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Objective: To assess whether women with a genetic predisposition to medical conditions known to increase pre‐eclampsia risk have an increased risk of pre‐eclampsia in pregnancy. Design: Case–control study. Setting and population: Pre‐eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene‐centric array. Methods: Significant single‐nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome‐wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre‐eclampsia. Odds of pre‐eclampsia were compared across quartiles of the genetic instrument and evaluated for significance. Main outcome measures: Genetic predisposition to medical conditions and relationship with pre‐eclampsia. Results: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre‐eclampsia (DBP, overall OR 1.11, 95% CI 1.01–1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00–1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82–0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early‐onset pre‐eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08–1.56, P = 0.005). For other traits, there was no evidence of an association. Conclusions: These results suggest that the underlying genetic architecture of pre‐eclampsia may be shared with other disorders, specifically hypertension and obesity. A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre‐eclampsia. A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre‐eclampsia. [ABSTRACT FROM AUTHOR]

Rare coding variants are a current focus in studies of complex disease. Previously, at least 68 rare coding variants were reported from candidate gene sequencing studies in non-syndromic cleft lip and palate ( NSCL/P), a common birth defect. Advances in sequencing technology have now resulted in thousands of sequenced exomes, providing a large resource for comparative genetic studies. We collated rare coding variants reported to contribute to NSCL/P and compared them to variants identified from control exome databases to determine if some might be rare but benign variants. Seventy-one percentage of the variants described as etiologic for NSCL/P were not present in the exome data, suggesting that many likely contribute to disease. Our results strongly support a role for rare variants previously reported in the majority of NSCL/P candidate genes but diminish support for variants in others. However, because clefting is a complex trait it is not possible to be definitive about the role of any particular variant for its risk for NSCL/P. [ABSTRACT FROM AUTHOR]

Bertolacini CDP, Ribeiro-Bicudo LA, Petrin A, Richieri-Costa A, Murray JC. Clinical findings in patients with GLI2 mutations - phenotypic variability. Mutations in the human GLI2 gene were first reported in association with defective anterior pituitary formation, panhypopituitarism, and forebrain anomalies represented by typical holoprosencephaly (HPE) and holoprosencephaly-like (HPE-L) phenotypes and postaxial polydactyly. Subsequently, anophthalmia plus orbital anomalies, heminasal aplasia, branchial arch anomalies and polydactyly have also been incorporated into the general phenotype. Here we described six Brazilian patients with phenotypic manifestations that range from isolated cleft lip/palate with polydactyly, branchial arch anomalies to semi-lobar holoprosencephaly. Novel sequence variants were found in the GLI2 gene in patients with marked involvement of the temporomandibular joint (TMJ), a new clinical finding observed with mutations of this gene. Clinical, molecular and genetic aspects are discussed. [ABSTRACT FROM AUTHOR]

Orofacial clefts are common and burdensome birth defects with a complex genetic and environmental etiology. The contribution of nutritional factors and supplements to the etiology of orofacial clefts has long been theorized and studied. Multiple studies have evaluated the role of folic acid in the occurrence and recurrence of orofacial clefts, using observational and non-randomized interventional designs. While preventive effects of folic acid on orofacial clefts are commonly reported, the evidence remains generally inconsistent. This paper reviews the findings of the main studies of the effects of folic acid on orofacial clefts, summarizes study limitations, and discusses research needs with a focus on studying the effects of high dosage folic acid on the recurrence of oral clefts using a randomized clinical trial design. The role of folic acid in the prevention of neural tube defects is also briefly summarized and discussed as a reference model for orofacial clefts. [ABSTRACT FROM AUTHOR]

Background: The effects of immobilization of the right lower limb on driving performance are unknown. Therefore, clinicians and legislators cannot put forth recommendations for road safety for patients requiring such immobilization. The objective of the present study was to evaluate the effect of two orthopaedic immobilization devices on the braking performances of healthy volunteers under simulated driving conditions.Methods: The braking performances of forty-eight healthy volunteers were evaluated under three conditions: wearing a running shoe, wearing a walking cast, and wearing an Aircast Walker on the right lower limb. A computerized driving simulator was used to measure the maximum force applied on the brake pedal during braking as well as the braking reaction time and the total braking time during emergency braking with and without a distractor.Results: The mean braking forces applied with the shoe, the walking cast, and the Aircast Walker were 293.8, 275.4, and 287.2 lb (133.3, 124.9, and 130.3 kg), respectively. The value with the walking cast was significantly lower than that with the shoe or Aircast Walker (p < 0.0001); there was no difference between the shoe and the Aircast Walker. The adjusted mean braking reaction times during emergency braking without a distractor were 0.580 second (shoe), 0.609 second (cast), and 0.619 second (Aircast Walker). The value with the running shoe was significantly lower than that with either type of immobilization (p < or = 0.0001). With a distractor, the mean braking reaction time was shorter with the running shoe than it was with either form of immobilization (p < or = 0.0001); the mean time was also shorter with the walking cast than it was with the Aircast Walker (p = 0.003). During both emergency braking tasks (with and without a distractor), the mean total braking time was shorter with the shoe than it was with either type of immobilization (p < 0.0001). With a distractor, the adjusted mean total braking time was shorter with the walking cast than it was with the Aircast Walker (p = 0.035).Conclusions: Immobilization of the right lower limb affects the braking force as well as the braking reaction time and total braking time during emergency braking by healthy volunteers. While these changes are significant, their impact on the ability to drive safely during emergency braking situations is questionable. Future research into the impact of such immobilization on the emergency braking performances of patients is warranted to confirm these observations. [ABSTRACT FROM AUTHOR]

Objective: Identification of the breakpoints of disease-associated chromosome rearrangements can provide informative clues to a positional cloning approach for genes responsible for inherited diseases. Recently, we found a three-generation Japanese family segregating balanced chromosome translocation t(9;17)(q32;q12). One of the subjects had cleft lip and palate. We examined whether regions near the breakpoint could be associated with cleft lip and/or palate. Methods: We determined the breakpoints involved in the translocation by fluorescence in situ hybridization analysis and subsequent long-range polymerase chain reaction. In order to study the role of these disrupted regions in nonsyndromic cleft lip and/or palate, we performed mutation analysis and a haplotype-based transmission disequilibrium test using tagging single-nucleotide polymorphisms in the flanking regions of the breakpoints in white and Filipino nonsyndromic cleft lip and/or palate populations. Results: Sequence analysis demonstrated that two genes, SLC31A1 (solute carrier family 31 member 1)on chromosome 9 and CCL2 (chemokine ligand 2) on chromosome 17, were rearranged with the breaks occurring within their introns. It is interesting that SLC31A1 lies closed to BSPRY (B-box and SPRY domain), which is a candidate for involvement with cleft lip and/or palate. Some of the variants in BSPRY and CCL2 showed significant p values in the cleft lip and/or palate population compared with the control population. There was also statistically significant evidence of transmission distortion for haplotypes on both chromosomes 9 and 17. Conclusions: The data support previous reports that genes on chromosomal regions of 9q and 17q play an important role in facial development. [ABSTRACT FROM AUTHOR]

The authors conducted a nationwide study of the occurrence of cancer among 8,093 Danish oral cleft cases born in 1936 through 1998 and followed in the Danish Cancer Registry from 1968 through 1998, a total of 175,863 person-years, to assess a possible association between cancer and oral clefts. Observed and expected numbers of cancers among oral cleft cases were summarized as the overall and as 52 site-specific standardized incidence ratios. The expected overall number of all cancers was 131, but 140 incident cancers were found, corresponding to a standardized incidence ratio of 1.07 (95% confidence interval (CI): 0.90, 1.26). Analyses of the 52 sites for all oral cleft cases and analyses stratified for three cleft subgroups and the two sexes revealed only a few significant associations: an increased occurrence of breast cancer among females born with cleft lip and/or cleft palate (standardized incidence ratio (SIR) = 1.52, 95% CI: 1.05, 2.14), primary brain cancer among females born with cleft palate (SIR = 3.11, 95% CI: 1.14, 6.78), and primary lung cancer among males born with both cleft lip and cleft palate (SIR = 2.49, 95% CI: 1.00, 5.14). The results do not provide evidence for an increased overall cancer risk for individuals born with oral clefts. [ABSTRACT FROM AUTHOR]

Background: Approximately 10% of patients with plantar fasciitis have development of persistent and often disabling symptoms. A poor response to treatment may be due, in part, to inappropriate and nonspecific stretching techniques. We hypothesized that patients with chronic plantar fasciitis who are managed with the structure-specific plantar fascia-stretching program for eight weeks have a better functional outcome than do patients managed with a standard Achilles tendon-stretching protocol.Methods: One hundred and one patients who had chronic proximal plantar fasciitis for a duration of at least ten months were randomized into one of two treatment groups. The mean age was forty-six years. All patients received prefabricated soft insoles and a three-week course of celecoxib, and they also viewed an educational video on plantar fasciitis. The patients received instructions for either a plantar fascia tissue-stretching program (Group A) or an Achilles tendon-stretching program (Group B). All patients completed the pain subscale of the Foot Function Index and a subject-relevant outcome survey that incorporated generic and condition-specific outcome measures related to pain, function, and satisfaction with treatment outcome. The patients were reevaluated after eight weeks.Results: Eighty-two patients returned for follow-up evaluation. With the exception of the duration of symptoms (p < 0.01), covariates for baseline measures revealed no significant differences between the groups. The pain subscale scores of the Foot Function Index showed significantly better results for the patients managed with the plantar fascia-stretching program with respect to item 1 (worst pain; p = 0.02) and item 2 (first steps in the morning; p = 0.006). Analysis of the response rates to the outcome measures also revealed significant differences with respect to pain, activity limitations, and patient satisfaction, with greater improvement seen in the group managed with the plantar fascia-stretching program.Conclusions: A program of non-weight-bearing stretching exercises specific to the plantar fascia is superior to the standard program of weight-bearing Achilles tendon-stretching exercises for the treatment of symptoms of proximal plantar fasciitis. These findings provide an alternative option to the present standard of care in the nonoperative treatment of patients with chronic, disabling plantar heel pain. [ABSTRACT FROM AUTHOR]

Vieira AR, Karras JC, Orioli IM, Castilla EE, Murray JC. Genetic origins in a South American clefting population. Clin Genet 2002: 62: 458–463. © Blackwell Munksgaard, 2002 It has been proposed that susceptibility to clefting in South America is related to Amerindian ancestry, where clefting is present at a higher frequency than in the other admixed populations (Caucasian and African) that make up the diverse racial mix of current South Americans. To clarify the genetic origins and establish a method for genetic mapping, mitochondrial DNA variation and Y-chromosome markers were studied in a South American population affected with clefting. Two-hundred and seventeen subjects and matched controls were selected through the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). The case group showed a higher frequency of Native American haplogroups and a lower frequency of African haplogroups (p < 0.00001). In addition, the case group showed a much higher frequency of the specific native American haplogroup D than the control group (p < 0.00001). For the Y-chromosome markers, the case group showed a lower frequency of the African-specific marker, YAP (p = 0.002), and a higher frequency of the Native American-specific marker, DYS199 (p < 0.00001). Even though differences were found in the frequencies of the markers studied, the contribution of each founder population was similar for both groups. Results suggest a strong Native American maternal contribution and a strong Caucasian (Spanish and Portuguese) paternal contribution to the population studied. The implications of this finding include the possibility of using admixture mapping approaches to this population. [ABSTRACT FROM AUTHOR]