Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.

Analysis of myelinated axon formation in zebrafish.

Myelin is a lipid-rich sheath formed by the spiral wrapping of specialized glial cells around axon segments. Myelinating glia allow for rapid transmission of nerve impulses and metabolic support of axons, and the absence of or disruption to myelin results in debilitating motor, cognitive, and emotional deficits in humans. Because myelin is a jawed vertebrate innovation, zebrafish are one of the simplest vertebrate model systems to study the genetics and development of myelinating glia. The morphogenetic cellular movements and genetic program that drive myelination are conserved between zebrafish and mammals, and myelin develops rapidly in zebrafish larvae, within 3-5days postfertilization. Myelin ultrastructure can be visualized in the zebrafish from larval to adult stages via transmission electron microscopy, and the dynamic development of myelinating glial cells may be observed in vivo via transgenic reporter lines in zebrafish larvae. Zebrafish are amenable to genetic and pharmacological screens, and screens for myelinating glial phenotypes have revealed both genes and drugs that promote myelin development, many of which are conserved in mammalian glia. Recently, zebrafish have been employed as a model to understand the complex dynamics of myelinating glia during development and regeneration. In this chapter, we describe these key methodologies and recent insights into mechanisms that regulate myelination using the zebrafish model.

Altered functioning of reward circuitry in youth offspring of parents with bipolar disorder.

BACKGROUND: Offspring of parents with bipolar disorder (BD) (BO) are at higher risk of BD than offspring of parents with non-BD psychopathology (NBO), although both groups are at higher risk than offspring of psychiatrically healthy parents (HC) for other affective and psychiatric disorders. Abnormal functioning in reward circuitry has been demonstrated previously in individuals with BD. We aimed to determine whether activation and functional connectivity in this circuitry during risky decision-making differentiated BO, NBO and HC. METHOD: BO (n = 29; mean age = 13.8 years; 14 female), NBO (n = 28; mean age = 13.9 years; 12 female) and HC (n = 23; mean age = 13.7 years; 11 female) were scanned while performing a number-guessing reward task. Of the participants, 11 BO and 12 NBO had current non-BD psychopathology; five BO and four NBO were taking psychotropic medications. RESULTS: A 3 (group) × 2 (conditions: win-control/loss-control) analysis of variance revealed a main effect of group on right frontal pole activation: BO showed significantly greater activation than HC. There was a significant main effect of group on functional connectivity between the bilateral ventral striatum and the right ventrolateral prefrontal cortex (Z > 3.09, cluster-p < 0.05): BO showed significantly greater negative functional connectivity than other participants. These between-group differences remained after removing youth with psychiatric disorders and psychotropic medications from analyses. CONCLUSIONS: This is the first study to demonstrate that reward circuitry activation and functional connectivity distinguish BO from NBO and HC. The fact that the pattern of findings remained when comparing healthy BO v. healthy NBO v. HC suggests that these neuroimaging measures may represent trait-level neurobiological markers conferring either risk for, or protection against, BD in youth.

The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38(SAPK) pathway.

Neurofibromatosis type 2 patients develop schwannomas, meningiomas and ependymomas resulting from mutations in the tumor suppressor gene, NF2, encoding a membrane-cytoskeleton adapter protein called merlin. Merlin regulates contact inhibition of growth and controls the availability of growth factor receptors at the cell surface. We tested if microtubule-based vesicular trafficking might be a mechanism by which merlin acts. We found that schwannoma cells, containing merlin mutations and constitutive activation of the Rho/Rac family of GTPases, had decreased intracellular vesicular trafficking relative to normal human Schwann cells. In Nf2-/- mouse Schwann (SC4) cells, re-expression of merlin as well as inhibition of Rac or its effector kinases, MLK and p38(SAPK), each increased the velocity of Rab6 positive exocytic vesicles. Conversely, an activated Rac mutant decreased Rab6 vesicle velocity. Vesicle motility assays in isolated squid axoplasm further demonstrated that both mutant merlin and active Rac specifically reduce anterograde microtubule-based transport of vesicles dependent upon the activity of p38(SAPK) kinase. Taken together, our data suggest loss of merlin results in the Rac-dependent decrease of anterograde trafficking of exocytic vesicles, representing a possible mechanism controlling the concentration of growth factor receptors at the cell surface.

Effects of diet composition on intake by adult wild European rabbits.

The voluntary dry matter intake (DMI) of several grass and legume diets, and the amount of dry matter (DM), nitrogen, fibre, and energy assimilated from each diet (i.e. the digestibility coefficients) are presented for the wild European rabbit Oryctolagus cuniculus. The DMI may be predicted from DM% and percentage of total nitrogen (on a DM basis) for a high DM diet (90-95%) but the general relationship may stand for fresh forage also. The metabolizable energy of a diet is correlated with DMI through the DM% and the percentage of nitrogen and fibre in the diet on a DM basis. The DM digestibility coefficient is correlated with fibre content. The wild rabbit's high efficiency of protein digestibility and low fibre digestibility compared with ruminants is also a characteristic of the domestic rabbit. It is suggested that the proportions of different nutrients required by wild rabbits are similar to those required by domestic animals.

Effects of theophylline and salbutamol on phosphate and calcium metabolism in normal subjects.

The acute effects of oral theophylline and salbutamol were studied in a randomised double-blind crossover study in 12 normal subjects. Theophylline resulted in a significant fall in plasma phosphate and a small rise in urine phosphate excretion which did not, however, account for the fall in plasma phosphate. The increase in urine phosphate excretion was accompanied by a rise in sodium, calcium and water excretion. These changes were not accompanied by a change in renal cyclic AMP production, plasma parathyroid hormone levels or plasma calcitonin levels. Salbutamol had only minor effects on urine calcium and phosphate excretion.

Anti-tissue antibodies and immunoglobulin levels in relation to HLA and other markers in Icelandic families.

Studies of 521 sera from the Icelandic cousin marriage project were made to assess the incidence of various anti-tissue antibodies and the levels of immunoglobulins, as these were considered to be useful markers of the humoral immune response. Comparisons were made between these parameters and the HLA-A and B antigens, the blood groups, the immunoglobulin allotypes (Gm, Km and Am), the properdin factor (Bf), and other markers. These investigations offered another approach to the study of the sites of action of immune response genes in man. Because the immune response may be expected to differ for each individual and depend at least in part, on the degree of exposure to different antigens, no absolute correlation was expected. There was, however, a marked association between certain IgG anti-tissue antibodies and HLA antigens. This was most marked for HLA-A10, B18 and b27, but not for HLA-A1 or B8. The comparison of immunoglobulin levels with HLA antigens, was less striking, although HLA-A2 appeared to be associated with low levels of IgE. There were also some associations between immunoglobulin levels and ABO blood groups.