Preliminary evidence for genetic overlap between body mass index and striatal reward response.

The reward-processing network is implicated in the aetiology of obesity. Several lines of evidence suggest obesity-linked genetic risk loci (such as DRD2 and FTO) may influence individual variation in body mass index (BMI) through neuropsychological processes reflected in alterations in activation of the striatum during reward processing. However, no study has tested the broader hypotheses that (a) the relationship between BMI and reward-related brain activation (measured through the blood oxygenation-dependent (BOLD) signal) may be observed in a large population study and (b) the overall genetic architecture of these phenotypes overlap, an assumption critical for the progression of imaging genetic studies in obesity research. Using data from the Human Connectome Project (N = 1055 healthy, young individuals: average BMI = 26.4), we first establish a phenotypic relationship between BMI and ventral striatal (VS) BOLD during the processing of rewarding (monetary) stimuli (ß = 0.44, P = 0.013), accounting for potential confounds. BMI and VS BOLD were both significantly influenced by additive genetic factors (H2r = 0.57; 0.12, respectively). Further decomposition of this variance suggested that the relationship was driven by shared genetic (ρ g = 0.47, P = 0.011), but not environmental (ρ E = -0.07, P = 0.29) factors. To validate the assumption of genetic pleiotropy between BMI and VS BOLD, we further show that polygenic risk for higher BMI is also associated with increased VS BOLD response to appetitive stimuli (calorically high food images), in an independent sample (N = 81; P FWE-ROI < 0.005). Together, these observations suggest that the genetic factors link risk to obesity to alterations within key nodes of the brain's reward circuity. These observations provide a basis for future work exploring the mechanistic role of genetic loci that confer risk for obesity using the imaging genetics approach.

Further support for association between GWAS variant for positive emotion and reward systems.

A recent genome-wide association study (GWAS) identified a significant single-nucleotide polymorphism (SNP) for trait-positive emotion at rs322931 on chromosome 1, which was also associated with brain activation in the reward system of healthy individuals when observing positive stimuli in a functional magnetic resonance imaging (fMRI) study. In the current study, we aimed to further validate the role of variation at rs322931 in reward processing. Using a similar fMRI approach, we use two paradigms that elicit a strong ventral striatum (VS) blood oxygen-level dependency (BOLD) response in a sample of young, healthy individuals (N=82). In the first study we use a similar picture-viewing task to the discovery sample (positive>neutral stimuli) to replicate an effect of the variant on emotion processing. In the second study we use a probabilistic reversal learning procedure to identify reward processing during decision-making under uncertainly (reward>punishment). In a region of interest (ROI) analysis of the bilateral VS, we show that the rs322931 genotype was associated with BOLD in the left VS during the positive>neutral contrast (PROI-CORRECTED=0.045) and during the reward>punishment contrast (PROI-CORRECTED=0.018), although the effect of passive picture viewing was in the opposite direction from that reported in the discovery sample. These findings suggest that the recently identified GWAS hit may influence positive emotion via individual differences in activity in the key hubs of the brain's reward system. Furthermore, these effects may not be limited to the passive viewing of positive emotional scenes, but may also be observed during dynamic decision-making. This study suggests that future studies of this GWAS locus may yield further insight into the biological mechanisms of psychopathologies characterised by deficits in reward processing and positive emotion.

Hyperconnectivity in juvenile myoclonic epilepsy: a network analysis.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) is a common idiopathic (genetic) generalized epilepsy (IGE) syndrome characterized by impairments in executive and cognitive control, affecting independent living and psychosocial functioning. There is a growing consensus that JME is associated with abnormal function of diffuse brain networks, typically affecting frontal and fronto-thalamic areas. METHODS: Using diffusion MRI and a graph theoretical analysis, we examined bivariate (network-based statistic) and multivariate (global and local) properties of structural brain networks in patients with JME (N = 34) and matched controls. Neuropsychological assessment was performed in a subgroup of 14 patients. RESULTS: Neuropsychometry revealed impaired visual memory and naming in JME patients despite a normal full scale IQ (mean = 98.6). Both JME patients and controls exhibited a small world topology in their white matter networks, with no significant differences in the global multivariate network properties between the groups. The network-based statistic approach identified one subnetwork of hyperconnectivity in the JME group, involving primary motor, parietal and subcortical regions. Finally, there was a significant positive correlation in structural connectivity with cognitive task performance. CONCLUSIONS: Our findings suggest that structural changes in JME patients are distributed at a network level, beyond the frontal lobes. The identified subnetwork includes key structures in spike wave generation, along with primary motor areas, which may contribute to myoclonic jerks. We conclude that analyzing the affected subnetworks may provide new insights into understanding seizure generation, as well as the cognitive deficits observed in JME patients.

Bone marrow and serum connective tissue polypeptides in idiopathic myelofibrosis.

The distribution of collagen type VI and tenascin has been determined in both normal and myelofibrotic bone marrow by immunohistological techniques. In normal sections positivity was demonstrated in the periosteum (collagen type VI and tenascin) and in the walls of small blood vessels (tenascin). In contrast, myelofibrotic bone marrow showed an increased deposition of both proteins, especially collagen type VI, although this increase was restricted to the later fibrotic stages of the disease. Serum concentrations of collagen type I (PICP), collagen type III (PIIIP) and laminin (laminin P1) related polypeptides were determined in a further 26 patients. PIIIP levels were significantly raised, in contrast to PICP and laminin P1 concentrations. All three markers, however, were significantly elevated in patients with active/transforming disease. Laminin P1 and PICP levels showed a strong correlation, indicating a relationship between basement membrane and interstitial collagen metabolism, although they do not appear to offer any advantage over PIIIP for the monitoring of disease activity.

Biological properties and molecular biology of the human macrophage growth factor, CSF-1.

CSF-1 is a growth and differentiation factor for the production of mononuclear phagocytes from undifferentiated bone marrow progenitors. In addition to previously described effects on mature cells, we show here that CSF-1 stimulates the production by monocytes of interferon, tumor necrosis factor, and myeloid CSF that produces mainly mixed neutrophil-macrophage colonies in bone marrow culture. Pretreatment with CSF-1 also promotes resistance to viral infection and tumor cytotoxicity in murine peritoneal macrophages. Based on amino acid sequence data of purified human urinary and murine L cell CSF-1, we have cloned the complementary DNA (cDNA) from messenger RNA (mRNA) of the human CSF-1 producing MIA PaCa cell line. The cDNA specifies a 32 amino acid signal peptide followed by a protein of 224 amino acids. Several facts suggest, however, that one-third of the molecule at the C-terminal end is processed off intracellularly to derive the secreted growth factor. The gene is about 18 kilobases (kb) in length and contains 9 exons. Although there appears to be a single copy gene for CSF-1, cells expressing the factor contain several mRNA species, suggesting that the gene may have several functions or levels of regulation. High level expression of the recombinant protein will allow preclinical testing in several disease models for therapeutic efficacy that has been suggested from in vitro and in vivo biological properties of CSF-1.

High level human interleukin 1 production by a hepatoma cell line.

The human hepatic adenocarcinoma cell line, SK-hep-1, was found to constitutively produce Interleukin 1. Addition of the ionophore A23187 and lipopolysaccharide resulted in a 30-fold enhancement in the release of biological activity. Serum supplementation did not affect the level of production. Interleukin 1 from these cells had a molecular weight of 10-20,000 daltons on gel exclusion chromatography. Polyadenylated RNA, when fractionated on sucrose density gradients and injected into Xenopus laevis oocytes, produced high levels of biological activity in the 14-16s region. An oligonucleotide probe, complementary to the coding sequence of the Interleukin 1 cDNA isolated from human monocytes, hybridized specifically to this part of the gradient. These results demonstrate that SK-hep-1 cells are a valuable source of material for studying the polypeptide and messenger RNA of Interleukin 1.

An improved assay for the detection of interleukin 1.

A 24 h, highly sensitive assay for detection of interleukin 1 (IL-1) is described. A thioguanine-resistant mutant of the murine lymphoma cell line LBRM 33 was selected (LBRM TG6). When this cell line was incubated with low concentrations of PHA and IL-1 it produced interleukin 2 (IL-2). IL-2-dependent HT2 cells were co-cultured with the LBRM cells to measure the released IL-2. Prior to addition of tritiated thymidine to the co-culture, hypoxanthine and azaserine were added to metabolically block DNA synthesis by LBRM TG6 cells. This resulted in a sensitive, short term assay requiring minimal technical manipulations and characterized by a high signal to noise ratio.

Stimulation of histamine release from human basophils by human platelet factor 4.

Human basophils were stimulated to release histamine noncytotoxically by purified human platelet factor 4 (PF4) and the synthetic substituent peptide PF4(59-70). Histamine release was augmented significantly by 10(-7) M PF4 and 10(-5) M PF4(59-70), increased in a concentration-dependent manner, and attained a maximum at 3 X 10(-5) M PF4 and 3 X 10(-4) M PF4(59-70) similar to that achieved by goat anti-human myeloma IgE. PF4 (1-60) failed to initiate the release of histamine, which confirmed that the critical determinant of activity is in the carboxy-terminal sequence. Histamine release from basophils by optimally effective concentrations of PF4 and PF4(59-70) reached a plateau by 1-3 min, as contrasted with 10 min or longer for anti-IgE. The elimination of calcium and magnesium from the buffer suppressed the release of histamine by anti-IgE by 79-83%, but had no effect on that elicited by PF4(59-70). The rate of uptake of [125I]PF4 by purified basophils was similar on a molar basis to the rate of release of histamine by the same concentrations of PF4. The noncytotoxic release of histamine from human basophils by PF4 thus is temporally and biochemically distinct from that mediated by IgE and may be similar to that evoked by other polycationic stimuli.

Enhancement of human neutrophil adherence by synthetic leukotriene constituents of the slow-reacting substance of anaphylaxis.

The functionally predominant constituents of the slow-reacting substance of anaphylaxis (SRS-A), designated leukotrienes C4 and D4 (LTC4 and LTD4), as well as the leucocyte chemotactic factor leukotriene B4 (LTB4) enhance the adherence of human neutrophils to Sephadex G-25. Enhancement of neutrophil adherence was significant at leukotriene concentrations of 3 X 10(-9) M -3 X 10(-7) M, and reached a maximum level for each of the leukotrienes that was similar in magnitude to that evoked by the neutrophil chemotactic peptide N-formyl-methionyl-leucylphenylalanine (FMLP). The leukotrienes and FMLP elicited optimum increases in neutrophil adherence within 1-2 min at 37 degrees. Indomethacin inhibited the increase in neutrophil adherence evoked by LTC4 and LTD4 and the concurrent elevation in the concentration of endogenous thromboxane B2. The smooth muscle contractile and vasoactive factors LTC4 and LTD4, which lack chemotactic activity for leucocytes, are as active as LTB4 in stimulating human neutrophil adherence, and the effect may be mediated in part by neutrophil-derived thromboxane A2.