Maternal periconceptional exposure to drinking water disinfection by-products and neural tube defects in offspring.

BACKGROUND: Associations between maternal periconceptional exposure to disinfection by-products (DBPs) in drinking water and neural tube defects (NTDs) in offspring are inconclusive, limited in part by exposure misclassification. METHODS: Maternal interview reports of drinking water sources and consumption from the National Birth Defects Prevention Study were linked with DBP concentrations in public water system monitoring data for case children with an NTD and control children delivered during 2000-2005. DBPs analyzed were total trihalomethanes, the five most common haloacetic acids combined, and individual species. Associations were estimated for all NTDs combined and selected subtypes (spina bifida, anencephaly) with maternal periconceptional exposure to DBPs in public water systems and with average daily periconceptional ingestion of DBPs accounting for individual-level consumption and filtration information. Mixed effects logistic regression models with maternal race/ethnicity and educational attainment at delivery as fixed effects and study site as a random intercept were applied. RESULTS: Overall, 111 case and 649 control children were eligible for analyses. Adjusted odds ratios for maternal exposure to DBPs in public water systems ranged from 0.8-1.5 for all NTDs combined, 0.6-2.0 for spina bifida, and 0.7-1.9 for anencephaly; respective ranges for average daily maternal ingestion of DBPs were 0.7-1.1, 0.5-1.5, and 0.6-1.8. Several positive estimates (≥1.2) were observed, but all confidence intervals included the null. CONCLUSIONS: Using community- and individual-level data from a large, US, population-based, case-control study, we observed statistically nonsignificant associations between maternal periconceptional exposure to total and individual DBP species in drinking water and NTDs and subtypes.

Sunlight-induced bromate formation in chlorinated seawater.

Chlorinated waters are being introduced into estuarine and coastal areas in increasing quantities. In such systems, the chlorine reacts with the natural bromide and ammonia to produce the highly toxic hypobromous acid, hypobromite ion, and haloamines. Sunlight causes up to 50 percent conversion to bromate ion, which is persistent in natural waters and has an unknown toxicity.

Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia.

BACKGROUND: Mutations in the JARID1C (Jumonji AT-rich interactive domain 1C) gene were recently associated with X-linked mental retardation (XLMR). Mutations in this gene are reported to be one of the relatively more common causes of XLMR with a frequency of approximately 3% in males with proven or probable XLMR. The JARID1C protein functions as a histone 3 lysine 4 (H3K4) demethylase and is involved in the demethylation of H3K4me3 and H3K4me2. METHODS: Mutation analysis of the JARID1C gene was conducted in the following cohorts: probands from 23 XLMR families linked to Xp11.2, 92 males with mental retardation and short stature, and 172 probands from small XLMR families with no linkage information. RESULTS: Four novel mutations consisting of two missense mutations, p.A77T and p.V504M, and two frame shift mutations, p.E468fsX2 and p.R1481fsX9, were identified in males with mental retardation. Two of the mutations, p.V504M and p.E468fsX2, are located in the JmjC domain of the JARID1C gene where no previous mutations have been reported. Additional studies showed that the missense mutation, p.V504M, was a de novo event on the grandpaternal X chromosome of the family. Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%). The degree of mental retardation consisted of mild (25%), moderate (12%) and severe (63%). CONCLUSION: Based on the clinical observations, male patients with mental retardation, short stature and hyperreflexia should be considered candidates for mutations in the JARID1C gene.

Wavelet-based analysis of surface mechanomyographic signals from subjects with differences in myosin heavy chain isoform content.

The purpose of this study was to use a wavelet analysis designed specifically for surface mechanomyographic (MMG) signals to determine if the % myosin heavy chain (MHC) isoform content affected the shape of the MMG frequency spectrum during isometric muscle actions. Five resistance-trained (mean +/- SD age = 23.2 +/-3.7 yrs), five aerobically-trained (mean +/- SD age = 32.6 +/- 5.2 yrs), and five sedentary (mean +/- SD age = 23.4 +/- 4.1 yrs) men performed isometric muscle actions of the dominant leg extensors at 20%, 40%, 60%, 80%, and 100% of the maximum voluntary contraction (MVC). Surface MMG signals were detected from the vastus lateralis during each muscle action and processed with the MMG wavelet analysis. In addition, muscle biopsies were taken from the vastus lateralis and analyzed for % MHC isoform content. The results showed that there were distinct differences among the three groups of subjects for % MHC isoform content. These differences were not manifested, however, in the isometric force-related changes in the total intensity of the MMG signal in each wavelet band. It is possible that factors such as the thicknesses of the subcutaneous adipose tissue and/or iliotibial band reduced the potential influence of differences in % MHC isoform content on the MMG signal.

The influence of muscle fiber type composition on the patterns of responses for electromyographic and mechanomyographic amplitude and mean power frequency during a fatiguing submaximal isometric muscle action.

The purpose of this investigation was to examine the influence of muscle fiber type composition on the patterns of responses for electromyographic (EMG) and mechanomyographic (MMG) amplitude and mean power frequency (MPF) during a fatiguing submaximal isometric muscle action. Five resistance-trained (mean +/- SD age = 23.2 +/- 3.7 yrs) and five aerobically-trained (mean +/- SD age = 32.6 +/- 5.2 yrs) men volunteered to perform a fatiguing, 30-sec submaximal isometric muscle action of the leg extensors at 50% of the maximum voluntary contraction (MVC). Muscle biopsies from the vastus lateralis revealed that the myosin heavy chain (MHC) composition for the resistance-trained subjects was 59.0 +/- 4.2% Type IIa, 0.1 +/- 0.1% Type IIx, and 40.9 +/- 4.3% Type I. The aerobically-trained subjects had 27.4 +/- 7.8% Type IIa, 0.0 +/- 0.0% Type IIx, and 72.6 +/- 7.8% Type I MHC. The patterns of responses and mean values for absolute and normalized EMG amplitude and MPF during the fatiguing muscle action were similar for the resistance-trained and aerobically-trained subjects. The resistance-trained subjects demonstrated relatively stable levels for absolute and normalized MMG amplitude and MPF across time, but the aerobically-trained subjects showed increases in MMG amplitude and decreases in MMG MPE The absolute MMG amplitude and MPF values for the resistance-trained subjects were also greater than those for the aerobi-cally-trained subjects. These findings suggested that unlike surface EMG, MMG may be a useful noninvasive technique for examining fatigue-related differences in muscle fiber type composition.

Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979-1997.

BACKGROUND: Surgical series and some population-based studies have documented a decrease in mortality from heart defects. Recent population-based data for the United States are lacking, however. We examined population-based data for patterns, time trends, and racial differences of mortality from heart defects for the United States from 1979 through 1997. METHODS AND RESULTS: We examined the multiple-cause mortality files compiled by the National Center for Health Statistics of the CDC from all death certificates filed in the United STATES: From these data, we derived death rates (deaths per 100 000 population) by the decedent's age, race, year of death, and heart defect type. We also analyzed age at death as an indirect indicator of survival. From 1979 through 1997, mortality from heart defects (all ages) declined 39%, from 2.5 to 1.5 per 100 000 population; among infants, the decline was 39%, or 2.7% per year. In 1995 to 1997, heart defects contributed to 5822 deaths per year. Of these deaths, 51% were among infants and 7% among children 1 to 4 years old. Mortality was on average 19% higher among blacks than among whites; this gap does not appear to be closing. Age at death increased for most heart defects, although less among blacks than among whites. CONCLUSIONS: Mortality from heart defects is declining in the United States, although it remains a major cause of death in infancy and childhood. Age at death is increasing, suggesting that more affected persons are living to adolescence and adulthood. The racial discrepancies should be investigated to identify opportunities for prevention.

Myocardial contrast echocardiography in humans: I. Safety--a comparison with routine coronary arteriography.

Myocardial contrast echocardiography is a new diagnostic cardiovascular imaging technique capable of defining perfusion zones of coronary vessels in vivo; ultimately, it may be used to measure absolute regional myocardial blood flow. However, before it can be used in humans, its safety must be clearly established. Accordingly, the electrocardiographic and hemodynamic effects of intracoronary injections of 2 cc of sonicated Renografin-76 were compared with 5 to 10 cc of non-sonicated Renografin-76 in 10 subjects with normal coronary arteries. Two cubic centimeters of sonicated Renografin provides optimal myocardial opacification during echocardiography, while 5 to 10 cc of Renografin is required for an adequate coronary arteriogram. During coronary arteriography, heart rate decreased while PR and QT intervals and QRS duration increased as compared with baseline and myocardial contrast echocardiography (p less than 0.01). Similarly, the decrease in aortic pressure and first derivative of left ventricular pressure (dP/dt) was significantly (p less than 0.01) greater during routine coronary arteriography than during myocardial contrast echocardiography. Changes in left ventricular end-diastolic or pulmonary capillary wedge pressure were similar during myocardial contrast echocardiography and coronary angiography. There were no significant differences in the duration of electrocardiographic and hemodynamic changes between myocardial contrast echocardiography and coronary arteriography. It is concluded that intracoronary injection of 2 cc of sonicated Renografin-76 provides optimal myocardial opacification. It is safe in humans, producing transient electrocardiographic and hemodynamic alterations that are less pronounced than those seen during routine coronary angiography.

goosecoid expression represses Brachyury in embryonic stem cells and affects craniofacial development in chimeric mice.

The homeobox gene goosecoid, originally identified in Xenopus, is expressed in the organizer or its equivalent during gastrulation in the frog, chick, zebrafish and mouse. To investigate the role of goosecoid in mouse development, we have generated embryonic stem cells that stably overexpress the murine homolog of goosecoid. These cells show a repression of the gastrulation-associated gene Brachyury. Interestingly, repression of Brachyury is conserved between Xenopus and mouse despite the lack of conservation of the Brachyury promoter. Further characterization of the goosecoid-overexpressing ES cells revealed that they maintain the expression of stage-specific embryonic antigen-1, and teratomas derived from goosecoid-overexpressing cells show the presence of cell types derived from all three germ layers. Some highly chimeric mice derived from goosecoid-overexpressing cells displayed skull defects. These observations suggest that goosecoid may play a role in specification of anterior mesendodermal fates and specifically in mouse craniofacial development.

RNA template-specific PCR: an improved method that dramatically reduces false positives in RT-PCR.

We report a novel modification of the reverse transcription PCR method, designated RNA template-specific PCR. With this approach, the 5' end of the first strand is tagged with a unique nucleotide sequence during reverse transcription that may then be exploited to amplify preferentially RNA-derived sequences. In our hands, RNA template-specific PCR retains the sensitivity of the traditional method, but greatly reduces the frequency of false positives, and virtually eliminates carryover contamination from PCR products amplified in previous experiments.

Impact of prenatal diagnosis on the birth prevalence of neural tube defects, Atlanta, 1990-1991.

OBJECTIVE: To determine the impact of prenatal diagnosis on the birth prevalence of neural tube defects (NTDs) in Atlanta during 1990 through 1991. METHODS: Live-born and stillborn infants with NTDs who were at least 20 weeks' gestation were ascertained by the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based birth defects registry. Prenatally diagnosed NTD-affected pregnancies were ascertained from the four perinatal centers and the three genetic laboratories operating in Atlanta during 1990 through 1991. Fetal death certificates were also reviewed for potential cases. RESULTS: During 1990 through 1991, MACDP ascertained 59 NTD cases, for a birth prevalence of 0.77/1000 live births. During this period, an additional 28 NTD-affected pregnancies were detected prenatally and terminated before 20 weeks' gestation. The adjusted NTD rate during 1990 through 1991, which includes prenatally diagnosed cases, was 1.13/1000 live births. CONCLUSIONS: Prenatal diagnosis is making a substantial impact on the birth prevalence of NTDs in Atlanta. However, since NTD rates in Atlanta were 2 to 2.5 per 1000 live births in 1970, prenatal diagnosis and termination of pregnancy does not completely account for the declining rate of NTDs.

Issues in computerized polysomnography.

Reliable, properly tested, computerized systems for recording and scoring polysomnographic data would be welcome assistants in sleep laboratories. They potentially could save time, effort, paper, storage and cost. There exists, however, questions of competence and confidence. The nature and scope of published literature fails to convince many cautious sleep specialists that the cost-benefit ratio is favorable. Nonetheless, computerized systems for polysomnography are here to stay and are improving. Most of us represent past, present or future consumers of these products. The market will adjust to our level of knowledge and demands. We can adopt a variety of perspectives; however, the three basic modes of use should guide our thinking. For clarity, it is helpful to dissect 1) recording issues, 2) scoring issues and 3) monitoring issues from one another. Also, we should insist on greater statistical sophistication in testing trials. Manufacturers face a dilemma. Sleep disorders medicine has few true standards and many idiosyncratic practices. The expertise of consultants vary and manufacturers may be in no position to judge their collaborators. We desperately need guidelines to meet both manufacturers' and clinicians' expectations for testing and using computerized polysomnography.

Uterine activity during sleep.

REM-related increases in uterine activity were found in 10 healthy young adult volunteer subjects. Contraction baseline pressures were elevated compared with NREM sleep, stage 2 sleep, stages 3 and 4 slow wave sleep (SWS), and stage 0. Contraction amplitudes during REM sleep were greater than those during SWS and stage 0, while contraction rates differed only between REM sleep and SWS. The results strongly indicated a cycle of genital activity in women that parallels the penile erection cycle in men. The implications of this finding and suggestions for future research are discussed.

Tibial hemimelia in Langer-Giedion syndrome-possible gene location for tibial hemimelia at 8q.

We report on a girl with Langer-Giedion syndrome or tricho-rhino-phalangeal syndrome, type II (TRPS II) with deletion on 8q, and the unusual findings of bilateral tibial hemimelia and unilateral absence of the ulna. An 8-year-old boy with TRPS II with bilateral tibial hemimelia was reported by Turleau et al. [1982: Hum. Genet. 62:183-187]. The critical region for TRPS II is 8q24.1. Although no genes involving limb development in the human have been identified in this region, two mouse syndromes are localized to the homologous chromosome region of 9A1-A4 which involve limb abnormalities. We propose that a gene involved in limb development is contiguous with the TRPS II gene which, when deleted, may cause tibial hemimelia.

Familial distal arthrogryposis with craniofacial abnormalities: a new subtype of type II?

We report on 5 relatives in 3 generations with an apparent new type of distal arthrogryposis. These individuals have manifestations of type I distal arthrogryposis, but in addition, have craniofacial anomalies that include facial asymmetry, hypertelorism, downslanting palpebral fissures, high nasal bridge, malar hypoplasia, micrognathia, highly arched palate, notched chin, and posteriorly angulated ears. Their intelligence is normal. Although these manifestations preclude us from placing this family in the type I (isolated) distal arthrogryposis category, we also are unable to place them in any of the recognized subtypes of type II distal arthrogryposis. Thus, we think this family may have a previously undescribed form of autosomal dominant type II distal arthrogryposis.

Asymmetric and symmetric long bone bowing in two sibs: an apparently new bone dysplasia.

We describe 2 sibs, one with congenital asymmetric long bone bowing and one with congenital symmetric long bone bowing. Other bony abnormalities in these sibs include beaten metal appearance of the skull, dolichomacrocephaly, ocular hypertelorism, and anterior beaking and bone-within-bone appearance of vertebrae. A differential diagnosis including campomelic dysplasia, kyphomelic dysplasia, hypophosphatasia, Grant syndrome, and osteogenesis imperfecta, and a discussion of potential mechanisms of long bone bowing are presented. The condition that these sibs have shares some characteristics of the above bone disorders, but appears to be a separate entity which to our knowledge has not been described previously.

Population study of congenital hypothyroidism and associated birth defects, Atlanta, 1979-1992.

Very little data are available from population-based studies on congenital hypothyroidism (CH) epidemiology and patterns of associated birth defects. By linking data from two population-based registries, we describe the epidemiology of CH and associated defects in Atlanta from 1979-1992. Cases included all infants with CH born from 1979-1992 to mothers residing in the metropolitan Atlanta area at the time of birth. We ascertained CH cases by reviewing newborn screening records and records of the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based registry of all serious birth defects diagnosed during a child's first year of life. We linked CH cases with MACDP records to ascertain the presence of serious birth defects among infants with CH. Of 97 infants identified with CH through newborn screening and/or MACDP (1:5,000 live births), 87 had primary CH and 10 had secondary. The rate of primary CH was higher among non-hispanic whites than among blacks (1:4,400 vs. 1:10,000) and among females compared with males (1:4,000 vs. 1:7,700). Among infants with primary CH, 77 had isolated CH, 3 had Down syndrome, and 7 had unrelated major structural defects. Based on Atlanta population rates of Down syndrome and major structural anomalies, we infer i) infants with Down syndrome have a 35-fold increased risk for primary CH compared with infants in the general population (P < .0001); ii) infants with primary CH have a 2.2-fold increased risk for major structural anomalies (P < .05). Because this is the first population study of CH in the United States in which data from two population-based registries were linked, the epidemiologic patterns and associated defects are more representative than those found in studies based on newborn screening records only.

Familial occurrence of renal and Müllerian duct hypoplasia, craniofacial anomalies, severe growth and developmental delay.

Absence of the kidneys and of the Müllerian structures has been reported in many patients. We report on a brother and sister, born to nonconsanguineous parents, with renal hypoplasia, Müllerian duct hypoplasia, and strikingly similar facial abnormalities. Both sibs have severe growth and developmental retardation. We think that the unique clinical findings in these sibs represent a new syndrome. The embryological and genetic implications of this condition are discussed.

Descriptive epidemiology of holoprosencephaly and arhinencephaly in metropolitan Atlanta, 1968-1992.

We report the descriptive epidemiology of holoprosencephaly and arhinencephaly using data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance system with multiple sources of ascertainment. From 1968-1992, we ascertained 63 cases of holoprosencephaly and arhinencephaly from approximately 734,000 births, for a birth prevalence of 0.86 per 10,000. Thirteen case infants with holoprosencephaly and four case infants with arhinencephaly were categorized as having syndromes. Of the case infants with non-syndromic holoprosencephaly, 55% had malformations not attributable to the underlying brain defect. The rate of holoprosencephaly and arhinencephaly increased from 0.58 per 10,000 during 1968-1972 to 1.2 per 10,000 during 1988-1992 (P for trend = 0.016). Rates were higher for females than for males (risk ratio = 1.45, 95% C.I. 0.88-2.41) and higher for nonwhites than for whites (risk ratio = 1.74, 95% C.I. 1.06-2.86). There was a U-shaped distribution of risk associated with maternal age with a slightly increased risk for younger women (risk ratio for maternal age < 20 years, compared with age 25-29 years = 1.68, 95% C.I. 0.77-3.62) and older women (risk ratio for maternal age > 34 years, compared with age 25-29 years = 2.30, 95% C.I. 0.93-5.7), but this was not statistically significant. The increased risk in the older age group could be largely explained by the presence of cases with autosomal trisomies. Neonatal mortality was higher for infants with malformations that were not attributable to the underlying brain defect and for infants with syndromes than for infants with isolated holoprosencephaly. This analysis is the first population-based study with long-term data on this rare defect. Further epidemiologic studies will be necessary to assess the risk factors for holo-prosencephaly and arhinencephaly.

Does periconceptional multivitamin use reduce the risk of neural tube defects associated with other birth defects? data from two population-based case-control studies.

The role of periconceptional folic acid in the prevention of neural tube defects (NTDs) is well established. However, it is not clear whether a protective effect exists for the subset of nonsyndromic NTD with other "unrelated" major structural birth defects (NTD-multiples). This question is important to investigate because of shared pathogenetic mechanisms between NTD and other types of birth defects, and because of the epidemiologic differences that have been shown between NTD-multiples and NTD-singles. We analyzed data from two population-based case-control studies of NTDs, Atlanta 1968-1980, and California 1989-1991, to assess whether periconceptional multivitamin use reduces the risk of NTD-multiples. Maternal vitamin histories were assessed for 47 and 65 NTD-multiples cases and 3,029 and 539 control babies in Atlanta, and California, respectively. There was a substantial risk reduction associated with periconceptional multivitamin use (-3 to +3 months) for NTD-multiples (pooled odds ratio = 0.36, 95% C.I. 0.18-0.72) that persisted after adjustment for maternal race/ethnicity and education. Also, no specific types of NTDs or NTDs with specific defects explained the risk reduction with vitamin use. These data suggest that multivitamins reduce the risk of nonsyndromic NTD cases associated with other major birth defects. The implication of this finding for the role of vitamins in the prevention of non-NTD birth defects should be further explored.

Infantile hypophosphatasia: autosomal recessive transmission to two related sibships.

Hypophosphatasia, a rare heritable form of rickets/osteomalacia, is characterized by deficient activity of the tissue nonspecific (liver/bone/kidney) isoenzyme of alkaline phosphatase (ALP). Signs may be present prenatally or not until late adult life. Although the infantile form of hypophosphatasia has usually been categorized as an autosomal recessive (AR) disorder, several studies suggest that childhood cases are the consequence of either AR or autosomal dominant (AD) inheritance and adult cases are primarily AD. Eastman and Bixler (J Craniofac Genet Dev Biol 3:213-234, 1983) propose that all cases of hypophosphatasia may reflect AD inheritance with 85% penetrance and homozygous lethality. We report on 3 patients with hypophosphatasia in a black family, first manifested clinically during infancy, where the pattern of inheritance for each is consistent with AR transmission. Two were brothers who died from the disorder. The other patient, a cousin, presented with classic stigmata of hypophosphatasia during infancy, but is now age 5 1/2 years and has had a much milder clinical course. Although consanguinity is absent, the maternal grandmothers are sibs as are the maternal grandfathers and the paternal grandmothers. The family history is otherwise negative for skeletal or dental disease. Laboratory and radiographic results are consistent with heterozygosity in each parent. Fibroblast ALP activity is less than 1% normal in all 3 patients with no complementation observed in heterokaryon analysis. Accordingly, the genetic defects appear to be identical in all 3 patients. Our findings show that infantile hypophosphatasia may be inherited as an AR condition where there is variable expressivity and that homozygosity or compound heterozygosity, as may be the case in this family, is not necessarily lethal.