Mild association between the A/G polymorphism in the promoter of the apolipoprotein A-I gene and apolipoprotein A-I levels: a meta-analysis.

A polymorphism caused by a G-to-A substitution in the promoter area (-75 bp) of the apolipoprotein AI (apo A-I) bene is common in the general population. Several studies have investigated its association with apo A-I levels, but the results were conflicting. Here, we undertook meta-analyses to increase the statistical power to further detect this association. Meta-analyses were first performed for each gender and then on the combined data. The overall sample in this meta-analysis included over 3,000 healthy individuals. Results from healthy individuals suggest that the rare allele A is associated with mildly increased apo A-I levels by about 5 mg/dl (95% CI 2.84 - 6.94). This association is weaker among healthy females than males. The present study cannot determine whether this small but significant association was due to a small genetic effect of the A/G polymorphism, or whether the A/G polymorphism is in linkage disequilibrium with a true mutant allele at a quantitative trait locus controlling apo A-I levels. Although smoking status may interact with genotypes, only three studies investigated this interaction and thus no conclusion could be drawn in this regard.

Survey of genetic counselors and clinical geneticists regarding recurrence risks for families with nonsyndromic cleft lip with or without cleft palate.

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common congenital malformation affecting about 1/1,000 caucasian infants. Although the familial clustering of CL/P has been studied thoroughly, estimation of recurrence risk for genetic counseling purposes can be difficult. A survey was mailed to 912 board-certified genetic counselors, 542 non-board-certified genetic counselors, and 776 board-certified clinical geneticists to investigate the recurrence risks they would assign to three example families with CL/P. Responses were received from 155 (17%) board-certified genetic counselors, 36 (6.6%) non-board-certified genetic counselors, and 100 (18.5%) board-certified clinical geneticists. No major differences were found in their responses, suggesting that for these three families, geneticists would provide similar estimates of risk, regardless of their amount of experience with oral clefts patients, where they are currently employed, or their board certification status.

Application of transmission disequilibrium tests to nonsyndromic oral clefts: including candidate genes and environmental exposures in the models.

Extensive epidemiological and genetic studies of the cause of oral clefts have demonstrated strong familial aggregation but have failed to yield definitive evidence of any single genetic mechanism. We used the transmission/disequilibrium test (TDT) to investigate the relationship between oral clefts and markers associated with five candidate genes by utilizing 160 parent-offspring trios. Conditional logistic regression models extended the TDT to include covariates as effect modifiers, thus permitting tests for gene-environment interactions. For four of these candidates [transforming growth factor alpha (TGFA), transforming growth factor beta 3 (TGFB3), retinoic acid receptor (RARA), and the proto-oncogene BCL3], we detected modestly elevated odds ratios for the transmission of one marker allele to cleft probands when all the trios were analyzed together. These odds ratios increased when information on type of cleft, race, family history, or maternal smoking were incorporated as effect modifiers. We detected significant interaction between maternal smoking and the transmission of alleles for markers near TGFA and TGFB3; excess transmission of allele 3 at BCL3 was most significant among cleft lip probands; and the odds ratios for transmission of alleles at D19S178 and THRA1 were significant when ethnic group was included in the model. We suggest that utilizing an analytical strategy that allows for stratification of data and incorporating environmental effects into a single analysis may be more effective for detecting genes of small effect.

Fifty years after the Nuremberg Nazi Doctors' Trial: reviewing how the laws of the Third Reich applied to individuals with oral clefts.

The Nazi Doctors' Trial, held in the city of Nuremberg 50 years ago, is a landmark in the history of medicine and science. For the first time, the horrors inflicted by a group of German scientists on innocent victims became widely known. Most of the defendants received sentences that ranged from relatively short imprisonment to death. The Trial also provided elements to develop standards for permissible medical experimentation, known as the Nuremberg Code. The atrocities judged in the Nazi Doctors' Trial, however, were not isolated. They were part of an overall eugenic system that encouraged euthanasia, compulsory sterilization, and selective marriages based on "genetic health" and "racial hygiene." Individuals with oral clefts were considered subject to these laws and suffered their consequences. This paper describes the main features of the Trial, reviews the state of knowledge on oral clefts in the 1930s and 1940s, presents how the laws of the Third Reich impacted the lives of individuals with oral clefts, and speculates on the implications of past and present eugenic policies in the future of humankind.

Assessment of nutritional status in a population of recently hospitalized patients.

Malnutrition in the hospital is not a new or rare problem, however, it is often unrecognized. In order to determine the baseline nutritional characteristics of recently hospitalized patients, we assessed the nutritional status of all medical in-patients between April and December 1994 in a large hospital in the province of Buenos Aires. One hundred and seventy patients were derived from the Internal Medicine ward and 176 patients from the General Surgery ward. Surgery patients were younger (median: 46 years vs 58 years of the Medicine patients). Among Medicine patients, cardiovascular and respiratory afflictions were the most common (30%), while gastrointestinal disorders were more often seen in Surgical patients (71%). A weight loss of more than 10% (%WL) was found in 12% of the Medicine and Surgery patients and a body mass index (BMI) of less than 19 kg/m2 was observed in about 5% of both groups. Ten percent of the Medicine patients and 14% of the Surgery patients were overweight. A mid-upper arm muscle circumference (MUAMC) less than the fifth percentile was found in 11% of the Medicine patients but in only 3% of the Surgery patients. These results suggest that this population of recently hospitalized patients is at high-risk for medical complications. Therefore, early nutrition assessment and appropriate nutrition intervention are required to improve clinical outcome and help reduce the cost of health care.

Medical informatics in perinatology project AGUSTINA in Argentina.

This paper reviews the development of the field of medical informatics in Latin America. It also describes the preliminary results of a computer-based data management system, named AGUSTINA, which is comprised of maternal and infant data on 6195 deliveries that occurred between June 1990 and December 1995 in a hospital in the surroundings of Buenos Aires, Argentina. These data were fundamental for the instrumentation of preventive community-oriented activities in the area. Finally, this paper describes recommendations for future actions in the area of medical informatics in Latin America.

Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy.

BACKGROUND: Pregnancy registries for women taking anticonvulsant drugs have been developed to determine more efficiently the fetal risks of each drug. A total of 722 drug-exposed pregnancies are needed to identify a sevenfold increase in the rate of occurrence of a specific abnormality, such as spina bifida, with a frequency of 1 in 1,000. METHODS: The infants with major malformations born to the 791 women who had taken lamotrigine as monotherapy and had enrolled in the North American AED Pregnancy Registry were identified. Medical records were obtained from the affected infants' doctors. A total of 107 of the 791 infants or pregnancies were excluded. RESULTS: A total of 16 (2.3%) of 684 infants exposed to lamotrigine had major malformations that were identified at birth. Five infants (7.3/1,000) had oral clefts: isolated cleft palate (3), isolated cleft lip (1), and cleft lip and palate (1). The rate among the lamotrigine-exposed infants showed a 10.4-fold increase (95% CI: 4.3-24.9) in comparison to 206,224 unexposed infants surveyed at birth at Brigham and Women's Hospital in Boston, where the prevalence of isolated oral clefts was 0.7/1,000. A comparison was made also to 1,623 infants exposed to lamotrigine, as monotherapy, who had enrolled in five other registries. There were four infants with oral clefts: prevalence 2.5/1,000 (RR: 3.8, 95% CI: 1.4-10.0). CONCLUSIONS: The infant exposed in the first trimester of pregnancy to the anticonvulsant drug lamotrigine has an increased risk to have an isolated cleft palate or cleft lip deformity.

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea.

The increase in fetal hemoglobin (HbF) in response to hydroxyurea (HU) varies among patients with sickle cell anemia. Twenty-nine candidate genes within loci previously reported to be linked to HbF level (6q22.3-q23.2, 8q11-q12 and Xp22.2-p22.3), involved in metabolism of HU and related to erythroid progenitor proliferation were studied in 137 sickle cell anemia patients treated with HU. Three-hundred and twenty tagging single nucleotide polymorphisms (SNPs) for genotyping were selected based on HapMap data. Multiple linear regression and the nonlinear regression Random Forest method were used to investigate the association between SNPs and the change in HbF level after 2 years of treatment with HU. Both methods revealed that SNPs in genes within the 6q22.3-23.2 and 8q11-q12 linkage peaks, and also the ARG2, FLT1, HAO2 and NOS1 genes were associated with the HbF response to HU. Polymorphisms in genes regulating HbF expression, HU metabolism and erythroid progenitor proliferation might modulate the patient response to HU.

Increased rate of major malformations in offspring exposed to valproate during pregnancy.

OBJECTIVE: To determine the rate of occurrence of major malformations in infants whose mothers had taken the drug valproic acid (VPA) as monotherapy during the first trimester of pregnancy and had enrolled in the North American Antiepileptic Drug Pregnancy Registry. METHODS: Data were collected from pregnant women throughout the United States and Canada through telephone-based interviews. Each woman was interviewed at enrollment, at 7 months' gestation, and postpartum. With her written permission, the medical records of each mother and her infant were obtained. The major malformations tabulated were those identified at or before 5 days of age. The prevalence of congenital malformations among offspring of monotherapy VPA-exposed women was compared with that among infants of women exposed to all other antiepileptic drugs (internal comparison group) and with that among newborns in the Active Malformations Surveillance Program at Brigham and Women's Hospital (external comparison group). RESULTS: Sixteen affected cases were identified among 149 VPA-exposed women (proportion: 10.7%; 95% CI: 6.3 to 16.9%). The prevalence in the internal comparison group was 2.9% (95% CI: 2.0 to 4.1%; odds ratio: 4.0, 95% CI: 2.1 to 7.4; p < 0.001). Assuming a 1.62% prevalence in the external comparison group, the relative risk of having an affected offspring for VPA-exposed women was 7.3 (95% CI: 4.4 to 12.2; p < 0.001). CONCLUSION: Maternal exposure to valproic acid during the first trimester of pregnancy significantly increased the risk of major malformations.

[Genetic epidemiology: an expanding scientific discipline]. / La epidemiología genética: disciplina científica en expansión.

Genetic epidemiology is a relatively new discipline that studies the interaction between genetic and environmental factors in the production of human diseases. Taking advantage of the genetic markers provided by molecular biological research, complex computerized algorithms, and large databases, the field of genetic epidemiology has undergone notable development in the past 10 years. This article describes the objectives and methodology of genetic epidemiology, using concrete examples from the recent scientific literature.

Dysmorphology in the Bible and the Talmud.

This article enumerates the congenital anomalies mentioned in the Bible and the Talmud, the two holiest and oldest texts in Judaism. Most of these conditions were described to regulate attributes that would disqualify a Priest from performing religious rituals in the Temple in Jerusalem. However, the cultural atmosphere in Biblical and Talmudical times was one in which physical deformity did not necessarily evoke a negative aesthetic reaction, an assumption of ill health, or the expectation of economic dependence.

Review of the role of potential teratogens in the origin of human nonsyndromic oral clefts.

Oral clefts are common birth defects affecting approximately 1 every 1,000 caucasian newborns. While many syndromes with cleft lip with or without cleft palate (CL/P) or with cleft palate (CP) are recognized, the majority of oral clefts fall into the category of "nonsyndromic oral clefts" and the etiology of this group remains incompletely understood. Investigators agree that oral clefts are multifactorial in origin, with both genetic and environmental factors in their etiology. While animal models have identified several teratogens for oral clefts, their precise relevance for humans remains unclear. The goal of this work is to review literature on environmental exposures potentially associated with non-syndromic oral clefts.

Parental sex effect in families with alcoholism.

Parental sex effects have been shown to influence the inheritance of a number of complex disorders. In this paper we performed affected sib-pair analyses on 105 families with recurrent alcoholism to evaluate the effects that the parent of origin might have on this disorder. Three alternative classification schemes were used and the families were grouped as maternal, paternal, mixed, or unknown. Paternal effects were observed at D9S64, D16S475, and D16S2622, while maternal effects were expressed at FABP2, D8S280, D8S1715, and D8S1988. Except for D16S2622, none of these markers resulted in a significant p-value when all families were analyzed together. These results suggest that the parental sex should not be ignored and that a discriminatory analysis should always be performed.

Maternal cigarette smoking and oral clefts: a meta-analysis.

OBJECTIVE: A meta-analysis was performed to estimate the association between maternal cigarette smoking and the risk of having a child with a nonsyndromic oral cleft (NSOC). DESIGN: Studies published from 1966 through 1996 were retrieved using MEDLINE, Current Contents, bibliographies, and other sources. MEDLINE and Current Contents search terms included "oral clefts," "cigarette smoking," "birth defects," and "congenital malformations." Cohort and case-control studies that enrolled oral cleft patients [cleft lip with or without cleft palate (CL/P), cleft palate (CP), or both] and controls, and presented information on maternal cigarette exposure during pregnancy were included in the analysis. Descriptive and outcome data from each study were independently abstracted by two authors. RESULTS: The overall odds ratio of the 11 studies satisfying criteria was 1.29 [95% confidence interval (CI), 1.18 to 1.42] for CL/P and 1.32 (95% CI: 1.10 to 1.62) for CP, indicating a small increase risk of having a child with either a CL/P or a CP for mothers who smoke during the first trimester of the pregnancy. CONCLUSIONS: These analyses suggest a small but statistically significant association between maternal cigarette smoking during the first trimester of gestation and increased risk of having a child with a CL/P or CP.

Health conditions in Argentina: facing the twenty-first century.

This paper describes the state of health in Argentina. As in other countries in the Latin American region, the public sector and the role of the state in Argentina are in the midst of structural transformation. Public policy has been formulated with the aim of improving economic efficiency in the long term, often at the cost of basic services, such as health, education and safety. Provision of health care services to a population characterized by high levels of poverty and unemployment, which is also rapidly growing and ageing, needs to be addressed when major policies are decided. Otherwise, a large group of inhabitants in Argentina will not be able to reach the universally proposed minimum levels of health by the year 2000.

Genetics of nonsyndromic oral clefts revisited.

Nonsyndromic oral clefts are among the most common birth defects, affecting approximately 1 in 1000 Caucasian newborns. In recent decades, many investigators have used genetic and epidemiologic methods to identify etiologic factors, but results have often been inconclusive or contradictory. Etiologic heterogeneity is undoubtedly a major component in these birth defects, and there may not be a single answer to this problem. Here, we describe the main features of published studies pointing out their strengths and limitations. Additionally, we give insight into current methods for detecting the presence of interaction between genetic markers and environmental exposures in the etiology of oral clefts.