratory distress syndrome (29.7 vs. 31.1%; p = 0.8). Six infants from the IUMR group and 13 infants from the control group developed chronic lung disease (16.2 vs. 17.5%; p = 0.9). The length of stay was 28 (range 2–82) days for the IUMR group and 24 (range 1–99) days (p = 0.09) for the control group. There was also no significant difference between groups with regard to intraventricular hemorrhage and days on ventilators. Conclusion: There is no difference between short-term complications of prematurity following IUMR and those associated with prematurity resulting from other causes.
Can Three-Dimensional Ultrasound Be Used for the Assessment of the Fetal Lung Volume in Cases of Congenital Diaphragmatic Hernia?
Authors: Ruano Rodrigo , Benachi Alexandra , Martinovic Jéléna , Grebille Anne-Gaëlle , Aubry Marie-Cécile , Dumez Yves , Dommergues Marc
Published: December 2003

We report on 2 fetuses with congenital diaphragmatic hernia (CDH) in whom the fetal lung volumes were estimated by three-dimensional ultrasound and the results compared with the postmortem lung volume measurements. Both examiners (sonographer and pathologist) were blinded to each other’s results. The 1st case was a right CDH diagnosed at 20 weeks of gestation. The 2nd case was a left CDH diagnosed at 22 weeks of gestation. Both pregnancies were terminated upon request of the parents. Three-dimensional ultrasound estimation of the fetal lung volume was performed 1 day before termination of pregnancy using the technique of rotation of the three perpendicular planes. The left and right lung volumes estimated by three-dimensional ultrasound were 3.88 and 1.87 cm3, respectively, in the 1st case and 0 and 5.52 cm3, respectively, in the 2nd case. On postmortem examination, the left and right lung volumes were 3.0 and 2.2 cm3, respectively, in case 1 and 1.1 and 5.6 cm3, respectively, in case 2. This suggests that a three-dimensional estimation of pulmonary volumes may be correlated with postmortem findings in cases with CDH.
Prenatal Demonstration of Major Aortopulmonary Collateral Arteries with Tetralogy of Fallot and Pulmonary Atresia
Authors: Miyashita Susumu , Chiba Yoshihide
Published: December 2003

Major aortopulmonary collateral arteries were prenatally demonstrated in a case of tetralogy of Fallot and pulmonary atresia (TOF-PA). Color Doppler and pulsed Doppler ultrasonography revealed abnormal arteries arising directly from the descending aorta. An aortogram after birth confirmed two collateral arteries arising from the descending aorta and one from the left subclavian artery. Fetal echocardiography was essential for the diagnosis of TOF-PA, but further examination was needed to find collateral arteries, which provided useful information for management after birth.
Functional Aortic Stenosis Diagnosed in Fetal Period
Authors: Kawamata Kazuya , Watanabe Ken , Chiba Yoshihide , Okada Yohko , Kohno Yukihiro
Published: December 2003

We report a case of fetal congenital heart disease prenatally diagnosed as critical aortic valve stenosis at 25 weeks of gestation. Fetal echocardiography demonstrated severe mitral regurgitation, aortic valve stenosis, hypocontractility of the left ventricle, and showed retrograde flow in the aortic arch like HLHS (hypoplastic left heart syndrome). However, soon after delivery, improvement in the baby’s hemodynamics and myocardial contractility were recognized without any treatment.
Asthma as a Paradigm for Autoimmune Disease
Authors: Rottem M. , Shoenfeld Y.
Published: December 2003

Allergy and autoimmunity result from dysregulation of the immune system. Until recently, it was generally accepted that the mechanisms that govern these disease processes are quite disparate; however, new discoveries suggest possible common pathogenetic effector pathways. This review illustrates the concomitant presentation of these conditions and the potential relationship or common mechanisms in some cases, by looking at the key elements that regulate the immune response in both asthma and autoimmune conditions: mast cells, antibodies, T cells, cytokines, and genetic determinants. The parallel appearance of asthma and autoimmune conditions in the same patients may reveal that such aberrations of the immune system have a common pathophysiologic mechanism. Mast cells, which play a key role in asthma, and the wealth of inflammatory mediators they express, make it likely that they have profound effects on many autoimmune processes. Activation of protein kinases by inflammatory cytokines and environmental stresses may contribute to both allergic and autoimmune diseases. The presence of autoantibodies in some allergic diseases suggests an autoimmune basis for these conditions. Because of the central role T cells play in immune reactivity, the T cell receptor loci have long been considered important candidates for a common disease susceptibility within the immune system such as asthma, atopy, and autoimmunity. Immunomodulation is the key to successful treatment of asthma and autoimmune conditions.
Sensitization Profiles of Malaysian and Singaporean Subjects to Allergens from Dermatophagoides pteronyssinus and Blomia tropicalis
Authors: Yeoh S.M. , Kuo I.C. , Wang D.Y. , Liam C.K. , Sam C.K. , de Bruyne J.A. , Lee B.W. , Cheong N. , Chua K.Y.
Published: December 2003

Background: The house dust mites Dermatophagoides pteronyssinus (Der p) and Blomia tropicalis (Blo t) are the most common house dust mite species in Southeast Asia. To date, there have only been a few studies on the sensitization profile of the general populations in Southeast Asia to house dust mites. The aim of this study was to determine the profiles of Der p and Blo t sensitization among Singaporean and Malaysian subjects. Methods: Enzyme-linked immunosorbent assay was used to detect specific IgE to Der p and Blo t mite crude extracts as well as purified Der p 1, Der p 2 and Blo t 5 allergens. Sera used were from 229 Singaporean subjects (124 with rhinitis, 105 without rhinitis) and 143 Malaysian subjects (94 adults and 49 children with asthma). Results: The sensitization profile of rhinitis subjects to the dust mite allergens used in this study was as follows: Blo t extract positive: 91/124 (73%); Blo t 5 positive: 62/124 (50%); Der p extract positive: 61/124 (49%); Der p 1 positive: 53/124 (43%); Der p 2 positive: 45/124 (36%). The nonrhinitis subjects’ sensitization profile was as follows: Blo t extract positive: 60/105 (57%); Blo t 5 positive: 24/105 (23%); Der p extract positive: 38/105 (36%); Der p 1 positive: 14/105 (13%); Der p 2 positive: 17/105 (16%). The study of Malaysian asthmatic adults showed that 39% of them were sensitized to Der p 1, 32% to Der p 2 and 37% to Blo t 5. Among the asthmatic children, sensitization to Blo t 5, Der p 1 and Der p 2 was 90, 57 and 39%, respectively. Conclusion: This study clearly revealed that dual sensitization to B. tropicalis and D. pteronyssinus is common in the general populations of Singapore and Malaysia. Sensitization to Blo t 5 is more prevalent than to Der p 1 and Der p 2.
Mast Cell Degranulation Induced by Lectins: Effect on Neutrophil Recruitment
Authors: Moreno A.N. , Jamur M.C. , Oliver C. , Roque-Barreira M.C.
Published: December 2003

The mammalian lectin macrophage-derived neutrophil chemotactic factor (MNCF) and the plant lectin KM+ were characterized for their ability to activate and degranulate mast cells. The association between mast cell activation and the induction of neutrophil migration was also investigated. Incubation of rat peritoneal mast cells with these lectins resulted in degranulation and mediator release. By confocal microscopy, both lectins were evenly distributed on the cell surface. MNCF activated RBL-2H3 mast cells only if the cells had been sensitized with IgE. KM+ was able to activate either unsensitized or IgE sensitized RBL-2H3 cells. In microplate assays MNCF, but not KM+, bound to rat IgE. In rats that were depleted of mast cells, neutrophil recruitment by MNCF and KM+ were significantly reduced indicating that mast cell activation provides an amplification loop for the neutrophil recruitment induced by these lectins. The present study supports the concept that mammalian lectins play a fundamental role in innate immunity.
Azelastine Inhibits Secretion of IL-6, TNF-α and IL-8 as well as NF-κB Activation and Intracellular Calcium Ion Levels in Normal Human Mast Cells
Authors: Kempuraj Duraisamy , Huang Man , Kandere-Grzybowska Kristiana , Basu Subimal , Boucher William , Letourneau Richard , Athanassiou Achilles , Theoharides Theoharis C.
Published: December 2003

Background: Mast cells are involved in allergic inflammation by secreting histamine, proteases and several cytokines, including interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and IL-8. Certain histamine-1 receptor antagonists, such as azelastine present in the ophthalmic solution Optivar®, have been reported to inhibit histamine and tryptase secretion, but its effect on inflammatory cytokine release from normal human umbilical cord blood-derived cultured mast cells (hCBMC) are not well known. Methods: We investigated the effect of azelastine on the secretion of IL-6, TNF-α and IL-8 from hCBMC, as well as its possible mechanism of action. hCBMC sensitized with IgE were pretreated for 5 min with azelastine at 0.01, 0.1, 1, 3, 6, 12, 24, or 60 µM of Optivar®, before stimulation with anti-IgE for 6 h. Optivar® vehicle without azelastine was used as control. Cytokines were measured by ELISA, intracellular calcium levels by calcium indicators confocal, and nuclear factor-ĸB (NF-ĸB) by electromobility shift assay. Results: Stimulation with anti-IgE led to substantial secretion of IL-6, TNF-α and IL-8. Preincubation for 5 min resulted in almost maximal inhibition with 6 µM azelastine for TNF-α (80%), with 24 µM for IL-6 (83%) and 60 µM for IL-8 (99%); the vehicle solution at the same concentrations as Optivar® had no effect. Stimulation with anti-IgE increased intracellular Ca2+ level and induced NF-ĸB expression in hCBMC, which was inhibited by 24 µM azelastine. Conclusion: Azelastine inhibited hCBMC secretion of IL-6, TNF-α and IL-8, possibly by inhibiting intracellular Ca2+ ions and NF-ĸB activation. Azelastine may, therefore, be helpful in treating allergic inflammation.
Bisphenol A Promotes IL-4 Production by Th2 Cells
Authors: Tian Xiaoli , Takamoto Masaya , Sugane Kazuo
Published: December 2003

Background: It has been proposed that estrogen plays an important role in modulating the Th1/Th2 cytokine balance. From this viewpoint, chemicals with estrogenic responses were expected to possess similar immunoregulatory roles which have not been defined to date. To address this, we studied the effects of one of the estrogenic chemicals, bisphenol A (BPA), on the in vitro production of Th1 and Th2 cytokines. Methods: Mesenteric lymph node cells from Trichinella spiralis (Ts)-infected mice were incubated with serialfold dilutions of BPA under stimulation with Ts antigen. The Th2 cytokine production in the supernatant was determined by ELISA. The Th2 cytokine production by mesenteric lymph node cells from Ts-infected mice inoculated orally with BPA was compared with that of uninoculated mice infected with Ts. Results: The antigen-stimulated interleukin (IL)-4 production by Th2-dominant mesenteric lymph node cells from Ts-infected mice increased significantly by addition of 3 µM of BPA. The IL-5 production was not affected. The production of IL-4, but not that of IL-5, by splenocytes of Th2-skewed Leishmania major-infected BALB/c mice increased at concentrations of 3 and 10 µM of BPA. However, the interferon gamma production was not affected by BPA in Th1-skewed L. major-infected C57BL/6 mice. The production of IL-4 and IL-10, but not that of IL-13, markedly increased in Ts-infected mice inoculated orally with BPA. Conclusions: We demonstrated that the IL-4 production was increased both in vitro and in vivo by treatment with BPA. This suggests that BPA might cause allergic diseases by stimulating the IL-4 production by Th2 cells.
Low-Dose Oral Tolerance due to Antigen in the Diet Suppresses Differentially the Cholera Toxin-Adjuvantized IgE, IgA and IgG Response
Authors: Christensen Hanne R. , Kjær Tanja M.R. , Frøkiær Hanne
Published: December 2003

Background: Cholera toxin (CT) is used as a mucosal adjuvant amongst other applications for studying food allergy because oral administration of antigen with CT induces an antigen-specific type 2 response, including IgE and IgA production. Priorly established oral tolerance due to antigen in the diet may radically impact on the CT-adjuvantized immune response. The present study served to evaluate the effect of priorly established low-dose oral tolerance on the CT-adjuvantized immune response towards a food antigen. Methods: Mice fed a diet containing microgram levels of the soy protein Kunitz soy-trypsin inhibitor (KSTI) (F0 mice) and mice fed a soy-free diet (F2 mice) were orally immunized with KSTI and CT. KSTI-specific serum IgG1, IgG2a, IgA and IgE and fecal IgA were monitored. KSTI-stimulated cell proliferation and interleukin (IL)-6 production were determined. Results: The anti-KSTI IgE and IgA responses in the F0 mice were substantially suppressed, while the IgG1 and IgG2a responses were not suppressed after five oral immunizations. The response suppression tended to decline with increasing numbers of immunizations suggesting that the suppression could be overcome by multiple immunizations. However, cell proliferation and IL-6 production were clearly suppressed even after five immunizations. Conclusions: Priorly established low-dose oral tolerance considerably suppressed the CT-adjuvantized KSTI-specific IgE, IgA and cellular immune response but only weakly and transiently the IgG response. The results revealed that low-dose oral tolerance includes the mucosal IgA response and that CT, albeit mediating an antigen-specific response, does not fully abrogate priorly established oral tolerance.
Safety of Subcutaneous Specific Immunotherapy with Pollen Allergen Extracts for Respiratory Allergy
Authors: Arifhodzic N. , Behbehani N. , Duwaisan A.R. , Al-Mosawi M. , Khan M.
Published: December 2003

Background: Specific immunotherapy (SIT) is a well-documented treatment for respiratory allergy. However, the major risk of SIT is the development of systemic anaphylactic reactions. Objectives: To evaluate the safety of SIT given by subcutaneous route for 3 years to patients with seasonal allergic rhinitis (AR) with or without asthma. Methods: A prospective open-label study of immunotherapy (Chenopodium album, Bermuda grass, or both) in 181 consecutive patients with AR with or without asthma. After an initial dose-escalation phase, a maintenance dose of 0.5 ml of 100,000 PNU/ml was administered monthly for 3 years. The occurrence and severity of systemic reaction (SR) and local reaction was recorded and graded according to the WHO position paper. Results: Of 181 patients enrolled, 57 (31%) did not complete the study (53 due to poor compliance and 4 due to systemic side effects). All 4 patients who developed SR had asthma and all the SR occurred during the dose- escalation phase. Three patients had moderate SR (grade 2), while 1 patient had severe reaction (grade 3). Three of the SR occurred within the first 20 min after injection and 1 SR occurred 2 h after injection. None of the reactions were life threatening and were managed easily. Total rhinitis symptom score decreased from 11.8 at baseline to 7.46 at the end of treatment (p < 0.001). The size of the skin prick test reaction to the main sensitising allergen was reduced from 7.48 ± 2.26 mm at baseline to 5.60 ± 2.18 mm at the end of treatment, p < 001. Conclusion: If a strict protocol is used, SIT is safe in AR patients with or without mild asthma and may result in significant subjective and objective improvement.
A Study Comparing the Inhibitory Effects of Single and Repeated Oral Doses of Ebastine and Fexofenadine against Histamine-Induced Skin Reactivity
Authors: Barbanoj M.J. , Antonijoan R.M. , García-Gea C. , Morte A. , Gich I. , Gispert J. , Garcia E. , Esbrí R. , Luria X.
Published: December 2003

Objective: The aim of this double-blind, randomized, crossover, placebo-controlled clinical trial was to compare the inhibition of the histamine-induced skin reaction induced by ebastine 20 mg with respect to that induced by fexofenadine 120 mg or placebo. Methods: Eighteen volunteers (10 males, 8 females) received the three treatments once daily for 5 days, with a mean 7-day washout period between treatments. Intradermal tests, using 0.05 ml from a solution containing 100 µg/ml of histamine, were performed at baseline and at 1, 1.5, 2, 3, 10 and 24 h after a single dose and repeated 5-day dose, and in addition after 34, 48, 58 and 72 h after repeated 5-day dose. Results:After 24 h of acute administration, ebastine 20 mg was significantly more effective than fexofenadine 120 mg in reducing the wheal and flare induced by histamine challenge (p < 0.001). Although fexofenadine 120 mg had the shortest onset of action (1.5 vs. 3 h in ebastine 20 mg), the duration of its antihistamine effect was the shortest (24 vs. 58 h in ebastine 20 mg) and wheal reduction after 24 h was not significantly different from placebo. The overall effect after single and repeated 5-day dose, expressed as the AUC of reduction of wheal and flare area (%/h), showed the following order of magnitude: ebastine 20 mg > fexofenadine 120 mg > placebo. No significant differences in the incidence of adverse events were found between the three treatments. Conclusions: The present results clearly show a superior and long-acting effect of ebastine 20 mg compared with fexofenadine 120 mg on the skin response to histamine 24 h after dosing.
Increase in Serum Levels of Autoantibodies after Attack of Seasonal Allergic Rhinitis in Patients with Graves’ Disease
Authors: Takeoka Keiko , Hidaka Yoh , Hanada Hiroyuki , Nomura Tomoko , Tanaka Susumu , Takano Toru , Amino Nobuyuki
Published: December 2003

Background: The prevalence of allergic disease is increasing worldwide, but its influence on the clinical course of autoimmune diseases is unknown. Objective: The purpose of this study was to assess the effect of seasonal allergic rhinitis on the clinical course of Graves’ disease, which has been considered a Th2-dominant autoimmune disease. Methods: Ten patients with Graves’ disease, who were considered to be in a state of remission or near remission, were serially examined for 18 months starting from August. Five of them had seasonal allergic rhinitis due to Japanese cedar pollen, and the remaining patients had no such allergic disorders. Peripheral eosinophil counts, serum concentrations of cedar-pollen-specific IgE, anti-TSH-receptor antibody, anti-thyroid-peroxidase antibody and antithyroglobulin antibody were assessed at 2- to 4-month intervals. Serum thyroid hormones and TSH levels were also measured to evaluate disease activity. Results: All patients with pollinosis had attacks of allergic rhinitis caused by cedar pollen in early March. Subsequently, peripheral eosinophil counts, pollen-specific IgE activity and serum levels of anti-thyroid-peroxidase and antithyroglobulin autoantibodies markedly increased. Serum levels of anti-TSH-receptor antibody increased in 3 patients in association with an increase in serum thyroid hormones but were always negative in 2 patients. The control patients without pollinosis showed no consistent change of these parameters. Conclusions: Seasonal allergic rhinitis aggravated the clinical course of Graves’ disease and induced an increase in serum antithyroid autoantibody concentrations as well as an increase in pollen-specific IgE concentration. These data suggest that environmental antigens induce not only local allergic reactions, but also stimulate thyroid immune reactions toward Th2 proliferation, and finally aggravate Th2-dependent autoimmune thyroid disease.
Frühgeburt und Risikofaktoren
Authors: Winter R. , Winter R. , Haller U. , Haller U. , Hepp H. , Hepp H.
Published: December 2003

Infektionen, Stress und Hämorrhagien sind Risikofaktoren in der Pathophysiologie der Frühgeburt. Genitale Infektionen können diagnostiziert und behandelt werden und beeinflussen so die Häufigkeit der Frühgeburt. Wie psychosoziale Belastungen als Stressfaktoren beeinflusst werden können, ist jedoch ungewiss.
Effiziente Frühgeburtenvermeidung – Das Thüringer Modell
Authors: Hoyme U.B. , Hoyme U.B. , Saling E. , Saling E.
Published: December 2003

In zwei prospektiven Erhebungen wurde die Effektivität der von Saling entwickelten Selbstvorsorge-Aktion zur Frühgeburtenvermeidung untersucht. In 16 der insgesamt 29 Erfurter Frauenarztpraxen erhielten interessierte Schwangere Informationsmaterial sowie eine Messausstattung (Careplan-VpH-Handschuhe). Die Frauen wurden angeleitet, vaginale pH-Messungen 2-mal wöchentlich selbst vorzunehmen. Die Schwangeren waren dahingehend aufgeklärt, bei erhöht gemessenen pH-Werten (≧4,7) oder anderen Auffälligkeiten ihren betreuenden Arzt umgehend zu konsultieren, um sich gegebenenfalls mit Lactobacillus-Präparaten oder bei gesicherter bakterieller Vaginose mit Clindamycin-Creme intravaginal behandeln zu lassen. In der Erfurter Untersuchung wurden 73 von 381 Frauen in der Interventionsgruppe als risikobelastet identifiziert. Die Frühgeburtenrate betrug 8,1% unter pH-Selbstmessung bzw. Intervention versus 12,3% in der Kontrollgruppe (p < 0,05, n = 2341); 0,3 vs. 3,3% der Neugeborenen zählten zur Gruppe der frühen Frühgeborenen mit <32 + 0 Schwangerschaftswochen (p < 0,01). In der zweiten Erhebung wurde versucht, beginnend mit März 2000, sämtliche Schwangere im Land Thüringen über die betreuenden Frauenärzte mit Messhandschuhen auszurüsten. Als Hypothese für den Erfolg dieser Aktion galt die Annahme, dass die Frühgeburtlichkeit beginnend mit Juli 2000 einen deutlichen Abfall aufweisen musste, was über die Perinatalerhebung des Landes zu bewerten war. Aus der Bewertung von 16 276 Schwangerschaften ist ein klares Resultat abzulesen: Sowohl die Gesamtzahl der frühen Frühgeburten (1,58 vs. 0,99%, p < 0.001) als auch der untergewichtigen Kinder war im zweiten Halbjahr entsprechend der im Ansatz formulierten Hypothese signifikant geringer. Die dargestellten Zahlen der Perinatalerhebung 2000 des Landes sprechen aus unserer Sicht für die Ausweitung der Aktion auf die Bundesrepublik Deutschland. Ein weiteres Argument ist auch die Beobachtung, dass nach Beendigung der Kampagne die Frühgeburtenraten wieder auf das gleiche Niveau wie vor der Aktion angestiegen sind.
Ethische Probleme bei extrem unreifen Frühgeborenen
Authors: Bucher H.U.
Published: December 2003

In den letzten 20 Jahren wurden in den industrialisierten Ländern immer kleinere Frühgeborene nach der Geburt reanimiert, maschinell beatmet, parenteral ernährt und mit verschiedenen Medikamenten behandelt. Je kleiner und unreifer die Kinder waren, desto länger dauerte die Intensivbehandlung, desto mehr Schmerzen und Leiden brachte sie für die betroffenen Kinder und desto schlechter wurden die Langzeitergebnisse. Zwar sank die Mortalität, hingegen nahmen bei den Überlebenden chronische Probleme von Lungen, Augen und Hirn (Zerebralparese) zu. Unter Fachleuten und in der Öffentlichkeit wurden deshalb Grenzen des Einsatzes der Intensivmedizin diskutiert. Umfragen bei Neonatologen und Pflegenden in ganz Europa ergaben ein breites Meinungsspektrum, wo diese Grenze z.B. in Bezug auf das Gestationsalter gezogen werden sollte. Eine Mehrheit befürwortet jedoch einen Abbruch von Intensivmassnahmen, wenn diese nicht mehr im besten Interesse des Kindes sind, d.h. wenn die Behandlung zur Qual und ein unausweichlicher Tod nur hinausgeschoben würde. Um eine solche schwierige medizinisch-ethische Entscheidung strukturiert, nachvollziehbar und breit abgestützt zu fällen, wurden besondere Verfahren entwickelt, die sich in der Praxis bewährt haben.