Are auditory P300 and duration MMN heritable and putative endophenotypes of psychotic bipolar disorder? A Maudsley Bipolar Twin and Family Study.

BACKGROUND: Impaired P300 auditory response has been reported in patients with psychotic bipolar disorder (BPD) and unaffected relatives of psychotic bipolar patients. Deficits in mismatch negativity (MMN), however, have not been observed in bipolar patients. To our knowledge, no family study of MMN in BPD has been reported. The current study combined the Maudsley twin and bipolar family samples using genetic model fitting analyses to: (1) assess the relationship between BPD and MMN, (2) substantiate the association between psychotic BPD and P300 variables, (3) verify the genetic overlap of BPD with P300 amplitude previously reported in the twin sample, and (4) examine the shared genetic influences between BPD and bilateral temporal scalp locations of P300 components. METHOD: A total of 301 subjects were included in this study, including 94 twin pairs, 31 bipolar families, and 39 unrelated healthy controls. Statistical analyses were based on structural equation modelling. RESULTS: Both P300 and MMN are heritable, with heritability estimates of 0.58 for MMN, 0.68-0.80 for P300 amplitude, and 0.21-0.56 for P300 latency. The bipolar patients and their relatives showed normal MMN. No significant association, either genetic or environmental, was found with BPD. BPD was significantly associated with reduced P300 amplitude and prolonged latency on midline and bilateral temporal-posterior scalp areas. Shared genetic factors were the main source of these associations. CONCLUSIONS: The results confirm that MMN is not an endophenotype for psychotic BPD whereas P300 amplitude and latency components are valid endophenotypes for psychotic BPD.

Twins discordant for schizophrenia: psychopathology of the non-schizophrenic co-twins.

OBJECTIVE: Patients with schizophrenia are more likely to suffer from mood and anxiety disorders compared with the general population. We explored the aetiology of this comorbidity using a twin study design. METHOD: We applied an additive genetic + unique environment (AE) random effects model in the analysis of 35 non-schizophrenic co-twins from pairs discordant for schizophrenia, and 131 control twins. RESULTS: Non-schizophrenic co-twins had significantly increased rates of depression (P = 0.006) and anxiety disorders (P = 0.021) compared with the control twins. CONCLUSION: Our results provide evidence for a familial association between schizophrenia and anxiety and depression. This could reflect common aetiological factors contributing to each of the disorders. Future studies should attempt to investigate the relative genetic and environmental contribution to the shared risk factors for schizophrenia, mood and anxiety disorders.

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder1.

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.

Pharmacokinetics of 5-fluorouracil following different routes of intrahepatic administration in the canine model.

In an effort to achieve high concentrations of 5-fluorouracil (5-FUra) in the hepatic circulation while minimizing systemic exposure, several routes of intrahepatic administration were compared in the canine model. To ascertain these data, 5-FUra (30 mg/kg) was given as a bolus into either a systemic vein (femoral vein), hepatic artery, hepatic artery distal to its ligation after hepatic dearterialization, or through the portal vein. Three dogs were studied for each route with concomitant blood samples taken from the inferior vena cava and hepatic vein at 1, 2, 3, 5, 10, 15, 30, and 60 min after injection. 5-FUra levels were determined in plasma by high-pressure liquid chromatography. Blood flow in the portal vein and hepatic artery was measured by an electromagnetic flowmeter. The data were best described by a multicompartmental model including the measured flows. Hepatic components of the model were separate arterial and portal compartments, with elimination from each described by linear kinetics. Analysis of the results indicated that the highest hepatic levels with the least systemic exposure, as indicated by drug levels in hepatic and peripheral vein, were realized following hepatic artery administration distal to its ligation after hepatic dearterialization.

Biological and mechanical characteristics of the interface between a new swelling anchor and bone.

We recently evaluated the peak pullout loads for anchors made from our new copolymeric swelling-type material compared with anchors made of a nonswelling material. In vitro and in vivo peak pullout loads of these anchors were evaluated after different intervals of implantation in the lateral femoral condyles of New Zealand White rabbits. Scanning electron microscopy and energy dispersive x-ray analyses were additionally performed on selected retrieved samples after pullout to examine the characteristics of bone attachment to the implant. The mean peak pullout load was greater for the swelling anchors than for the nonswelling anchors after 48 hours in vitro (46.0 +/- 15.8 compared with 10.8 +/- 9.1 N, p = 0.0541). After 2 weeks in vivo, it was significantly greater for the swelling anchors than for the nonswelling controls (177.7 +/- 41.3 compared with 53.7 +/- 17.5 N, p = 0.0024). The peak pullout load was also greater for the swelling anchors after 8 weeks in vivo; however, this difference was less pronounced than at 2 weeks (101.8 +/- 35.0 compared with 58.9 +/- 9.7 N, p = 0.0508). Furthermore, the swelling implants tended to induce bone deposition at the bone-implant interface. Results from this investigation reveal that the new family of dynamic implants has potential for applications requiring fixation to cancellous or osteoporotic bone.

Chordae tendineae rupture resulting in pulmonary edema in a patient with discrete subvalvular aortic stenosis--a case report and literature review.

This report concerns an apparently healthy elderly woman who presented with gradually worsening mitral regurgitation secondary to chordae tendineae rupture leading to pulmonary edema in the presence of discrete subvalvular aortic stenosis with a severe gradient reflecting the left ventricular outflow tract obstruction. The gradual worsening of heart failure took place parallel to the increase in severity of mitral regurgitation in a short period. The patient underwent successful mitral valve replacement with myectomy. Surgical inspection revealed rupture of the chordae tendineae to the posterior leaflets without any significant primary intrinsic disease of the mitral valve. The predominant mechanism of chordae tendineae rupture in this patient with discrete subvalvular aortic stenosis is a severe pressure gradient. It is suggested that increased awareness of chordae tendineae rupture as a cause of mitral regurgitation and the prompt use of appropriate diagnostic tools may facilitate the timely recognition of this potentially fatal, but treatable, cause of mitral regurgitation in patients with left ventricular outflow tract obstruction.

No association of Disrupted-in-Schizophrenia-1 variation with prefrontal function in patients with schizophrenia and bipolar disorder.

The Disrupted-in-Schizophrenia-1 (DISC1) gene has been implicated in both schizophrenia and bipolar disorder by linkage and genetic association studies. Altered prefrontal cortical function is a pathophysiological feature of both disorders, and we have recently shown that variation in DISC1 modulates prefrontal activation in healthy volunteers. Our goal was to examine the influence of the DISC1 polymorphism Cys704Ser on prefrontal function in schizophrenia and bipolar disorder. From 2004 to 2008, patients with schizophrenia (N = 44), patients with bipolar disorder (N = 35) and healthy volunteers (N = 53) were studied using functional magnetic resonance imaging while performing a verbal fluency task. The effect of Cys704Ser on cortical activation was compared between groups as Cys704 carriers vs. Ser704 homozygotes. In contrast to the significant effect on prefrontal activation we had previously found in healthy subjects, no significant effect of Cys704Ser was detected in this or any other region in either the schizophrenia or bipolar groups. When controls were compared with patients with schizophrenia, there was a diagnosis by genotype interaction in the left middle/superior frontal gyrus [family-wise error (FWE) P = 0.002]. In this region, Ser704/ser704 controls activated more than Cys704 carriers, and there was a trend in the opposite direction in schizophrenia patients. In contrast to its effect in healthy subjects, variation in DISC1 Cys704Ser704 genotype was not associated with altered prefrontal activation in patients with schizophrenia or bipolar disorder. The absence of an effect in patients may reflect interactions of the effects of DISC1 genotype with the effects of other genes associated with these disorders, and/or with the effects of the disorders on brain function.

Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces.

A distributed, serotonergically innervated neural system comprising extrastriate cortex, amygdala and ventral prefrontal cortex is critical for identification of socially relevant emotive stimuli. The extent to which a genetic variation of serotonin transporter gene 5-HTTLPR impacts functional connectivity between the amygdala and the other components of this neural system remains little examined. In our study, neural activity was measured using event-related functional magnetic resonance imaging in 29 right-handed, white Caucasian healthy subjects as they viewed mild or prototypical fearful and neutral facial expressions. 5-HTTLPR genotype was classified as homozygous for the short allele (S/S), homozygous for the long allele (L/L) or heterozygous (S/L). S/S showed greater activity than L/L within right fusiform gyrus (FG) to prototypically fearful faces. To these fearful faces, S/S more than other genotype subgroups showed significantly greater positive functional connectivity between right amygdala and FG and between right FG and right ventrolateral prefrontal cortex (VLPFC). There was a positive association between measure of psychoticism and degree of functional connectivity between right FG and right VLPFC in response to prototypically fearful faces. Our data are the first to show that genotypic variation in 5-HTTLPR modulates both the amplitude within and the functional connectivity between different components of the visual object-processing neural system to emotionally salient stimuli. These effects may underlie the vulnerability to mood and anxiety disorders potentially triggered by socially salient, emotional cues in individuals with the S allele of 5-HTTLPR.

Role of imaging end points in atherosclerosis trials: focus on intravascular ultrasound.

Increasing attention has been focused on the appropriate role of surrogate markers in the development of novel anti-atherosclerotic therapies. Technological advances in imaging modalities allow for visualisation of the entire arterial wall. Intravascular ultrasound (IVUS) has been increasingly employed to precisely quantify the extent of coronary atherosclerosis. Use of IVUS has provided a number of important insights into the natural history of atherosclerosis and the remodelling changes of the arterial wall in response to plaque accumulation. More recently, clinical trials have employed serial evaluations of arterial segments by IVUS to assess the impact of medical therapies.

Dynamic elastic hysteretic solids and dislocations.

Recently we showed that the quasistatic response of nonlinear mesoscopic elastic solids to stress can be explained by invoking the formation of dislocation-based incipient kink bands. In this Letter, using resonant ultrasound spectroscopy, we confirm that the dynamical behavior of these nonlinear elastic systems is due to the interaction of dislocations with the ultrasound waves, thus resolving a long-standing mystery.

A numerical investigation of the mechanics of swelling-type intramedullary hip implants.

The novel concept of swelling-type intramedullary hip implants that attain self-fixation by an expansion-fit mechanism resulting from controlled swelling of the implant (by absorption of body fluids) was examined in detail using a finite element model of the implant-femur system. Some of the potential advantages of this technique over traditional techniques include enhanced fixation, lower relative micromotions, improved bony ingrowth, and elimination of acrylic cement. The finite element model created in this study incorporated: (i) the major aspects of the three-dimensional geometry of the implant and femur, (ii) the anisotropic elastic properties of bone and implant materials and the changes in orientation of the principal axes of anisotropy along the length of the implant-femur system, (iii) a layer of cancellous bone between the implant and cortical bone in the proximal femoral region, and (iv) frictional sliding between the bone and implant. The model was used to study quantitatively the parametric influence of various material design variables on the micromotions and stress fields in the bone-swelling-type implant system. The results of the finite element analyses were used to establish material behavior goals and provide targets for a material development study.

Fixation strength of swellable bone anchors in low-density polyurethane foam.

This study represents a natural extension of our previous efforts in the design and development of a new class of swellable bone anchors, which absorb body fluids and achieve fixation by an expansion-fit mechanism. Specifically, this study investigates (i) correlations between the optimal swelling strain for highest fixation strength and the foam (or bone) density, and (ii) the influence of a threaded surface on the fixation strength of the swellable implant. For this purpose, the immediate and the final (after swelling) fixation strengths of two variations of the swellable bone anchor designs (a smooth anchor and a screw anchor) were measured in two different foams (used to simulate bone) with different densities. The amount of swelling was varied systematically for each foam and anchor design combinations. This study indicates that the screw swellable anchors have higher initial fixation strength than smooth swellable anchors, but the final fixation strengths of both anchors are quite similar. Further, it is observed that the optimal swelling strain decreased with increasing foam density. Both the smooth and screw swellable anchors were also found to exhibit higher fixation strengths than the metallic screws of similar geometry.

Development of self-anchoring bone implants. I. Processing and material characterization.

We recently designed and produced a family of new swelling-type materials that are potentially capable of self-fixation in bone. These materials are designed to absorb body fluids and swell by small amounts, which will allow the implants made from these materials to achieve self-fixation by an expansion-fit mechanism. The developed material system is essentially a crosslinked random copolymer based on poly (methyl methacrylate-acrylic acid). For potential structural (load-bearing) bioimplant applications, we reinforced this copolymer with AS-4 carbon and Kevlar 49 fibers. The details of processing these materials and the steps involved in optimizing their microstructures are presented in this article. A set of mechanical tests were performed on these materials in both dry and swollen conditions to measure their moduli and yield strengths. In the dry state, the copolymers were found to exhibit Young's moduli in the range of 3 to 4 GPa and yield strengths in the range of 70 to 85 MPa. The reinforced composites exhibited moduli in the range of 15 to 65 GPa and yield strengths in the range of 125 to 500 MPa. Upon controlling the volumetric swelling in these materials to be less than about 10%, the loss in mechanical properties was found to be less than about 30%. These hygromechanical properties are well suited for self-anchoring bone implant applications.

Development of self-anchoring bone implants. II. Bone-implant interface characteristics in vitro.

A new swelling copolymeric material suitable for self-anchoring bone implants was introduced in part I of this two-part article. The main goal in the second part of the study was to investigate the in vitro fixation characteristics of these novel implants in bone using push-out mechanical testing. Specifically, we examined the various factors that influence the in vitro fixation levels achieved by these anchors and identified a range of copolymer compositions that provide good fixation characteristics for these implants. The factors studied included the copolymer composition, presence of AS-4 carbon fiber reinforcement, and the time of implantation (in an environment of saline solution). The push-out tests were conducted on smooth cylindrical plugs of the swelling materials that were implanted in bovine cortical bone. The bone-implant system was then immersed in saline solution for various periods of time ranging from 1 to 28 days prior to push-out testing. The refixation characteristics of the implants were also investigated in this study by performing repeated push-out tests on a single implant without completely dislodging the implant from the bone. Holding strengths comparable and often exceeding many current orthopedic fixation techniques were obtained (push-out load exceeding 1000 N and shear strength exceeding 7 MPa) with the implant having 80/20 to 70/30 methyl methacrylate/acrylic acid ratios. Furthermore, more than 80% of the ultimate holding strength could be achieved within 7 days of implantation at ambient temperature for the 80/20 composite implants. Excellent refixation properties were demonstrated in which the implant regained its full holding strength in the bone immediately after an initial failure. These results indicate great potential for the possible use of these implants for orthopedic applications such as suture anchoring and internal fracture fixations.

Fully reversible, dislocation-based compressive deformation of Ti3SiC2 to 1 GPa.

Dislocation-based deformation in crystalline solids is almost always plastic. Here we show that polycrystalline samples of Ti3SiC2 loaded cyclically at room temperature, in compression, to stresses up to 1 GPa, fully recover on the removal of the load, while dissipating about 25% (0.7 MJ x m(-3)) of the mechanical energy. The stress-strain curves outline fully reversible, rate-independent, closed hysteresis loops that are strongly influenced by grain size, with the energy dissipated being significantly larger in the coarse-grained material. At temperatures greater than 1,000 degrees C, the loops are open, the response is strain-rate dependent, and cyclic hardening is observed. This hitherto unreported phenomenon is attributed to the reversible formation and annihilation of incipient kink bands at room-temperature deformation. At higher temperatures, the incipient kink bands dissociate and coalesce to form regular irreversible kink bands. The loss factor for Ti3SiC2 is higher than most woods, and comparable to polypropylene and nylon. The technological implications of having a stiff, lightweight machinable ceramic that can dissipate up to 25% of the mechanical energy per cycle are discussed.

Kinking nonlinear elastic solids, nanoindentations, and geology.

The physical mechanism responsible for nonlinear elastic, hysteretic, and discrete memory response of nonlinear mesoscopic elastic solids has to date not been identified. We show, by nanoindenting mica single crystals, that this response is most likely due to the formation of dissipative and fully reversible, dislocation-based kink bands. We further claim that solids with high c/a ratios, which per force are plastically anisotropic, should deform by kinking, provided they do not twin. These kinking nonlinear elastic solids include layered ternary carbides, nitrides, oxides, and semiconductors, graphite, and the layered phases, such as mica, present in nonlinear mesoscopic elastic solids.