Search

Background: Nonalcoholic fatty liver disease (NAFLD) and insulin resistance are common in overweight adolescents., Objective: The purpose of this study was to determine the relation between NAFLD and insulin sensitivity in liver and skeletal muscle by studying overweight adolescents with a normal or high intrahepatic triglyceride (IHTG) content, who were matched for age, sex, body mass index (BMI; in kg/m(2)), and Tanner stage., Design: Stable-isotope-labeled tracer infusion and the hyperinsulinemic-euglycemic clamp procedure were used to assess skeletal muscle and hepatic insulin sensitivity, and magnetic resonance spectroscopy was used to assess the IHTG content in 10 overweight (BMI = 35.9 +/- 1.3) adolescents with NAFLD (IHTG = 28.4 +/- 3.4%) and 10 overweight (BMI = 36.6 +/- 1.5) adolescents with a normal IHTG content (3.3 +/- 0.5%)., Results: The baseline plasma glucose concentration and the rate of appearance of glucose in plasma were the same in subjects with a normal (87.1 +/- 1.2 mg/dL, 16.2 +/- 1.1 micromol . kg fat-free mass(-1) . min(-1)) or high (89.2 +/- 2.5 mg/dL, 16.3 +/- 1.2 micromol . kg fat-free mass(-1) . min(-1)) IHTG content. However, compared with subjects who had a normal IHTG content, subjects with NAFLD had a lower hepatic insulin sensitivity index, based on baseline glucose kinetics and insulin concentrations (4.0 +/- 0.5 compared with 2.4 +/- 0.4; P < 0.05) and an impaired increase in glucose uptake during insulin infusion (169 +/- 28.1% compared with 67 +/- 9.6% above baseline; P < 0.01). In addition, the plasma triglyceride concentration was greater and the plasma HDL-cholesterol concentration was lower in subjects with NAFLD than in those with a normal IHTG content., Conclusion: An elevated IHTG content in overweight adolescents is associated with dyslipidemia and with insulin-resistant glucose metabolism in both liver and skeletal muscle.

Background: A 9-month-old boy with Proteus syndrome and a de novo germline mutation in the tumor suppressor PTEN was referred to a specialist centre for management. Over the first years of life, the patient developed life-threatening respiratory dysfunction and malnutrition because of progressive growth of hamartomas affecting the chest, mediastinum, abdomen and pelvis., Investigations: Physical examination, CT scans of the mediastinum, pelvis and abdomen, measurement of serum insulin-like growth factor binding protein-2, and investigation of the effect of the PTEN mutation on phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling in an in vitro cell model., Diagnosis: PTEN hamartoma tumor syndrome, specifically Proteus syndrome., Management: Oral rapamycin.

We report the second instance of a complex unbalanced rearrangement consisting of distal trisomy 6p and 20q due to the concurrent transposition of distal 6p and 20q to the 22q telomere, previously described as a benign familial chromosomal variant. In the previous case, the nonpathogenicity of the rearrangement was based on the absence of genotypic differences between the affected proband and his normal father, and on the absence of imprinted genes in the unbalanced region. We now describe the same variant in an unrelated affected subject, in whom testing confirmed the diagnosis of Angelman syndrome, and in his healthy father. Molecular investigations confirmed that the two families have an identical subtelomeric rearrangement. However, genotyping of the flanking sequences on 22q showed a completely different pattern in the two families, demonstrating that they are indeed unrelated. Array-CGH analysis with a resolution of approximately 20 kb (Kit 244A, Agilent) defined a deletion size of 5.9 Mb on 15q11.2. No other imbalances were visible at subtelomeric regions. Further Array-CGH analysis using DNA of the proband (as test) and his mother (as reference) did not detect any duplication at the 6p and 20q subtelomeric regions. The proband and his father appear to have a copy number of the transposed regions equal to that of individuals with a normal repartition of the subtelomeric regions. This is not suggestive of a trisomy but rather of CNV regions. This type of rearrangement could define a new class of polymorphic variants, i.e. positional variants, as observed for pericentromeric heterochromatin.

Purpose: To determine whether 16 months of moderate-intensity exercise training changes resting metabolic rate (RMR) and substrate oxidation in overweight young adults., Methods: Participants were randomly assigned to nonexercise control (CON, 18 women, 15 men) or exercise (EX, 25 women, 16 men) groups. EX performed supervised and verified exercise 3-5 d/wk, 20-45 min/session, at 60-75% of heart-rate reserve. Body mass and composition, maximal oxygen consumption (VO2max), RMR, and resting substrate oxidation were assessed at baseline and after 9 and 16 months of training., Results: EX men had significant decreases from baseline to 9 months in body mass (94.6+/-12.4 to 89.2+/-9.5 kg) and percent fat (28.3+/-4.6 to 24.5+/-3.9). CON women had significant increases in body mass (80.2+/-8.1 to 83.2+/-9.2 kg) from baseline to 16 months. VO2max increased significantly from baseline to 9 months in the EX men (3.67+/-0.62 to 4.34+/-0.58 L/min) and EX women (2.53+/-0.32 to 3.03+/-0.42 L/min). RMR increased from baseline to 9 months in EX women (1,583+/-221 to 1,692+/-230 kcal/d) and EX men (1,995+/-184 to 2,025+/-209 kcal/d). There were no significant differences within genders for either EX or CON in fat or carbohydrate oxidation. Fat oxidation was significantly higher for women than for men at 9 months in both CON and EX groups., Conclusions: Regular moderate-intensity exercise in healthy, previously sedentary overweight and obese adults increases RMR but does not alter resting substrate oxidation. Women tend to have higher RMR and greater fat oxidation, when expressed per kilogram fat-free mass, than men.

The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.

Background: There is some evidence that calcium consumption improves weight loss during energy restriction but the effects of calcium consumption in conjunction with chronic exercise are unknown., Objective: The purpose of the study was to determine the degree to which calcium consumption influences weight and fat weight change as a result of 9 months of verified supervised exercise in the absence of energy restriction., Methods: Participants were 50 previously sedentary, overweight and moderately obese men (n=20) and women (n=30). Exercise of moderate intensity was performed for 45 min/d, 5 d/wk, under supervision. Diet intake was ad libitum and was measured for energy, macronutrient and micronutrient composition at baseline, 4 and 9 months by use of observer recorded weighed plate waste and multiple-pass 24-h dietary recall procedures., Results: Average calcium consumption was 987 +/- 389 mg/day for men and 786 +/- 276 mg/day for women. Weight change over the 9 months was -4.6 +/- 4.6 kg for men and 0.2 +/- 3.3 kg for women. Calcium consumption was associated with weight change (r =-0.47, p<0.05) in men. The calcium to protein ratio was associated with weight change (r=0.56) and fat weight change (r=-0.53) in men. There was no observed association between calcium and weight or fat weight change in women., Conclusion: Weight and fat weight loss as a result of nine months of moderate intensity exercise may be improved by increased calcium consumption in men but was not observed in women.

This study sought to determine the impact of different levels of weight loss on blood pressure in overweight/obese women. One hundred fifty-nine overweight/obese women (age 48.7 +/- 9.7, weight 101.3 +/- 18.7 kg, BMI 37.3 +/- 6.6 kg/m(2)) completed a six-month clinical weight loss program that included weekly nutrition, behavior, and exercise instruction. Participants consumed a very-low-energy diet (VLED) for 12 weeks. VLED was followed by four weeks of gradual reintroduction to solid foods. At week 16, participants received a diet to maintain weight or slightly reduce weight (<0.5 lb/week) which they followed for the duration of the study. All lab and blood pressure assessments were performed at baseline and six months. Three groups were formed according to the proportion of weight loss after six months; Group 1 had < 10% (n = 19), Group 2 had 10%-20% (n = 64), and Group 3 had >20% (n = 76) weight loss. Differences in systolic blood pressure (mm Hg) were found in dose response fashion for weight loss at six months with 125 +/- 17 (<10%), 119 +/- 13 (10%-20%), and 117 +/- 15 (>20%; p = 0.005). Differences in diastolic blood pressure (mm Hg) were also found in dose response fashion with 81 +/- 9 (<10%), 77 +/- 9 (10%-20%), and 75 +/- 9 (20%; p = 0.003). These data indicate that increasing weight loss beyond 10% of initial body weight may provide added improvements in blood pressure compared to less than 10% weight loss in overweight or obese women.

To determine the effects of a 6-month supervised low-volume resistance training (RT) program (1 set, 85-90%, one repetition maximum, 1RM, 3 d x wk(-1)) on muscular strength (1RM) and skeletal muscle mass (SMM) in previously sedentary, overweight men on an ad libitum diet. Nineteen men were randomly assigned to a control (CON, n = 8) or RT (n = 11) group. The exercise protocol consisted of 5 upper- and 4 lower-body exercises using weight machines. CON maintained their sedentary lifestyle. One RM for upper body (chest press [CP] + lat pull-down [LPD]) and lower body (leg press [LP]) and SMM were assessed at baseline, and at 3 and 6 months. Adherence was 96 +/- 2% with an average time to complete each exercise session of 15 +/- 2 minutes. Volume completed per exercise session significantly increased from baseline (2,812 +/- 670 kg) to 6 months (6,411 +/- 2,128 kg). There was a group by time interaction in 1RM for CP, LPD, and LP. Upper-body strength increased significantly (p < 0.001) (31.3 +/- 9.3%) from baseline to 3 months and from 3 to 6 months (17.9 +/- 8.7%). Lower-body strength also increased significantly from baseline to 3 months (17.8 +/- 16.6%) and from 3 to 6 months (32.0 +/- 33.7%). No changes in upper- or lower-body strength occurred in the CON group. There was no group by time interaction for SMM (CON, 34.5 +/- 2.9 kg vs. RT, 34.2 +/- 2.9 kg; p > 0.05) or for energy intake (p > 0.05). In conclusion, a single set resistance training program at 85% of 1RM, 3 d x wk(-1) resulted in continued increases in muscular strength and a very high adherence rate over a 6-month period in sedentary, overweight men independent of significant changes in SMM. This training protocol may increase adherence and produce long-term increases in muscular fitness as part of an adult fitness program.

We describe mutations in the PML nuclear body protein Sp110 in the syndrome veno-occlusive disease with immunodeficiency, an autosomal recessive disorder of severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, absent tissue plasma cells and hepatic veno-occlusive disease. This is the first report of the involvement of a nuclear body protein in a human primary immunodeficiency and of high-penetrance genetic mutations in hepatic veno-occlusive disease.

Atrial septal defect (ASD) is a common congenital heart disease (CHD) occurring in 5 to 7 per 10,000 live births. Mutations in 5 human genes (NKX2.5, TBX5, GATA4, MYHC, ACTC) are known to cause dominant ASD, but these account for a minority of cases. Human and mouse data suggest that ASD exists in an anatomical continuum with milder septal variants patent foramen ovale (PFO) and atrial septal aneurysm, strongly associated with ischemic stroke and migraine. We have previously shown in inbred mice that the incidence of PFO strongly correlates with length of the interatrial septum primum, defining a quantitative trait underlying PFO risk. To better understand genetic causation of atrial septal abnormalities, we mapped quantitative trait loci (QTL) influencing septal morphology using mouse strains (QSi5 and 129T2/SvEms) maximally informative for PFO incidence and 3 quantitative septal anatomical traits including septum primum length. [QSi5x129T2/SvEms]F2 intercross animals (n=1437) were phenotyped and a whole genome scan performed at an average 17-cM interval. Statistical methodology scoring PFO as a binary phenotype was developed as a confirmatory mapping technique. We mapped 7 significant and 6 suggestive QTL modifying quantitative phenotypes, with 4 supported by binary analysis. Quantitative traits, although strongly associated with PFO (P<0.001), correlated poorly with each other and in all but 1 case QTL for different traits were nonoverlapping. Thus, multiple anatomical processes under separate genetic control contribute to risk of PFO. Our findings demonstrate the feasibility of modeling the genetic basis of common CHD using animal genetic and genomic technologies.

Objectives: The mode of contact and response levels of authors who had been asked to provide missing or incomplete data for a systematic review on diet and exercise interventions for weight loss was examined., Methods: We contacted authors by electronic mail, letter, or both. Survival analyses were performed with the Kaplan-Meier method to determine differences in the proportion of responders over time among the different modes of contact and to determine whether response rates differed between authors from the United States and those from other countries. Logistic regression was used to determine whether the number of items requested and publication date influenced the likelihood of response., Results: Two hundred forty-one (39.9 percent) studies had missing or incomplete data (e.g., sample size, age, caloric restriction, exercise amount, and so on). We were unable to locate ninety-five authors (39.4 percent). Of the remaining authors, forty-six authors (31.5 percent) responded to information requests. Time to respond differed by contact method (p < .05): e-mail (3 +/- 3 days), letter (27 +/- 30 days), and both (13 +/-12 days). Response rates from U.S. authors did not differ from those of other countries., Conclusions: Our study suggests poor success in the acquisition of essential information. Given considerable time and resources, weight loss studies require improved reporting standards to minimize the relatively unsuccessful attempt to contact authors for important and necessary information.

Background: To adequately assess individual studies and synthesize quantitative research on weight loss studies, transparent reporting of data is required. The authors examined the reporting quality of randomized trials in the weight loss literature, focusing exclusively on subject characteristics as they relate to enrollment, allocation, and follow-up., Methods: An extensive literature review, which included a computerized search of the MEDLINE database, manual searches of bibliographic references, and cross-referencing of 92 review articles was conducted. A checklist, based on CONSORT recommendations, was used to collect information on whether or not authors reported age, gender, co-morbid disease, medication use, race/ethnicity, and postmenopausal status. Also tracked was whether or not initial and final sample size was reported and stratified by gender., Results: Of 604 possible articles, 231 articles met eligibility criteria. Important subject characteristics were not reported as the following breakdown indicates: age (11%), gender (4%), race/ethnicity (86%), co-morbid disease states (34%), and medication use (92%). Additionally, 21% of articles failed to report initial sample size by gender while 69% neglected to report final sample size by gender., Conclusion: Inadequate reporting can create difficulties with interpretation and can lead to biased results receiving false credibility. The quality of reporting for weight loss studies needs considerable improvement.

Unlabelled: We report on a favourable case of MCAD deficiency (homozygous 985A > G) that presented as lethargy, poor feeding, pulmonary haemorrhage and cardiac arrest without hypoglycaemia. The cessation of intralipid and the commencement of carnitine supplementation were associated with a rapid clinical improvement., Conclusion: Mild carnitine depletion and secondary impairment of long-chain fatty acid metabolism may have contributed to post-asphyxial myocardial dysfunction and ventricular arrhythmias. Metabolic disorders must be kept in mind as a differential diagnosis in acutely ill infants, but it must also be emphasized that carnitine therapy is not uniformly effective in all MCAD patients.

We have screened 13 patients with neurological abnormalities and 3-methylglutaconic aciduria (3MGA) for mutations in the OPA3 gene, which are known to be the cause of Costeff syndrome (optic atrophy, chorea and spasticity; type III 3MGA). We aimed to explore whether mutations in the OPA3 gene are present in patients with 3MGA but without classic Costeff syndrome. OPA3 mutations (IVS1-1G>C) were identified in 2 patients with the classic phenotype of type III 3MGA, but not in the other 11 patients with differing non-Costeff phenotypes associated with developmental delay and neurological signs and symptoms as described. We identified a previously described sequence variation in the OPA3 gene (c.231T>C) in 12/13 patients. The alteration was homozygous in 8/12 and heterozygous in 4/12. This alteration was also found in 60 of 98 normal control alleles. In a single patient, a novel sequence variation in the 5' UTR was identified, (c.-38A>G). Our studies suggest that the c.231T>C sequence variation is of no clinical significance, whereas the significance of the 5' UTR sequence variation remains open to speculation. Our study of the OPA3 gene in patients with 3MGA without Costeff syndrome suggests that mutations in OPA3 are not a common cause of 3MGA in the absence of signs of Costeff syndrome.

complex I deficiency, the most common respiratory chain defect, is genetically heterogeneous: mutations in 8 nuclear and 7 mitochondrial DNA genes encoding complex I subunits have been described. However, these genes account for disease in only a minority of complex I-deficient patients. We investigated whether there may be an unknown common gene by performing functional complementation analysis of cell lines from 10 unrelated patients. Two of the patients were found to have mitochondrial DNA mutations. The other 8 represented 7 different (nuclear) complementation groups, all but 1 of which showed abnormalities of complex I assembly. It is thus unlikely that any one unknown gene accounts for a large proportion of complex I cases. The 2 patients sharing a nuclear complementation group had a similar abnormal complex I assembly profile and were studied further by homozygosity mapping, chromosome transfers, and microarray expression analysis. NDUFS6, a complex I subunit gene not previously associated with complex I deficiency, was grossly underexpressed in the 2 patient cell lines. Both patients had homozygous mutations in this gene, one causing a splicing abnormality and the other a large deletion. This integrated approach to gene identification offers promise for identifying other unknown causes of respiratory chain disorders.

We report a case of direct interstitial duplication of chromosome 4 from 4q28.1 to 4q35 associated with bilateral choanal atresia. The child also had dysmorphic features including a broad nasal bridge, telecanthus, downward slanting palpebral fissures, prominent ears, mild bilateral clinodactyly of the 5th fingers and bilateral hypoplasia of the 2nd-5th toenails. There was also a slightly dilated renal collecting system. At the age of 2.5 years, he had moderate global developmental delay, short, wide and tapering fingers, and short toes with hypoplastic toenails. To our knowledge, this is the second report of choanal atresia in a patient with trisomy 4q involving this region.

The existence of Kousseff syndrome as a distinct entity has been thrown into doubt by a recent study conducted on the family originally reported by Kousseff. In all cases where chromosome 22q11.2 FISH testing has been undertaken, including the original sibship, a chromosome 22q11.2-microdeletion has been identified. We report two cases of sacral myelomeningocele associated with a conotruncal cardiac anomaly or "Kousseff syndrome." The first case, a 4-year-old girl, had a sacral myelomeningocele, tetralogy of Fallot, microcephaly, hydrocephalus, hypoplasia of the corpus callosum and mild-moderate developmental delay. Chromosome 22q11.2 FISH was normal and the facial phenotype was not that of velocardiofacial syndrome. Sequencing of the entire coding region of CITED2 did not reveal a mutation. The second case, a male infant, was found to have a 22q11.2-microdeletion. These cases confirm Kousseff syndrome to be a causally heterogeneous disorder., (Copyright 2003 Wiley-Liss, Inc.)

Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid alpha-glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid alpha-glucosidase gene (GAA) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid alpha-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease., (Copyright 2003 Wiley-Liss, Inc.)

Four experiments examined performance on the 100 "basic facts" of subtraction and found a discontinuous "stair step" function for reaction times and errors beginning with 11 - n facts. Participants' immediate retrospective reports of nonretrieval showed the same pattern in Experiment 3. The degree to which elementary subtraction depends on working memory (WM) was examined in a dual-task paradigm in Experiment 4. The reconstructive processing used with larger basic facts was strongly associated with greater WM disruption, as evidenced by errors in the secondary task: this was especially the case for participants with lower WM spans. The results support the R. S. Siegler and E. Jenkins (1989) distribution of associations model, although discriminating among the alternative solution processes appears to be a serious challenge., (((c) 2003 APA, all rights reserved))

Objective: To determine the time course for changes in aerobic capacity, body weight (BW), and composition in overweight adults in response to a supervised exercise trial with a targeted energy expenditure of 2000 kcal week(-1)., Design: The Midwest Exercise Trial (MET) was a randomized, controlled, 16-month verified, supervised exercise trial. Aerobic exercise progressed to 45 min day(-1), 5 days week(-1) over 6-months and was then maintained for 10 months. Controls maintained their normal physical activity and all participants maintained ad libitum diets., Subjects: A total of 131 participants were randomized to exercise or control groups and 74 completed the intervention and all laboratory testing., Measurements: At baseline and months 4, 9, 12, and 16, aerobic capacity (VO(2max) ) was measured by indirect calorimetry, BW by digital scale, and fat weight and fat-free weight by hydrostatic weighing., Results: Aerobic capacity (ml kg(-1) min(-1)) increased (P<0.05) from baseline (39.2+/-5.2, mean+/-s.d.) to 9 months (48.8+/-4.3) in exercising men as well as women (32.8+/-4.2-39.6+/-5.5) with no significant changes occurring at 12 or 16 months. From baseline to 9 months BW (94.0+/-12.6-88.7+/-9.7 kg) and fat weight (26.8+/-6.8-21.8+/-4.5 kg) significantly decreased in exercising men with no changes occurring at 12 or 16 months. There were no changes in fat-free weight across the 16 months for exercising men or for BW or composition in exercising women. Further, there were no significant changes for the control men for aerobic capacity, BW, or body composition across 16 months. Women in the control group showed significant increases in weight of 2.9+/-5.5 kg and fat weight of 2.1+/-4.8 kg at 16 months only., Conclusions: We recommend that investigations that use exercise without diet as the stimulus for weight loss have at least a 9-month duration to provide sufficient time for the full effects to be realized, should such effects be present.

D-2-hydroxyglutaric aciduria (D2HGA) is a rare autosomal recessive disorder with variable clinical expression. The biochemical defect is unknown at present. Previously reported cases have either followed a severe clinical course characterized by neonatal epileptic encephalopathy, cortical blindness, and profound developmental delay, or a mild course characterized by mild developmental delay, manageable epilepsy, and mild hypotonia. To date there has been a clear distinction between these two groups. We report the second case of a child with D2HGA who has followed an intermediate course. She presented in infancy with hypotonia, manageable epilepsy and developed moderate to severe developmental delay, and cortical visual impairment. The proposita had a coarse facial appearance, flat face, broad nasal bridge, up-turned nose, and simple, anteverted ears. These facial anomalies have been noted in other children with D2HGA and this case strengthens the proposed association between this facial phenotype and D2HGA. We also report the third and fourth instances of prenatal diagnosis for D2HGA. At each prenatal diagnosis, an affected fetus was diagnosed on the basis of markedly increased levels of D-2-hydroxyglutaric acid in amniotic fluid., (Copyright 2003 Wiley-Liss, Inc.)

Objectives: We sought to examine the importance of mutations in the cardiac transcription factor gene NKX2-5 in patients with an atrial septal defect (ASD), patent foramen ovale (PFO), or hypoplastic left heart syndrome (HLHS)., Background: Mutations in NKX2-5 have been found in families showing secundum ASD and atrioventricular (AV) conduction block and in some individuals with tetralogy of Fallot. The prevalence of NKX2-5 mutations in sporadic cases of ASD/PFO and other forms of congenital heart disease is unknown., Methods: A cohort of 146 individuals with secundum ASD, PFO complicated by paradoxical embolism, or HLHS were evaluated. Patients with ASD or PFO were ascertained irrespective of family history or associated cardiac abnormalities. The coding region of the NKX2-5 locus was amplified by polymerase chain reaction and sequenced., Results: Among 102 ASD and 25 PFO patients screened, 13 patients (10%) had a positive family history and 5 patients (4%) had AV conduction block. We found one previously documented NKX2-5 missense mutation, T178M, in members of a family with ASD without AV conduction block. One NKX2-5 mutation-positive child from this family had HLHS, although no mutations were subsequently found in 18 patients with sporadic or familial HLHS. In a second ASD family without AV conduction block, we found a missense change, E21Q, previously reported as pathogenic. Because this change did not segregate with disease status, we propose that it is a non-disease-causing polymorphism., Conclusions: Our findings suggest that NKX2-5 mutations are a relatively infrequent cause of sporadic ASD and HLHS. Screening for NKX2-5 mutations may be warranted in individuals with ASD and a positive family history, irrespective of the presence or absence of AV conduction block.

We report a family in which a father and his three children are affected with microstomia, micrognathia and partial or complete cleft of the hard and soft palate. The probands were non-identical twins, a boy and a girl, both noted to have the above features soon after birth. Their father was diagnosed with a submucous cleft of the palate at the age of 4 years and their older brother has milder facial features and a bifid uvula. All affected family members were demonstrated to have a fragile site on chromosome 16q22 but otherwise normal karyotypes. Of interest is a previously described family with autosomal dominant inheritance of U-shaped cleft palate, microstomia, micrognathia and oligodontia where all affected members were shown to have the fragile site at 16q22 in a proportion of their cells [Bettex et al. (1998) Eur J Pediatr Surg 8:4-8]. We propose that these two conditions are the same and represent a distinctive syndrome involving aberrant orofacial development that may be linked to the fragile site at 16q22.

Individuals with high math anxiety demonstrated smaller working memory spans, especially when assessed with a computation-based span task. This reduced working memory capacity led to a pronounced increase in reaction time and errors when mental addition was performed concurrently with a memory load task. The effects of the reduction also generalized to a working memory-intensive transformation task. Overall, the results demonstrated that an individual difference variable, math anxiety, affects on-line performance in math-related tasks and that this effect is a transitory disruption of working memory. The authors consider a possible mechanism underlying this effect--disruption of central executive processes--and suggest that individual difference variables like math anxiety deserve greater empirical attention, especially on assessments of working memory capacity and functioning.

The problem size effect in adult arithmetic performance is generally attributed to direct retrieval processes operating on a network representation in long-term memory. J. LeFevre and her colleagues (J. LeFevre, J. Bisanz, et al., 1996; J. LeFevre, G. S. Sadesky, & J. Bisanz, 1996) challenged this explanation using verbal report evidence that adults also use time consuming nonretrieval strategies to solve simple addition and multiplication. The authors replicated J. LeFevre and colleagues' methods, but added instructional biasing and silent control conditions to test these methods. Both reaction time and report results suggest that LeFevre and colleagues' conclusions about nonretrieval frequency may have been influenced by instructions that revealed the experimental hypothesis and affected participants' strategy reports. Obtaining evidence about adult strategy use in simple arithmetic will require understanding instructional demand and appropriate report methodology.

We report a family in which four members of three generations are affected by median cleft palate. The proband and her mother have additional features including bilateral single transverse palmar creases, broad great toes and hypoplastic fifth toenails. Dominant isolated cleft palate has rarely been reported, and there are no previous reports of dominant cleft palate with these associated features. We believe that this represents a previously unreported syndrome, which needs to be considered when assessing recurrence risk for cleft palate.

We report on a family in which two sibs had apparently absent ribs and severe micrognathia on prenatal ultrasonography. The pregnancies were terminated at 19 and 12 weeks of gestation, respectively. Autopsy findings in the first fetus (19 weeks of gestation) included severe micrognathia, a U-shaped defect of the soft palate, marked postnuchal edema, absent olfactory bulbs, and cribriform plate and rib abnormalities. The ribs consisted of cartilage anteriorly, with only a small amount of fibrous tissue present laterally and posteriorly. The second fetus (12 weeks gestation) had agnathia, with a large U-shaped defect in the soft palate. There was moderate postnuchal edema. The ribs were unossified and there were gaps in the cartilage where primitive mesenchyme was present posteriorly and laterally. These findings are consistent with a severe form of cerebro-costo-mandibular syndrome. The early fetal histopathology of both cases suggests a possible mechanism by which the characteristic "rib gaps" of cerebro-costo-mandibular syndrome may develop, with evidence for abnormal function of a gene or genes involved in regulation of rib chondrogenesis.

Objective: Our purpose was to assess whether legislative action influenced the role of obstetrician-gynecologists as primary care physicians., Study Design: An observational study was performed on the basis of a questionnaire sent to 410 obstetrician-gynecologists and 27 medical directors of managed-care organizations., Results: Of 67% of obstetrician-gynecologists and 96% of medical directors who responded, there was agreement as to the content of primary care, but a minority (38%) of obstetrician-gynecologists identified themselves as primary care providers. A minority of medical directors (35%) felt that obstetrician-gynecologists should serve in that role. Both obstetrician-gynecologists and medical directors felt that legislation had little impact., Conclusion: The reticence of obstetrician-gynecologists to assume a major role in primary care appears to be the result of an uneasiness with accepting a more comprehensive role in patient management and gatekeeping. They appear comfortable with the more traditional roles but feel that training and experience has not prepared them well for the management of more complex medical problems.

Our objective was to review the Australasian experience of X-linked adrenoleukodystrophy (ALD), to compare the spectrum of disease seen in Australasia with previously published data from elsewhere, and to assess the reliability of carrier testing. Study design was a retrospective review of records collected over a 15-year period, the setting was an international referral laboratory for the study of metabolic disease, and the subjects were all known cases of ALD diagnosed in Australia and New Zealand between 1981 and 1996 and their families. We estimate that the combined incidence of ALD and its variants in Australasia is at least 1.6 per 100,000. Of 95 affected males, 51 had cerebral adrenoleukodystrophy, 24 had adrenomyeloneuropathy, 15 had Addison's disease only, and 5 remained asymptomatic when last examined. However, the distribution of phenotypes among newly diagnosed patients has changed substantially over the last 15 years, with cerebral forms of the disease forming a decreasing proportion of new diagnoses. The measurement of plasma very long chain fatty acids (VLCFAs) alone detects 93% of women who can be proven to be carriers. The addition of genetic linkage studies or assay of VLCFAs in cultured fibroblasts improved this detection rate to the point that there were no obligate carriers who could not be detected using a combination of two or more techniques.

Objective: To clarify the relation between metroplasty for correction of uterine anomalies and subsequent pregnancy, we reviewed the charts of all patients for whom a diagnosis of bicornuate, septate, or didelphic uterus had been made between 1972 and 1982 and analyzed their obstetric outcomes., Design: Of the 146 patients evaluated, 23 received a metroplasty procedure, and 123 patients did not have surgical intervention. Fifteen of the nonsurgical patients could be matched with 15 of the surgical patients by age, chief complaint, gravidity, and type of anomaly and therefore served as matched controls., Results: The percentage of patients with living children after the diagnosis of uterine anomaly was 67% for the matched nonsurgical group and 73% for the patients who underwent metroplasty. The difference was not statistically significant. Although marked improvement in fetal salvage rates was noted when reproductive outcomes before and after metroplasty were compared, the obstetric outcome was similar to that of the control groups after the diagnosis was made and surgery deferred., Conclusion: The efficacy of metroplasty in the treatment of multiple pregnancy losses is thus being questioned.

We measured the PO2, pH, and temperature in the vaginal canals of nine patients with symptomatic Trichomonas vaginitis and those of 10 healthy women. The patients included eight women with primary infections caused by metronidazole-susceptible strains and one refractory case that resulted from infection with a metronidazole-resistant Trichomonas vaginalis. The median vaginal PO2, pH, and temperature in the patient group were 1 mm Hg, 6, and 37.3 degrees C respectively; these medians were 1 mm Hg, less than or equal to 4.5, and 37.2 degrees C in the healthy group. These data show that vaginal environment is anaerobic or microaerophilic (it has reduced oxygen tension). Because the activity of metronidazole is reduced under aerobiosis, the vaginal environment should enhance the biologic activity of the drug.

The 1980s has been described as the "decade of transplantation" and organ transplantation as a "paradigm of medical progress." The considerable improvements in immunosuppression that have been made in the last few years have led to an increased repertoire of organ-to-organ combination transplants, more procedures, and markedly increased survival time for both grafts and recipients. Inevitably, there will be an increased number of women recipients who later undergo pregnancy. Although there is a wide experience with pregnancy after renal transplantation, there are as yet relatively few reports of pregnancy after other major organ transplants. A case is presented of a 22-year-old primiparous woman who elected to conceive and complete a pregnancy 2 years after cardiac transplantation because of cardiomyopathy. The pregnancy was complicated by a rejection episode early in the third trimester but eventually resulted in forceps delivery of a live male infant at 41 weeks' gestation. The pregnancy and organ transplantation literature is reviewed with special attention, illustrated by the case report, to the physiologic adaptation to pregnancy of the transplanted organ, the potential teratogenic effects of the immunosuppressive drugs used in pregnancy, and the contrasts between renal and other major organ transplants.

The Oregon Health Services Commission is composed of a group of 11 consumers and health care professionals. It was appointed by the governor as required by the "Oregon Basic Health Services Act" to produce a prioritized list of health services ranked on the basis of their relative importance to populations served. Following actuarial analysis, the legislature will determine the extent to which the "list" of services can be funded to provide health care access for Medicaid recipients earning up to the 100th percentile of the federal poverty level. Prioritization will be based on a cost-benefit formula applied to each treatment/condition unit and assignment of each of these to a general category, which itself has been ranked on the basis of "public value."

Despite the known medical safety and success of vaginal birth after cesarean section, rates of planned repeat cesarean sections remain high. The process involved in women's decisions to choose vaginal birth after cesarean section or repeat cesarean section was investigated by a questionnaire study at a private and a public hospital. Women were questioned regarding timing, influence of others, reasons for their choice, satisfaction with the decision, etc. Results from 160 respondents showed that over half the women identified themselves as the primary decision maker. Physicians exerted more influence on the decisions of patients at the public hospital than on the patients at the private hospital. Overall, social exigencies appeared to play a more important role than an assessment of the medical risks in making these decisions.

Inulin was administered to eight volunteer patients at term gestation over a period of 3 hours before cesarean section. Inulin concentrations were repeatedly measured in maternal plasma, in fetal plasma, and in amniotic fluid at the time of delivery. Total inulin uptake of the conceptus was taken to be the sum of the inulin in the amniotic fluid and in the newborn infant. Amniotic fluid volumes were measured by ultrasound examination, and the distribution volume of inulin in the neonate was assumed to be 180 ml/kg on the basis of animal experiments. The mean permeability was 0.15 microliter/(s.g) placenta. This value and the previously measured permeability for cyanocobalamin delimit a range of molecular weights from 1350 to 5200 daltons. In this range permeability to lipid-insoluble molecules is roughly proportional to the coefficients of free diffusion in water without further discrimination of molecular size by the placental barrier.

The prenatal diagnosis of an abdominal wall defect in the fetus has led some obstetricians to recommend delivery by cesarean section in order to avoid trauma to the defect and reduce the risk of dystocia. A review was made of the obstetric management of 112 infants with abdominal wall defects who were admitted to a neonatal surgical unit. Cesarean section was performed in 16%, but no cesarean sections were performed because of the prenatal diagnosis, which was made in only four cases. The mortality rate for infants with omphalocele was 29%, and that for infants with gastroschisis was 13.5%. Visceral injury from the delivery process was suggested in one case. Decisions about obstetric management were made in the absence of the knowledge of the anomaly, and vaginal delivery did not appear to adversely affect outcome. It remains to be seen whether more accurate prenatal diagnosis will identify subgroups of infants who would benefit by cesarean section. Until that time, elective cesarean section does not seem to be justified.

Serious short-term and long-term psychological sequelae may result from unresolved loss. It is now recognized that perinatal loss presents a situation where the early activation of the grief process may be prevented by the circumstances of the loss. Some theoretical aspects of the management of perinatal loss are considered together with a description of a program that has been set up to try to help to create some reality out of an unreal situation. The possible sequelae of unresolved loss are briefly reviewed.