Endocrine analytes in multiple-marker screening

Prenatal serum screening is based on the observation that secretory products of the placenta and fetus are altered in maternal serum of pregnancies affected with certain birth defects. Most of these products are hormones that have been previously characterized, although the pathophysiologic basis of the altered maternal serum levels of these products that occurs in association with fetal chromosome for the most part is unknown. Prenatal serum screening is in a period of transition, with the relatively recent advance of second trimester triple-marker screening (AFP, uE3, hCG) and now the improved performance of the four-marker test that adds inhibin. A. Proposed first trimester screening and other new second trimester serum markers may dramatically change prenatal screening practices as we enter the next century.     

Maternal serum screening for trisomy 18 in the first trimester of pregnancy

It is widely accepted that thrombocytopenia associated with liver cirrhosis is caused by increased platelet destruction in the enlarged spleen, but this issue has not yet been analysed sufficiently in terms of platelet production. Thrombopoietin is produced mainly in the liver and strongly promotes platelet production. We studied serum thrombopoietin and the levels of its mRNA in liver tissue of cirrhotic patients and also in a rat model of liver cirrhosis. Furthermore, to clarify the influence of the spleen, we investigated thrombopoietin mRNA in splenectomized rats. The serum thrombopoietin level in humans with liver cirrhosis was not significantly reduced instead of thrombocytopenia. The expression of thrombopoietin mRNA in liver tissue decreased with the progression of liver cirrhosis in both patients and the rat model and no compensatory expression was observed in other organs or non-parenchymal cells. The level of thrombopoietin mRNA did not differ significantly in splenectomized cirrhotic rats before or after administration of dimethylnitrosamine, but was lower than that in splenectomized rats without cirrhosis. We conclude that thrombocytopenia in liver cirrhosis is caused not only by platelet destruction but also by decreased platelet production, perhaps due to reduction of thrombopoietin mRNA in the liver.     

Pregnancy outcomes following false-positive multiple marker screening tests

Pregnancy outcomes in women with a false-positive midtrimester multiple marker screening test (MMST) were reviewed. A genetic database was used to identify all women > or = age 30 who had a MMST at 15-20 weeks of gestation, a targeted ultrasound, and amniocentesis, and complete pregnancy outcome data. All patients with an abnormal fetal ultrasound (US) or karyotype were excluded. The incidence of adverse outcomes (defined as fetal death, preterm delivery, or a birth weight less than the 10th percentile for gestational age), in those women with a positive MMST (risk of Down's syndrome > or = 1:190) was compared to the incidence of adverse outcomes in control women with negative MMST. Chi-square analysis and Fisher's exact tests were used for comparisons as appropriate. Complete data was available from 1135 women. Seventy-seven percent were over age 35. Two hundred and forty-six women (22%) had a positive multiple marker test. No significant differences in outcomes were discovered after comparisons to controls: fetal death 1 of 246 (0.4%) versus 12 of 889 (1.3%), p = 0.32; preterm delivery 32 of 246 (13.0%) versus 147 of 889 (16.5%), p = 0.17; birth weight less than the 10th percentile, 9 of 246 (3.7%) versus 30 of 889 (3.4%), p = 0.83. Our data suggest that women > or = age 30 with a false-positive MMST and a normal midtrimester obstetrical sonogram are not at an increased risk for adverse pregnancy outcomes in later gestation.     

Three-dimensional sonography in diagnosing trisomy 18

The minimally invasive reversed Z sternotomy is a surgical approach for aortic valve operations that provides an excellent view of the aortic root and allows access to the right atrium. It confers the advantages of preservation of the sternocostal articulations and both internal thoracic arteries with no need to enter either pleural cavity. It facilitates aortic and atrial cannulation for cardiopulmonary bypass and allows access for a superior pulmonary vein cardiac vent.     

Definition of false-positive reactions in screening for hepatitis C virus antibodies

The rate of false-positive hepatitis C virus enzyme immunoassay results was determined to be at least 10% among 1,814 reactive serum samples based on (i) negative results in an independent confirmation assay, (ii) negative PCR results, and (iii) no patients developing clinical or biochemical signs of hepatitis during a 1-year follow-up.     

Morphological classification of nuchal skin in human fetuses with trisomy 21, 18, and 13 at 12-18 weeks and in a trisomy 16 mouse

An increase in the nuchal translucency that can be detected at 10-14 weeks of gestation by ultrasound forms the basis for a screening test for chromosomal abnormality. Several mechanisms leading to this increase in skin thickness have been proposed, including changes of the extracellular matrix, cardiac defects and abnormalities of the large vessels. This study examines the composition of the extracellular matrix of the skin in gestational age-matched fetuses with trisomy 21, 18 and 13 from 12-18 weeks. Immunohistochemistry was applied with monoclonal and polyclonal antibodies against collagen type I, III, IV, V and VI and against laminin and fibronectin. Collagen type VI gene expression was further studied by in situ hybridization to detect differences in expression patterns of COL6A1, COL6A3 and COL1A1 between normal fetuses and those with trisomy 21. The ultrastructure of tissue samples was studied by transmission electron microscopy (TEM) and additionally by immunogold TEM. Further, we examined the morphology of the skin in an animal model for Down's syndrome, the murine trisomy 16, by light and TEM. The dermis of trisomy 21 fetuses was richer in collagen type VI than that of normal fetuses and other trisomies, and COL6A1, located on chromosome 21, was expressed in a wider area than COL6A3, which is located on chromosome 2. Collagen type I was less abundant in the skin of trisomy 18 fetuses, while the skin of all three trisomies contained a dense network of collagen type III and V in comparison with normal fetuses. Collagen type IV, of which two genes are located on chromosome 13, was expressed in the basement membranes of the skin in all fetuses and additionally in the dermal fibroblasts only of trisomy 13 fetuses. Likewise, laminin was present in all basement membranes of normal and trisomic fetuses as well as in dermal fibroblasts of fetuses with trisomy 18. LAMA1 and LAMA3 genes are located on chromosome 18. Dermal cysts were found in the skin of trisomy 18 and 13, but not in trisomy 21 and normal fetuses. Ultrastructural findings showed that an extracellular precipitate containing glycosaminoglycans was regularly present in the skin of trisomy 21 fetuses and murine trisomy 16 embryos. In conclusion, this study suggests that the skin edema in fetal trisomies is characterized by specific alterations of the extracellular matrix that may be attributed to gene dosage effects as a result of a genetic imbalance due to the condition of fetal trisomy.     

Hyperventilation test: a noninvasive screening test for coronary vasospasm

3 patients with coronary vasospasms in different clinical situations are presented. One patient had typical Prinzmetal angina but coronary arteries without significant stenosis. One patient without typical angina pectoris showed sudden significant ST elevations on anterior and lateral ECG tracings accompanied by typical ischemic chest pain. At angiography, a 70% LAD stenosis was found without high degree lesions. One patient (aged 30 years) had a documented anterior infarction with angiographically normal coronary arteries. In all these cases coronary vasospasms were recognized as the underlying cause of the symptoms. All the patients were treated with calcium channel blockers and have been asymptomatic since. Currently available data comparing the diagnostic value of hyperventilation with other tests for coronary vasospasms, such as ergonovine or acetylcholine, are discussed. The hyperventilation test can be recommended as the first test in the work up of suspected vasospastic angina pectoris.     

Tonic pupil: a simple screening test

The influence of chronic intrapregnancy hypoxia caused by mother's diseases (toxemia, gravidarum, hypochromic anemia, diabetes) on the brain of a mature newborn has been investigated. Besides the vast damages of the parieto-occipital cortex, Ammon's horn (entorhinal) motor and insula cortex there were also some damages of the cerebellum and the brain stem cells. The damages of the cells in the brain stem seem to be one of the causes of the abnormal perinatal adaption.     

Diagnosis of hyperventilation for elimination of false-positive results of physical exercise test

The study was conducted in 55 patients with cardiac pains. Electrocardiography was used successively prior to, during and following physical exercises, followed by Seldinger selective coronary angiography, and electrocardiography prior to, during and following hyperventilation tests. In 2 of 55 patients the result of the exercise test was interpreted as false-positive, since the coronary angiography demonstrated intact vessels, and during hyperventilation ECG recorded a decreased ST segment. To avoid false-positive results in patients with suspected angina pectoris the physical exercises tests can be considered positive only in cases in which hyperventilation caused no ECG changes typical for angina pectoris.     

Possibilities for false-negative findings in trisomy 21 screening with FISH

In approximately 5% of individuals with Down syndrome aneuploidy results from a chromosomal rearrangement. FISH analysis on chromosome metaphases and interphase nuclei of 5 individuals with Down syndrome carrying different types of chromosome 21 translocations demonstrated the diagnostic efficiency of this method. By use of different commercially available chromosome 21 specific probes we were able to show that only the cosmid probe specific for the Down syndrome critical region (DCR) in 22qll gave reliable results for interphase analysis of trisomy 21, while the use of chromosome 21 centromere- or of painting probes carry a high risk of a false-negative diagnosis in translocation trisomy 21.     

Laparoscopy as a cause of a false-positive Meckel's scan

A new cause of a false-positive result of a Meckel's scan is reported. An 11-year-old girl had a 3-week history of constant right lower quadrant pain that was initially managed by laparoscopic appendectomy. A repeated laparoscopy for persistent pain was nondiagnostic. A missed Meckel's diverticulum was considered as the cause of this pain, which prompted a Meckel scan. This scan revealed a periumbilical focus of activity that was interpreted as a Meckel's diverticulum attached to the anterior abdominal wall by a band. The laparotomy showed no Meckel's diverticulum. The false-positive result of the Meckel scan may be the result of inflammation from the periumbilical laparoscopic port site.     

Echogenic fetal bowel in the third trimester associated with trisomy 18

Obstructive sleep apnea has been associated with various cardiac arrhythmias; however, supraventricular tachycardia has not been reported to occur in this disorder. This case report describes a patient who developed episodes of supraventricular tachycardia during periods of apnea and oxygen desaturation. With the initiation of nasal continuous positive airway pressure during sleep, the arrhythmia was abolished. The etiology and possible mechanisms responsible for the supraventricular tachycardia are discussed.     

Analysis of a large pedigree with elliptocytosis, multiple lipomatosis, and biological false-positive serological test for syphilis

Elliptocytosis, multiple lipomatosis, and biological false-postive serological test for syphilis (BFPSTS) were found in a single individual. One hundred eighty relatives were tested for the three diseases: 74 were typed for seven blood group antigens, and 58 were typed for four electrophoretic enzyme markers. Likelihood analysis of the pedigree data confirmed independent dominant inheritance for elliptocytosis and lipomatosis. BFPSTS appears dominant, but the analysis was inconclusive. No linkages were found between any disease gene and any marker gene. Two female pedigree members with BFPSTS developed systemic lupus erythematosus, a finding in agreement with the previously described association. The analysis did not lead to any conclusions about the causal relationship between the two traits.     

Modified recalcification time: a global coagulation screening test

Hypercoagulability with resultant thrombosis as a leading cause of death remains unproven due to the lack of a global screening coagulation test documenting antecedent hypercoagulability. To fill this need a modified recalcification time (MRT) test that incorporates the contribution of all the circulating cellular and chemical mediators, including the important but neglected tissue factor, to coagulation is described. Aliquots of blood are incubated with saline and with endotoxin, and the MRT is instrumentally determined. Values outside the normal ranges of 5.3 to 8.5 minutes (saline) and 4.5 to 7.5 minutes (endotoxin) in the coagulation spectrum of 0 to 10 minutes to infinity are abnormal. Shorter values are inversely related to the degree of hypercoagulability. To assess MRT in detecting hypercoagulability, MRT values in conditions with known thrombotic risk that were reported individually are presented by indicating the percentages of each in the abnormal ranges. The conditions, all with statistically significant hypercoagulability, included early breast cancer, diabetes, head, neck, and colon cancer, peripheral vascular disease, and pregnancy. Modified recalcification time meets the criteria of a global coagulation screening test because of: 1) age-related prevalence of asymptomatic cancer and thrombotic cardiovascular disease, 2) specificity and sensitivity, and 3) expected lower morbidity and mortality with early intervention.