Neuropsychological functioning in girls with premature adrenarche.

Contemporary research indicates that brain development occurs during childhood and into early adulthood, particularly in certain regions. A critical question is whether premature or atypical hormone exposures impact brain development (e.g., structure) or function (e.g., neuropsychological functioning). The current study enrolled 40 girls (aged 6-8 years) diagnosed with premature adrenarche (PA) and a comparison group of 36 girls with on-time maturation. It was hypothesized that girls with PA would demonstrate lower IQ and performance on several neuropsychological tasks. The potential for a sexually dimorphic neuropsychological profile in PA was also explored. No significant univariate or multivariate group differences emerged for any neuropsychological instrument. However, effect size confidence intervals contained medium-sized group differences at the subscale level. On-time girls performed better on verbal, working memory, and visuospatial tasks. Girls with PA showed improved attention, but not a sexually dimorphic profile. These results, though preliminary, suggest that premature maturation may influence neuropsychological functioning.

Effect of arsenic on regulatory T cells.

INTRODUCTION: Arsenic (As) affects the function and survival of lymphocytes, and some arsenic compounds exert a relevant antineoplastic effect. We have explored the effect of As on T regulatory cells. RESULTS AND DISCUSSION: In vitro experiments with peripheral blood mononuclear cells from healthy subjects showed that low concentrations of As tended to increase the number of natural T regulatory (nTreg) lymphocytes, whereas concentrations >5.0 muM had an opposite effect. Furthermore, rats exposed to As showed redistribution of nTreg cells, and As administration to rats with experimental allergic encephalomyelitis increased the levels of nTreg cells in spleen and diminished the severity of this condition. On the other hand, in 47 apparently healthy subjects chronically exposed to As, we found significant inverse correlation between urinary As levels and the number and function of nTreg lymphocytes. Although most of these individuals showed enhanced levels of apoptotic lymphocytes in peripheral blood, with a diminution of mitochondrial membrane potential, no significant correlation between these parameters and urinary As was detected. CONCLUSION: Our data indicate that As seems to have a relevant and complex effect on nTreg cells.

Minor salivary gland punch biopsy for evaluation of Sjögren's syndrome.

Incisional biopsy of labial salivary glands has been a valuable technique for diagnosis of Sjögren's syndrome. This report describes a new technique using punch biopsies that requires fewer resources and appears to be equally effective. Fifty patients evaluated by punch biopsy all yielded adequate pieces averaging 6 glands per specimen. Two patients had transient numbness of the lip. There were no other complications. Classical findings of Sjögren's histopathology were demonstrable with these specimens. This technique is safe, less expensive, and is proposed as a reliable alternative to incisional biopsy.

Fetal tissue derived from spontaneous pregnancy losses is insufficient for human transplantation.

OBJECTIVE: To determine if sufficient fetal tissue with desirable transplant characteristics can be obtained from spontaneous abortions. METHODS: A survey of fetal tissues collected from newly diagnosed spontaneous pregnancy losses from three Indianapolis hospitals was conducted from December 1992 to September 1993. Forty-nine of 356 mothers (13.8%) with spontaneous abortions or ectopic pregnancies consented to the evaluation of their products of conception by gross and microscopic pathologic examination, bacterial culture, cytogenetic analysis, cell culture, and maternal serologic tests. RESULTS: Forty-nine pregnancies (gestational age range 5-30 weeks) provided four identifiable embryos, 12 second-trimester fetuses, and one third-trimester fetus. Nine samples (18.4%) were of excellent or good quality on pathologic grading. Twenty-five of 38 samples tested (66%) grew pathogenic bacteria. Maternal serologic tests were negative for antibodies to human immunodeficiency virus, human T-cell lymphotropic virus, syphilis, and hepatitis B in all cases. One of 43 sera was reactive for hepatitis C, and 33 (77%) were positive for cytomegalovirus. Cytogenetic abnormalities were found in 25% of cultured samples. Five fetal brain samples had cell viabilities of 50% or more. Few viable fetal hepatocytes were found. Only two fetal brain samples (4.1%) were potential candidates for human transplantation. CONCLUSION: Spontaneous pregnancy losses yield minimal usable tissue for human transplantation because of a lack of embryonic or fetal tissues, delayed collection, decomposition, genetic abnormality, and bacterial contamination.

The lack of NK cytotoxicity associated with fresh HUCB may be due to the presence of soluble HLA in the serum.

Human bone marrow transplantation is becoming more common in the treatment of certain forms of cancer despite the scarcity of HLA matched donors. Because human umbilical cord blood (HUCB) has been used as a source for stem cells in bone marrow transplantation, and because NK cells appear to be important in graft versus leukemia response, we investigated the lytic activity of freshly isolated HUCB NK cells (HUCB-NK) against tumor targets and their ability to differentiate into LAK cells following stimulation with various cytokines. Although cytotoxicity mediated by fresh HUCB-NK was low compared to that of adult peripheral blood lymphocyte-derived NK cells (PBL-NK), the ability of HUCB-NK to bind to K562 target cells (TC) was similar to PBL-NK. In addition, the PBL-NK cytotoxicity of postpartum mothers was also low compared to that of normal adult PBL-NK. When we incubated HUCB for 18 hr in either IL-2 or IL-12, we boosted the level of HUCB-NK cytotoxicity to approximately the level observed in PBL-NK and increased the level of perforin, granzyme A, and granzyme B mRNA expression. In addition, when we incubated HUCB in IL-2, IL-4, IL-7, IL-12, TNF-alpha, IFN-alpha, IFN-gamma, or TGF-beta for 5 days, we observed that HUCB was capable of generating LAK cells only when incubated with either IL-2 or IL-12. In contrast, IL-2, IL-7, IL-12, TNF-alpha, and IFN-gamma all generated LAK cells from adult PBL. When we added to the medium low-dose IL-2 and irradiated K562 as feeder cells (mini-LAK), we were unable to generate LAK activity from HUCB-NK, whereas we could generate it with PBL-NK cells under the same conditions. Addition of serum derived from HUCB in a 4-hr 51Cr release assay with PBL-NK as the effector cells (EC) and K562 as the TC resulted in a 42% decrease in PBL-NK-mediated cytotoxicity. Although we detected no TGF-beta in HUCB serum, we did detect high concentrations of soluble class I MHC (sHLA). To our knowledge, sHLA has not previously been shown to inhibit NK cytotoxicity, although the expression of class I HLA on the surface of TC has been shown to inhibit NK cytotoxicity. To study further the effect of sHLA on cell-mediated cytotoxicity, we added various concentrations of sHLA to EC mediating NK, ADCC, and CTL activities. All were inhibited in a dose-dependent manner.(ABSTRACT TRUNCATED AT 400 WORDS)

Cook obstetrics and gynecology catheter multicenter chorionic villus sampling trial: comparison of birth defects with expected rates.

OBJECTIVE: The null hypothesis was that offspring of women undergoing first-trimester chorionic villus sampling do not experience a rate of birth defects exceeding background rates. STUDY DESIGN: Follow-up information regarding major malformations was prospectively sought on offspring of 4105 women undergoing first-trimester chorionic villus sampling from nine centers participating in a collaborative study with the Cook obstetrics and gynecology catheter. These data were compared with data from the Collaborative Perinatal Project and other registries. RESULTS: A total of 84 offspring with major malformations was identified (2.36%). Compared with background rates, there was no increase in the incidence of total malformations or specific malformations (including limb reduction defects) in the subjects. One institution experienced all three limb reduction defects in this series; the probability of this occurring by chance alone is < 1%. CONCLUSION: Chorionic villus sampling was not found to result in an increase in major birth defects or in specific categories of birth defects in this series.

[Management of severe pre-eclampsia/eclampsia. Comparison between nifedipine and hydralazine as antihypertensive agents]. / Manejo de la preeclampsia severa/eclampsia. Comparación entre Nifedipina e Hidralazina como medicamentos antihipertensivos.

The objective was to compare the fetal and maternal effects between parenteral hydralazine and sublingual nifedipine used like antihypertensive drugs in the management of severe preeclampsia. Study design was prospective, comparative, longitudinal, randomized clinical trial. It was carried out at Centro Medico Nacional IMSS Torreon, Coah. Gynecology and Obstetrics Department. The patients were women in the last trimester of pregnancy with severe preeclampsia were randomized to receive parenteral hydralazine or sublingual nifedipine as antihypertensive drugs. The only difference observed in this study was the Apgar of neonates whose mothers received hydralazine, that was significatively lesser than the Apgar of neonates whose mothers received nifedipine. Both medicaments are a good alternative as antihypertensive drugs in severe preeclampsia. Neonates whose mothers received Nifedipine had a higher Apgar.

Quantitation of craniofacial anomalies in utero: fetal alcohol and Crouzon syndromes and thanatophoric dysplasia.

The study of fetal growth and development by ultrasound has been greatly facilitated in the past few years by the availability of anthropometric standards for the fetal body. Thus, the obstetrician is able to discern between normal and grossly abnormal, and even to quantitate certain fine fetal structures such as the face. This paper presents results obtained from a group of 5 patients referred to the Medical Center from private practices in Indianapolis, Indiana. Prenatal cephalometric analyses by ultrasound suggested the presence of craniofacial anomalies in all 5 cases. However, such defects were not detectable by routine ultrasonographic examination. A clinical examination after birth of each of these 5 patients suggested the following diagnoses: Fetal Alcohol Syndrome (FAS) in 2 individuals, Fetal Alcohol Effects (FAE) in one individual, Crouzon Syndrome (CS) in one patient, and Thanatophoric Dysplasia (TD) in one patient. In order to compare the craniofacial measurement values for each patient to normal standards, we developed Z-Score profiles and Pattern Variability Indexes (PVI) as described by Garn et al. [1984, 1985]. The values presented here support the idea that even mildly abnormal fetal craniofacial patterns are detectable by this relatively new application of ultrasound. At the present time, no conclusions can be made regarding the diagnostic accuracy of these patterns and profiles. However, the potential value of fetal cephalometry for documenting craniofacial dysmorphology is clearly indicated.

Bone dysplasias: the prenatal diagnostic challenge.

The prenatal diagnosis of bone dysplasias presents difficult challenges for the clinician involved in monitoring pregnancies. Such diagnoses highlight delicate ethical issues and may require difficult decision-making when the differential diagnosis includes a lethal bone dysplasia. Despite the rapid technological advances in ultrasonography, the ability to make prenatal diagnoses within this group of disorders is limited by the restricted ultrasonographic capability to appreciate fully the detailed fetal anatomy. However, we perceive that a significant further limitation involves the lack of a systematic protocol to guide the clinician in the ultrasonographic evaluation of a fetus suspected of having a skeletal dysplasia. In an attempt to aid the clinician who is evaluating these suspected pregnancies, we report here 8 cases and propose a model protocol for the ultrasonographic diagnostic approach to fetal skeletal problems in utero.

A morphometric analysis of the fetal craniofacies by ultrasound: fetal cephalometry.

We present here a set of 24 standardized linear measurements that describe the growth of different craniofacial structures in the normal fetus from 16 to 36 weeks of gestation. These measurements were taken from 89 pregnant women, who had from 1 to 3 ultrasonographic evaluations during the pregnancy (16, 26, and 36 weeks of gestation). All the values presented here were obtained using the technique described by Escobar et al. The mean and standard deviation was calculated for each measurement and was used to estimate the normal growth pattern of each variable. Approximate confidence intervals for the mean of each variable were constructed for use in identifying unusually low or high values. The confidence intervals are available in graphic form by request. These data will not only contribute to an understanding of fetal craniofacial growth and development in utero, but in addition, it will help to make the diagnoses of mild craniofacial anomalies that would not be detected by the routine ultrasonographic examination. We suggest that this procedure should be included if not in all routine obstetrical ultrasound evaluations, then at least in the more extensive level II obstetrical ultrasound.

Prenatal detection of a gene for hereditary amyloidosis.

Autosomal dominant amyloidosis of the Indiana/Swiss type (familial amyloidotic polyneuropathy type II) is a late-onset disorder characterized by carpal tunnel syndrome, peripheral neuropathy, vitreous opacities, and cardiomyopathy. The genetic basis of the disease is a variant of plasma prealbumin (transthyretin) which has a serine for isoleucine substitution at amino acid 84 of the 127 residue prealbumin molecule. Using the polymerase chain reaction (PCR), we amplified exon 3 of the prealbumin gene in DNA extracted from amniocytes of a fetus at-risk of carrying the serine-84 prealbumin gene. By allele-specific oligonucleotide analysis as well as restriction enzyme analysis of the amplification products it was determined that the fetus was a carrier of the serine-84 variant gene. This finding was confirmed at birth by Southern blot analysis using DNA obtained from cord blood. This is the first report of the prenatal detection of a gene for hereditary amyloidosis.

Fetal craniofacial morphometrics: in utero evaluation at 16 weeks' gestation.

Although ultrasound has proved useful in the diagnosis of fetal craniofacial malformations, its success has been based primarily on subjective clinical observations of apparent abnormal fetal structures, their proportions, and unusual features. However, such clinical observations may be misleading and ideally should be validated by standardized quantitative measurements. We describe here an ultrasonographic methodology that has provided quantitative data describing the normal fetal craniofacies at 16 weeks of gestation. This report is part of an ongoing research project directed at describing fetal facial morphology in utero at different gestational ages. Such data can be used to construct growth curves to which observations from suspected abnormal fetuses can be compared. A total of 53 patients were evaluated at 16 weeks of gestation, at which time 24 craniofacial linear and angular measurements were made. The landmarks employed for these measurements were those used in roentgencephalometry so that this fetal data base could be related to postnatal populations. Such data will contribute not only to a description of facial dysmorphogenesis but also to a better understanding of normal facial growth and development. Furthermore, they constitute a useful tool for prenatal diagnosis, gestational aging, growth predictions, and perhaps for as yet relatively unexplored fields such as fetal therapy.

Neural tube defects and omphalocele in trisomy 18.

A trisomy 18 fetus with severe congenital anomalies including craniorachischisis, large omphalocele, and bilateral cleft lip and palate is reported. The occurrence of neural tube defects and/or omphalocele in reported cases of trisomy 18 is discussed and the frequency of these anomalies in 85 trisomy 18 patients evaluated at Indiana University School of Medicine from 1963 to 1986 is reviewed. In this series of patients the frequency of neural tube defects was 7.0% and the frequency of omphaloceles was 5.9%. The percentage of these findings in our cases supports the premise that neural tube defects and omphaloceles are part of the trisomy 18 phenotype. Since fetuses with trisomy 18 are subject to early fetal loss or premature birth, the more subtle physical features of this condition may not be apparent. Thus, karyotyping of fetuses and premature infants with either neural tube defect or omphalocele should be considered.

Ethical considerations in medical genetics--the prenatal diagnosis of hemophilia B.

A couple is presented who underwent prenatal counseling and amniocentesis for sex determination because the wife was an obligate carrier of hemophilia B. Although the fetus was determined to be male, the parents elected not to have further testing to determine if he had hemophilia or not. The difficulties in the in utero diagnosis of hemophilia B are presented and discussed. In addition, the moral reasoning and decision-making process that this couple went through regarding the decision not to have further fetal testing and to continue the pregnancy is presented and analyzed. These moral decisions appear to be based on family and personal ties, and bonding to the fetus after perception of fetal movement. They combine considerations of the duties and rights involved in such situations, and attend to the anticipated consequences as well.

Hirschsprung disease: etiologic implications of unsuccessful prenatal diagnosis.

We describe an infant with Hirschsprung disease (congenital aganglionosis of the intestine) involving the colon and terminal ileum. Midtrimester prenatal diagnosis of this disorder in this infant was attempted utilizing amniotic fluid disaccharidase analyses, ultrasound, and amniography. Decreased disaccharidase activities in amniotic fluid have been reported previously in association with other forms of intestinal obstruction. At 15 weeks' gestation, normal amniotic fluid disaccharidase levels were obtained. Serial ultrasound evaluations did not indicate any pathology, and the results from amniography were inconclusive. The implication of the normal disaccharidase values is that Hirschsprung disease may in some cases result from degeneration of intestinal ganglia after 16 weeks' gestation rather than from faulty migration of neural crest cells. The inheritance of Hirschsprung disease is generally consistent with sex-modified multifactorial inheritance with a lower threshold of expression in males. The case we report has a family history of three affected first- and second-degree relatives. Autosomal dominance with variable expressivity is a possible explanation in this family.