Bronwen Hughes

University of Toronto, Toronto, Ontario, Canada

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Publications (5)24.76 Total impact

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    ABSTRACT: The nuclear-encoded mitochondrial complex I subunit gene, NDUFV2, has been implicated in the pathogenesis of bipolar disorder (BD) in Japanese by virtue of association of variants in its promoter with BD and decreased NDUFV2 messenger ribonucleic acid (mRNA) levels in B lymphoblasts (BLCL) in BD patients compared to controls. We sought to determine if these same changes occur in non-Japanese populations and, if so, their relationship to altered basal intracellular Ca(2+) ([Ca(2+)](B)) in BLCL from BD patients. Bipolar disorder patients and healthy subjects included 298 subjects of European Caucasian descent. The 5'-nuclease allelic discrimination TaqMan assay was used to detect selected single nucleotide polymorphisms (SNPs) in promoter, introns and 3'UTR regions, spanning the NDUFV2 gene. NDUFV2 mRNA levels and [Ca(2+)](B) in BLCLs were determined. The A allele of the NDUFV2 SNP rs1156044 was significantly associated (Bonferroni-corrected) with BD (p = 0.013) but differed in allele (rs1156044 G allele) from that previously reported as associated with BD. There was a trend for elevated BLCL [Ca(2+)](B) associated with SNP rs977581 in BD patients, but NDUFV2 mRNA levels in BLCLs did not differ between patients and controls, nor represented genotypes. While genetic variants of NDUFV2 may increase risk for BD, the role of its altered expression and the link to intracellular Ca(2+) abnormalities in BD remains equivocal.
    Bipolar Disorders 03/2008; 10(1):105-10. DOI:10.1111/j.1399-5618.2008.00535.x · 4.97 Impact Factor
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    Brian M Ross · Bronwen Hughes · Stephen J Kish · Jerry J Warsh ·
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    ABSTRACT: Phospholipases A2 (PLA2) are a family of enzymes involved in membrane phospholipid metabolism and cell signalling. The gene encoding one form, type VI calcium-independent phospholipase A2, is located in a region of DNA that may contain a gene important in the aetiology of psychosis. Moreover, the activity of calcium-independent PLA2 is reported to be elevated in the blood and brain of patients with schizophrenia. In this study we determined whether a similar change takes place in patients with bipolar disorder with and without a history of psychosis. Serum calcium-independent and -dependent PLA2 activities were determined in 24 patients with bipolar I disorder. Serum calcium-independent and -dependent PLA2 activities in bipolar cases did not differ significantly from that in healthy volunteers (HVs). However, calcium-independent PLA2 activity was significantly (p < 0.05) higher in patients with a history of psychosis compared with those with no history of psychosis (by 55%) or to HVs (by 31%). Our data suggest that a subset of bipolar I disorder patients with a history of psychosis have elevated calcium-independent PLA2 activity. Given that this enzyme activity is also increased in schizophrenia, elevated rates of phospholipid turnover mediated by the enzyme could represent a common biochemical feature of psychotic illness.
    Bipolar Disorders 07/2006; 8(3):265-70. DOI:10.1111/j.1399-5618.2006.00299.x · 4.97 Impact Factor
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    ABSTRACT: Disturbed intracellular calcium (Ca(2+)) homeostasis has been implicated in bipolar disorder (BD). Reduced mRNA levels of the transient receptor potential Ca(2+) permeable channel melastatin type 2, TRPM2, in B lymphoblast cell lines (BLCL) from bipolar I disorder (BD-I) patients showing elevated basal intracellular Ca(2+) ([Ca(2+)](B)), an index of altered intracellular Ca(2+) homeostasis, along with its location within a putative BD susceptibility locus (21q22.3), implicates the involvement of this gene in the Ca(2+) abnormalities and the genetic diathesis to BD. We tested this hypothesis by examining the association of selected single nucleotide polymorphisms (SNPs) and their haplotypes, spanning the TRPM2 gene, with BD and BLCL [Ca(2+)](B), in a case control design. The 5' TaqMan SNP assay was used to detect selected SNPs. BLCL [Ca(2+)](B) was determined by ratiometric fluorometry. SNP rs1618355 in intron 18 was significantly associated with BD as a whole (P < 7.0 x 10(-5); odds ratio (OR) = 2.60), and when stratified into BD-I (P < 7.0 x 10(-5), OR = 2.48) and BD-II (P = 7.0 x 10(-5), OR = 2.88) subgroups. In addition, the alleles of the individual SNPs forming a seven marker at-risk haplotype were in excess in BD (12.0% in BD vs. 0.9% in controls; P = 2.3 x 10(-12)). A weak relationship was also detected between BLCL [Ca(2+)](B) and TRPM2 SNP rs1612472 in intron 19. These findings suggest genetic variants of the TRPM2 gene increase risk for BD and support the notion that TRPM2 may be involved in the pathophysiology of BD.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2006; 141B(1):36-43. DOI:10.1002/ajmg.b.30239 · 3.42 Impact Factor
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    Brian M Ross · Bronwen Hughes · Sylvie Turenne · Mary Seeman · Jerry J Warsh ·
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    ABSTRACT: The normal vasodilatory response to topically applied methylnicotinate has been reported to be absent or reduced in patients with schizophrenia, a finding thought to be related to aberrant phospholipid metabolism. Previous studies have however failed to measure vasodilation using a direct and objective method. In addition, it is unknown whether methylnicotinate insensitivity is specific to schizophrenia. To address these issues we compared the magnitude of methylnicotinate-induced vasodilation in chronically ill patients with schizophrenia (SCZ) (n=27) or bipolar disorder (BP) (n=26) to that in healthy controls (n=32). Blood flow was monitored using laser Doppler flowmetry. Vasodilatory response to 1 and 10 mM methyl nicotinate was markedly and significantly reduced in patients with schizophrenia compared to that in subjects with bipolar disorder and healthy controls. In conclusion, reduced methyl nicotinate response in schizophrenia has been demonstrated using an objective measure of vasodilation. Our data further support the potential utility of this measure as a diagnostic marker for schizophrenia.
    European Neuropsychopharmacology 06/2004; 14(3):191-7. DOI:10.1016/S0924-977X(03)00145-7 · 4.37 Impact Factor
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    ABSTRACT: Elevated vasodilatory response (blushing) to social situations is characteristic of social phobia (SP). A relatively unexplored basis for this phenomenon is alteration in underlying vasodilatory mechanisms. To investigate this possibility, we evaluated the vasodilatory response induced by methyl nicotinate (niacin ester derivative) in 31 generalized SP patients and 41 matched healthy volunteers (HV). A patch impregnated with 0, 0.1, 0.5, 1, and 10 mM methyl nicotinate was applied to the forearm or face of subjects for 1 min, followed by 20-min laser Doppler spectroscopy blood flow monitoring. Blood flow stimulation with 1 and 10 mM methyl nicotinate was significantly reduced in SP patients by 35 and 17%, respectively. Induced blood flow was negatively correlated with patients' Leibowitz Social Phobia Scale (LSAS) at 1 and 10 mM doses. Furthermore, the maximal rate of change of vasodilatory reaction was correlated with symptom scores at 1 and 10 mM doses. Induced increases in the arm and face blood flow measurements correlated, supporting the external validity of the former location. Generalized SP patients vasodilate less to topical methyl nicotinate challenges, with effect amplification in severely ill patients. Although the mechanism for this is unclear, we propose desensitization of the prostaglandin-mediated vasodilating system as an explanation. Neuropsychopharmacology (2003) 28, 1846-1851, advance online publication, 23 July 2003; doi:10.1038/sj.npp.1300227
    Neuropsychopharmacology 11/2003; 28(10):1846-51. DOI:10.1038/sj.npp.1300227 · 7.05 Impact Factor