Genetic and phenotypic overlap of specific obsessive-compulsive and attention-deficit/hyperactive subtypes with Tourette syndrome.

BACKGROUND: The unique phenotypic and genetic aspects of obsessive-compulsive (OCD) and attention-deficit/hyperactivity disorder (ADHD) among individuals with Tourette syndrome (TS) are not well characterized. Here, we examine symptom patterns and heritability of OCD and ADHD in TS families. METHOD: OCD and ADHD symptom patterns were examined in TS patients and their family members (N = 3494) using exploratory factor analyses (EFA) for OCD and ADHD symptoms separately, followed by latent class analyses (LCA) of the resulting OCD and ADHD factor sum scores jointly; heritability and clinical relevance of the resulting factors and classes were assessed. RESULTS: EFA yielded a 2-factor model for ADHD and an 8-factor model for OCD. Both ADHD factors (inattentive and hyperactive/impulsive symptoms) were genetically related to TS, ADHD, and OCD. The doubts, contamination, need for sameness, and superstitions factors were genetically related to OCD, but not ADHD or TS; symmetry/exactness and fear-of-harm were associated with TS and OCD while hoarding was associated with ADHD and OCD. In contrast, aggressive urges were genetically associated with TS, OCD, and ADHD. LCA revealed a three-class solution: few OCD/ADHD symptoms (LC1), OCD & ADHD symptoms (LC2), and symmetry/exactness, hoarding, and ADHD symptoms (LC3). LC2 had the highest psychiatric comorbidity rates (⩾50% for all disorders). CONCLUSIONS: Symmetry/exactness, aggressive urges, fear-of-harm, and hoarding show complex genetic relationships with TS, OCD, and ADHD, and, rather than being specific subtypes of OCD, transcend traditional diagnostic boundaries, perhaps representing an underlying vulnerability (e.g. failure of top-down cognitive control) common to all three disorders.

The genetic architecture of pediatric cognitive abilities in the Philadelphia Neurodevelopmental Cohort.

The objective of this analysis was to examine the genetic architecture of diverse cognitive abilities in children and adolescents, including the magnitude of common genetic effects and patterns of shared and unique genetic influences. Subjects included 3689 members of the Philadelphia Neurodevelopmental Cohort, a general population sample comprising those aged 8-21 years who completed an extensive battery of cognitive tests. We used genome-wide complex trait analysis to estimate the SNP-based heritability of each domain, as well as the genetic correlation between all domains that showed significant genetic influence. Several of the individual domains suggested strong influence of common genetic variants (for example, reading ability, h(2)g=0.43, P=4e-06; emotion identification, h(2)g=0.36, P=1e-05; verbal memory, h(2)g=0.24, P=0.005). The genetic correlations highlighted trait domains that are candidates for joint interrogation in future genetic studies (for example, language reasoning and spatial reasoning, r(g)=0.72, P=0.007). These results can be used to structure future genetic and neuropsychiatric investigations of diverse cognitive abilities.

Genome-wide association study of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Efficiency of molar distalization with the XBow appliance related to second molar eruption stage.

To quantitatively evaluate on lateral cephalograms horizontal, vertical, and angular changes in the position of the maxillary first molar based on the presence and absence of erupted maxillary second molars when it is distalized with the XBow appliance. In this retrospective study, a total of 102 consecutively treated cases were assessed. Lateral cephalograms were obtained at the start and after completion of active treatment with the XBow appliance. In one group of patients, distal movement of the maxillary first molars was performed before the eruption of maxillary second molars; in the other group of patients, both first and second maxillary molars were simultaneously moved distally. All cephalograms were superimposed on palatal plane using the method of best-fit. In order to compare the mean horizontal, vertical, and angular changes in molar position between the treatment groups and gender, a multivariate analysis of covariance (MANCOVA) was performed with the pre-treatment class II severity used as a covariate. Regression analysis was also performed to further explore any possible relationships between the predictor variables and the quantity and quality of distalization. A MANCOVA revealed that the eruption stage of the maxillary second molar did not have a significant effect on the change in position of the maxillary first molar after treatment with a XBow appliance. When distalizing maxillary first molars with a XBow appliance, there is no difference in the amount of distalization in patients with erupted and unerupted maxillary second molars.

A latent modeling approach to genotype-phenotype relationships: maternal problem behavior clusters, prenatal smoking, and MAOA genotype.

This study illustrates the application of a latent modeling approach to genotype-phenotype relationships and gene × environment interactions, using a novel, multidimensional model of adult female problem behavior, including maternal prenatal smoking. The gene of interest is the monoamine oxidase A (MAOA) gene which has been well studied in relation to antisocial behavior. Participants were adult women (N = 192) who were sampled from a prospective pregnancy cohort of non-Hispanic, white individuals recruited from a neighborhood health clinic. Structural equation modeling was used to model a female problem behavior phenotype, which included conduct problems, substance use, impulsive-sensation seeking, interpersonal aggression, and prenatal smoking. All of the female problem behavior dimensions clustered together strongly, with the exception of prenatal smoking. A main effect of MAOA genotype and a MAOA × physical maltreatment interaction were detected with the Conduct Problems factor. Our phenotypic model showed that prenatal smoking is not simply a marker of other maternal problem behaviors. The risk variant in the MAOA main effect and interaction analyses was the high activity MAOA genotype, which is discrepant from consensus findings in male samples. This result contributes to an emerging literature on sex-specific interaction effects for MAOA.

Integration and decontamination of Bacillus cereus in Pseudomonas fluorescens biofilms.

AIMS: The hypothesis that surrogate planktonic pathogens (Bacillus cereus and polystyrene microspheres) could be integrated in biofilms and protected from decontamination was tested. METHODS AND RESULTS: Pseudomonas fluorescens biofilms were grown on polyvinyl chloride coupons in annular reactors under low nutrient conditions. After biofilm growth, B. cereus spores and polystyrene microspheres (an abiotic control) were introduced separately. Shear stress at the biofilm surface was varied between 0.15 and 1.5 N m(-2). The amount of surrogate pathogens introduced ranged from approximately 10(5) CFU ml(-1) to 10(10 )spheres ml(-1). The quantity of surrogate pathogens integrated in the biofilm was proportional to the amount introduced. In 14 of the 16 cases, 0.4-3.0% of the spores or spheres introduced were measured in the biofilms. The other two cases had 10% and 21% of the spores detected. Data suggested that the spores germinated in the system. The amount of surrogate pathogens detected in the biofilms was higher in the mid-shear range. Chlorine treatment reduced the quantity of both surrogate pathogens and biofilm organisms. In one experiment, the biofilms and B. cereus recovered when the chlorine treatment was terminated. CONCLUSIONS: Planktonic surrogate pathogens can be integrated in biofilms and protected from chlorination decontamination. SIGNIFICANCE AND IMPACT OF THE STUDY: This knowledge assists in understanding the impact of biofilms on harbouring potential pathogens in drinking-water systems and protecting the pathogens from decontamination.

Agents and spectres: Life-space on a medium secure forensic psychiatric unit.

Medium secure forensic psychiatric units are unique environments within the broader 'post asylum' landscape of mental health services. Length of stay is much greater, a recovery-focused care system is much more difficult to implement, and there is a paucity of suitable "step-down" services. The aim of this study was to examine how forensic psychiatric environments contribute to the shaping of recovery, by examining key features such as social interactions and agency. Here, we report on the findings from patients participating in a qualitative-visual study. This analysis forms part of larger study on staff and patient experiences of secure hospital space. In this paper, the analytical focus is directed towards two key elements of recovery - agency and relationality, using the concept of 'topology' and 'life-space', developed by the social psychologist Kurt Lewin. First, we explore how patients have relative freedom to move within institutional spaces, yet lack relational space. Secondly, we explore how life-space is expanded or compressed by the manner in which the patient's present life in hospital is connected or disconnected from their past or pending future. Finally, we discuss the implications of these findings for a recovery model within secure forensic settings, focused on personalisation and expanded life-space.

Protein Separation and Hemocompatibility of Nitride Membranes in Microfluidic Filtration Systems.

Improving the health outcomes for end-stage renal Disease (ESRD) patients on hemodialysis (HD) requires new technologies for wearable HD such as a highly efficient membrane that can achieve standard toxic clearance rates in small device footprints. Our group has developed nanoporous silicon nitride (NPN) membranes which are 100 to 1000 times thinner than conventional membranes and are orders-ofmagnitude more efficient for dialysis. Counter flow dialysis separation experiments were performed to measure urea clearance while microdialysis experiments were performed in a stirred beaker to measure the separation of cytochrome-c and albumin. Hemodialysis experiments testing for platelet activation as well as protein adhesion were performed. Devices for the counter flow experiments were constructed with polydimethylsiloxane (PDMS) and a NPN membrane chip. The counter flow devices reduced the urea by as much as 20%. The microdialysis experiments showed a diffusion of ~ 60% for the cytochrome-c while clearing ~ 20% of the Albumin. Initial hemocompatibility studies show that the NPN membrane surface is less prone to both protein adhesion and platelet activation when compared to positive control (glass).

Formation of a lipid gradient across the human aortic wall during ageing and the development of atherosclerosis.

The smooth muscle cell invasion and macrophage stimulation within the intima during prolonged exposure to high blood levels of cholesterol esters contribute to increased production of connective tissue matrix. The thickened intima in turn immobilising more LDL derived lipid from the plasma. With damage to the internal elastic lamellae, from essential hypertension, the absorbed lipid can move down a concentration gradient into the medial tissue. This model was supported by our laboratory finding of a lipid gradient across the aorta wall. The gradient commenced shortly after completion of body growth, when the transmedial gradient became detectable. The slope of the gradient progressively increased during ageing. Association of the lipid medial gradient with the degree of atherosclerotic involvement suggested that the gradient influenced the development of intimal lesions. Accumulation of lipid within the medial tissue may then reduce the inward lipid transfer rate from the intima, promoting increased intimal retention and cause the formation of atherosclerotic plaques from the fat saturated intima.

Effect of dietary fish oil supplementation on peroxidation of serum lipids in patients with non-insulin dependent diabetes mellitus.

Lipid peroxidation may be important in the development of cardiovascular disease, a common cause of mortality and morbidity in non-insulin dependent diabetes mellitus (NIDDM). We assessed the degree of lipid peroxidation by measuring plasma malondialdehyde, as thiobarbituric acid reacting substances (TBARS), in 23 non-insulin diabetic patients. Plasma levels of standardised alpha-tocopherol (vitamin E), lipid content of whole plasma and lipoprotein fractions, glycosylated haemoglobin, glycosylated low density lipoprotein (LDL) and fasting blood glucose were also measured. On completion of the baseline studies patients randomly received either fish oil or matching olive oil capsules in a double blind crossover fashion for 6 weeks followed by a 6 week washout period and a final 6 week treatment phase. Studies, identical to the initial baseline studies, were performed at the end of the of the active treatment periods at 6 and 18 weeks. Treatment with olive oil did not change levels of TBARS, vitamin E or indices of glycaemic control compared with baseline. Total cholesterol and triglyceride (TG) content of plasma and lipoprotein fractions were not significantly altered. Treatment with fish oil resulted in elevation of TBARS (P < 0.001) and reduction of vitamin E (P < 0.01) compared with baseline and olive oil treatment. Plasma cholesterol was unchanged. A reduction in plasma TG compared with baseline occurred but failed to reach significance (P =0.07). Changes in apo B containing lipoproteins induced by fish oil failed to reach significance. No significant changes were observed in concentration or composition of high density lipoprotein (HDL). Fish oil treatment showed no change in glycaemic control as assessed by glycosylated haemoglobin and LDL although a rise in fasting blood glucose just failed to reach significance (P = 0.06). Lipid peroxidation in NIDDM can be exacerbated by dietary fish oil. This potentially adverse reaction may limit the therapeutic use of fish oils in such patients.

Localized endocrine conversion of ventricular cardiocytes in ventricular aneurysm.

Atrial natriuretic peptide (ANP) is synthesized and stored in the atria of the heart, but not or at very low concentrations in the ventricles. We investigated the occurrence of ANP and its messenger RNA (mRNA) in human ventricular aneurysm where the cardiocytes were physically over-stretched. The techniques of light and electron microscopic immunocytochemistry, and RNA-RNA tissue in situ hybridization were employed. A large amount of ANP immunoreactivity was found in the cytoplasm of the cardiocytes in and around the aneurysm, but not in fibrous scar tissue or in the normal ventricles. Immunoelectron microscopy localized the immunoreactivity mainly to specific secretory granules in the cytoplasm of the cardiocytes. ANP mRNA was also detected in these cardiocytes. The abundance of both was much higher than that found in the hypertrophic ventricles of other types. The highest concentration of ANP immunoreactivity and of ANP mRNA was found in the cardiocytes located at the border zone. The quantities of both ANP and its mRNA decreased in cardiocytes more distant from the lesion. Our findings suggest that human ventricular cardiocytes in and around aneurysm can convert to produce large amounts of the endocrine peptide ANP. This ventricular endocrine conversion was localized and was probably caused by physical over-stretch of the cardiocytes.

Actuarial survival, freedom from reoperation, and other events after repair of atrioventricular septal defects.

Repair of an atrioventricular septal defect was performed in 134 patients from 1973 to 1985. Interventricular communication was present in 54 (40%) and none was present in 80 (60%). There were 12 hospital deaths (9%; 70% confidence limits 6%-12%). Earlier date of operation (p = 0.03) and younger age at repair (p = 0.005) were incremental risk factors for hospital death after repair of partial atrioventricular septal defect. Smaller size (p = 0.003) and longer cross-clamp time (p = 0.002) were risk factors for hospital death in those patients with complete atrioventricular septal defect. Higher preoperative pulmonary vascular resistance was a risk factor for death in both groups (p = 0.007). The 10 year actuarial survival rate was 82% overall. Increasing preoperative severity of left atrioventricular valve incompetence was not a risk factor for early (p = 0.001) or late (p = 0.002) death. The 10 year actuarial freedom from reoperation after repair of partial atrioventricular defects was 85%, and it was 68% for complete atrioventricular defects (p = 0.06). We conclude that the intermediate term results after repair of atrioventricular septal defects are good. Incompetence of the left atrioventricular valve has apparently been neutralized as a risk factor for hospital death in this series. However, the durability of the repair has been disappointing. A policy of earlier repair has been adopted and should improve hospital mortality and permit better preservation of the atrioventricular valve structures with resultant improved late term functional status.

Determination of the need for a ventriculotomy in the repair of tetralogy of Fallot.

Fifty-two patients with tetralogy of Fallot underwent repair between March 1985 and July 1987. The repair was made without a ventriculotomy whenever feasible. There were no (0%) early or late-phase deaths (70% confidence limits 0% to 3.6%). Operative reports and preoperative angiocardiograms were retrospectively reviewed to delineate determinants for operative approach. Two distinct morphologic subgroups were observed angiographically and confirmed intraoperatively. Thirty-two patients (62%) had severe hypertrophy of the infundibular septal structures. Each of these 32 underwent transatrial and transpulmonary repair of the infundibular stenosis, and 12 of them also required a limited ventriculotomy to enlarge a hypoplastic pulmonary valve anulus. The other 20 patients (38%) were found to have hypoplasia and not hypertrophy of the infundibular septum. Each of these required a formal transventricular approach to the repair with an infundibular patch inserted to relieve the infundibular stenosis. Right ventricular/left ventricular systolic pressure ratios after repair were not different between the groups (p = 0.79). In conclusion, tetralogy of Fallot was satisfactorily repaired by means of a transatrial and transpulmonary approach in two thirds of these patients. The avoidance of a ventriculotomy to accomplish repair may be suggested preoperatively by selective angiocardiogram and confirmed by intraoperative assessment. These findings have important implications for the development of treatment protocols.

Secondary left atrioventricular valve replacement in atrioventricular septal (AV canal) defect: a method to avoid left ventricular outflow tract obstruction.

Patients with atrioventricular septal defects are morphologically predisposed to subaortic obstruction. Some individuals require secondary left atrioventricular valve replacement for severe incompetence persisting after repair, and they are especially susceptible to left ventricular outflow tract obstruction. A surgical technique is described for replacement of the atrioventricular valve which seems to avoid the complication of left ventricular outflow tract obstruction by the prosthesis.

Safety of the right atrial approach for combined mitral and tricuspid valve procedures.

Patients undergoing operation for combined mitral and tricuspid valvular disease may have the repair performed through the right atrium and the interatrial septum. Although the transseptal method is an established procedure, recent reports have stressed the disadvantages of this operation and underscored the risk of the development of complete atrioventricular dissociation with this technique. A review of our results with this approach confirms the efficacy and safety of this method. The surgical protocols used are described.

Heat shock protein (HSP 72) expression in patients undergoing cardiac operations.

The major mammalian stress-inducible protein, heat shock protein 72, protects cells from certain stresses and rapidly accumulates in cells after ischemia. Heat shock protein 72 is rapidly synthesized in the myocardium of various species in response to ischemia, but it has not been investigated in human heart. To determine if heat shock protein 72 accumulated in the ischemic myocardium of patients undergoing cardiac operations, we obtained sequential right atrial biopsy specimens from 12 patients undergoing repair at three intervals: before bypass, after reperfusion, and after bypass. Immunoblot analysis for heat shock protein 72 demonstrated a high expression in the human heart compared with other mammalian hearts, p (Binomial) = 0.01. Compared with before bypass, heat shock protein 72 contents after reperfusion and after bypass were 98.2% +/- 8.9%, p (signed-rank) = 0.65, and 87.6% +/- 17.1%, p (signed-rank) = 0.28, respectively. Although heat shock protein 72 concentration was unchanged in hearts after reperfusion and after bypass, the initial prebypass level of heat shock protein 72 was high. The high heat shock protein 72 level detected in human hearts may reflect preoperative disease and drug therapy, or inherently high levels may be usual in the human myocardium. These findings indicate that the myocardium of patients undergoing cardiac operations contains relatively high concentrations of heat shock protein 72, which are not increased during the surgical procedure.

Efficacy of combined coronary revascularization and valve procedures in octogenarians.

From January 1982 to October 1991, 42 consecutive patients 80 years of age and older underwent a combined cardiac procedure with coronary revascularization and valve repair or replacement. There were 20 women and 22 men. Mean age at operation was 82.8 years (range, 80 to 89.7 years). Twenty-seven patients (64%) were in New York Heart Association (NYHA) functional class III or IV preoperatively. Six patients (14.3%) had undergone previous cardiac procedures. There were six hospital deaths (14.3%). The only significant preoperative risk factor identified for the event hospital death was aortic insufficiency (p = 0.005). The 36 hospital survivors were followed up at a mean of 21.1 months after hospital discharge. There were nine (21%) late deaths occurring at a mean of 21.3 months postoperatively: two from acute myocardial infarctions and seven from chronic heart failure. Survival analysis indicated that higher preoperative NYHA class (p = 0.0003), hypertension (p = 0.015), hypercholesterolemia (p = 0.03), and elevated left atrial/left ventricular gradient (p = 0.04) were incremental risk factors for overall mortality. The actuarial survival at 40 months was 51.9%, with no significant difference as compared with an age-, sex-, and race-matched population. Of the 27 late survivors, 26 were in NYHA class I or II. We conclude that octogenarians may undergo complex cardiac surgical procedures with an expectation of an acceptable mortality rate and significant improvement in their functional status. These results must be taken into consideration in light of reported strategies to ameliorate health-care costs by limiting availability of complex medical care to the elderly.

Effect of adenosine triphosphate on the postischemic left ventricular function of the immature myocardium.

In this study, the effect of exogenous adenosine triphosphate (ATP) on the immature myocardium was evaluated. Isolated working neonatal rabbit hearts were perfused aerobically for 15 min with Krebs-Henseleit buffer (KHB) at 37 degrees C, and then arrested with St. Thomas solution (STS) in group 1 and STS containing 500 mumol/L of ATP in group 2 at 4 degrees to 6 degrees C and maintained at 10 degrees to 14 degrees C for 60 min. Hearts were reperfused with KHB aerobically at 37 degrees C for 15 min. Each heart served as its own control before and after arrest. Systolic function was significantly depressed in group 1 compared with group 2. There was a significant decrease in the peak left ventricular (LV) systolic pressure in group 1 (preischemia mean [PIM] 54 mm Hg to postischemia mean [PoIM] 42 mm Hg, Student's t test p = 0.007) than in group 2 (PIM 66 to PoIM 62 mm Hg, p = 0.5). The LV pulse pressure decreased in group 1 (PIM 72 to PoIM 54 mm Hg, p = 0.02) but not in group 2 (PIM 84 to PoIM 86 mm Hg, p = 0.9) and the rate of rise of LV pressure (dP/dT) in group 2 improved (PIM 5718 to PoIM 6926 mm Hg, p = 0.4) compared with group 1 (PIM 7021 to PoIM 4125 mm Hg, p = 0.008). The PoIM LV flow (LVF) was greater in group 2 than group 1 (LVF group 1 = 2.7 ml/min, group 2 = 4.5 ml/min). Diastolic pressures were not significantly different in the two groups. Our findings suggest that the incorporation of ATP in STS has a significant effect in improving postischemic LV systolic function in neonatal rabbit hearts.

Factors determining in-hospital or late survival after aortic valve replacement.

To ascertain incremental risk factors for in-hospital and late mortality of patients undergoing AVR with the bovine pericardial valve, multiple variables were analyzed in a group of 240 patients undergoing AVR between 1977 and 1983. Follow-up totaled 12,023 patient-months (mean, 52.7 +/- 1.7 patient-months) and was 100 percent complete. Univariate analysis of incremental risk factors for in-hospital mortality identified the following: age over 60 years (p = 0.015); and advanced preoperative NYHA class (p = 0.003). Multivariate analysis of risk factors for in-hospital mortality identified the following: age (p = 0.038); NYHA class (p = 0.018); and year of operation (p = 0.049). Incremental risk factors for late mortality were identified as age (p = 0.003), year of operation (p = 0.003), concomitant procedure (p = 0.047), and valvular lesion (regurgitation) (p = 0.053). Actuarial survival of patients (+/- SE) was 87 +/- 2 percent, 75 +/- 3 percent, and 61 +/- 5 percent at 2, 5, and 8.7 years, respectively. The actuarial survival of patients experiencing valve-related events was 62.6 +/- 10.1 percent at 8.7 years, compared to 55.4 +/- 7 percent for those who did not (p = 0.38).

The experimental relationship between leaflet clearance and orientation of the St. Jude Medical valve in the mitral position.

The optimal orientation of the St. Jude Medical mechanical prosthesis in the mitral position has not yet been determined. While in the majority of cases the valve can perform satisfactorily regardless of valve orientation, certain circumstances can increase the risk of leaflet impingement. These valves are commonly implanted with their leaflets oriented parallel to the anatomic axis of the native leaflets (anatomic orientation) or with their prosthetic leaflets perpendicular to the axis of the native leaflets (antianatomic orientation). To determine the influence of valve orientation on the clearance from the prosthetic leaflet to the posterior ventricular wall, we calculated the clearances on all available models of the St. Jude Medical mitral valve. Clearances were computed from measurements of valve dimensions with use of an electronic caliper. In all cases the clearance in antianatomic orientation was at least 49.5% greater (mean 59%, range 49.5% to 77.5%) than in anatomic orientation.