Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones.

The Bicaudal C Homolog 1 (BICC1) gene, which encodes an RNA binding protein, has been identified by genome wide association studies (GWAS) as a candidate gene associated with major depressive disorder (MDD). We explored the hypothesis that MDD associated single-nucleotide polymorphisms (SNPs) affected the ability of cis-regulatory elements within intron 3 of the BICC1 gene to modulate the activity of the BICC1 promoter region. We initially established that the BICC1 promoter drove BICC1 mRNA expression in amygdala, hippocampus and hypothalamus. Intriguingly, we provide evidence that MDD associated polymorphisms alter the ability of the BICC1 promoter to respond to PKA signalling within amygdala neurones. Considering the known role of amygdala PKA pathways in fear learning and mood these observations suggest a possible mechanism through which allelic changes in the regulation of the BICC1 gene in amygdala neurones may contribute to mood disorders. Our findings also suggest a novel direction for the identification of novel drug targets and the design of future personalised therapeutics.The Pharmacogenomics Journal advance online publication, 6 October 2015; doi:10.1038/tpj.2015.62.

Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity.

The obese gene product leptin is an important signaling protein that regulates food intake and body weight via activation of the hypothalamic leptin receptor (Ob-Rb; Jacob et al., 1997). However, there is growing evidence that Ob-Rb is also expressed in CNS regions, not directly associated with energy homeostasis (Mercer et al., 1996; Hakansson et al., 1998). In the hippocampus, an area of the brain involved in learning and memory, we have found that leptin facilitates the induction of synaptic plasticity. Leptin converts short-term potentiation of synaptic transmission induced by primed burst stimulation of the Schaffer collateral commissural pathway into long-term potentiation. The mechanism underlying this effect involves facilitation of NMDA receptor function because leptin rapidly enhances NMDA-induced increases in intracellular Ca(2+) levels ([Ca(2+)](i)) and facilitates NMDA, but not AMPA, receptor-mediated synaptic transmission. The signaling mechanism underlying these effects involves activation of phosphoinositide 3-kinase, mitogen-activated protein kinase, and Src tyrosine kinases. These data indicate that a novel action of leptin in the CNS is to facilitate hippocampal synaptic plasticity via enhanced NMDA receptor-mediated Ca(2+) influx. Impairment of this process may contribute to the cognitive deficits associated with diabetes mellitus.

Clothing and exercise. I: Biophysics of heat transfer between the individual, clothing and environment.

Despite large environmental variations, the human body maintains a tightly regulated core temperature. Effective thermoregulation must balance the interaction between skin surface, clothing and ambient air. Indices of thermal stress (wet bulb globe temperature, heat stress index, maximum evaporation rate, required evaporative rate and wind chill) provide valuable information concerning the heat exchange between the individual and the environment, and serve as protective guidelines while working in environmental extremes. The role of clothing, as an interactive barrier, greatly affects thermal balance. Clothing is varied according to prevailing environmental conditions, metabolic heat production, gender and age differences, fabric thermal properties, garment design and intended use. Models (static, dynamic and human) have investigated the biophysical transfer of heat between the skin surface area, clothing and ambient air. Additionally, the role of metabolic heat production during exercise can greatly influence tolerance to thermal stress during a variety of environmental conditions.

Serological prevalence of herpes simplex virus type 2 amongst GUM clinic attenders in a district general hospital setting.

Our objective was to determine the seroprevalence of herpes simplex virus (HSV) type 2 infection amongst genitourinary medicine (GUM) clinic attenders at a district general hospital using a commercially available enzyme immunoassay (EIA). In a prospective study, heterosexual patients attending the Department of GUM at Trafford General Hospital attending with a new clinical problem and having a blood sample taken for routine syphilis serology had the same sample tested for HSV type 2 antibodies. The prevalence of HSV type 2 seropositivity amongst participants was 9.9% (24/242) for men and 18.7% (46/246) for women. With respect to undiagnosed, asymptomatic infection the seroprevalence was 8.6% and 17% respectively. For those attenders locally resident the seroprevalence was 10.1% and 17.5% respectively, and undiagnosed, asymptomatic infection 8.5% and 17.1% respectively. Although seroprevalence figures in this study are lower than the only previous report in the UK, these results, nevertheless, show that seropositivity is not confined to large urban centres. Patients attending GUM clinics are likely to have high rates of undiagnosed HSV type 2 infection.

Leptin: a potential cognitive enhancer?

It is well documented that the hormone leptin signals information regarding the status of fat stores to hypothalamic nuclei, which in turn control feeding behaviour and body weight. However, leptin and its receptor are widely expressed in many extra-hypothalamic brain regions, including hippocampus, brain stem and cerebellum. Moreover, evidence is accumulating that leptin has other neuronal functions that are unrelated to its effects on energy homeostasis. Indeed a role for leptin in neuronal development has been suggested as leptin-deficient rodents display abnormal brain development and leptin actively participates in the development of the hypothalamus. In the hippocampus, leptin is a potential cognitive enhancer as genetically obese rodents with dysfunctional leptin receptors display impairments in hippocampal synaptic plasticity. Moreover, direct administration of leptin into the hippocampus can facilitate hippocampal LTP (long-term potentiation) in vivo and improve memory processing in mice. At the cellular level, we have also shown that leptin has the capacity to convert short-term potentiation into LTP. Here, we review the data that leptin influences hippocampal synaptic plasticity via enhancing NMDA (N-methyl-D-aspartate) receptor function. We also provide evidence that rapid trafficking of NMDA receptors to the plasma membrane may underlie the effects of leptin on excitatory synaptic strength.

Leptin inhibits epileptiform-like activity in rat hippocampal neurones via PI 3-kinase-driven activation of BK channels.

The obese gene product, leptin is an important circulating satiety factor that regulates energy balance via its actions in the hypothalamus. However, leptin receptors are also expressed in brain regions not directly associated with energy homeostasis, such as the hippocampus. Here, leptin inhibits hippocampal neurones via activation of large conductance Ca(2+)-activated K(+) (BK) channels, a process that may be important in regulating neuronal excitability. We now show that leptin receptor labelling is expressed on somata, dendrites and axons, and is also concentrated at synapses in hippocampal cultures. In functional studies, leptin potently and reversibly reduces epileptiform-like activity evoked in lean, but not leptin-resistant Zucker fa/fa rats. Furthermore, leptin also depresses enhanced Ca(2+) levels evoked following Mg(2+) removal in hippocampal cultures. The ability of leptin to modulate this activity requires activation of BK, but not K(ATP), channels as the effects of leptin were mimicked by the BK channel activator NS-1619, and inhibited by the BK channel inhibitors, iberiotoxin and charybdotoxin. The signalling mechanisms underlying this process involve stimulation of phosphoinositide 3-kinase (PI 3-kinase), but not mitogen-activated protein kinase (MAPK), as two structurally unrelated inhibitors of PI 3-kinase, LY294002 and wortmannin, blocked the actions of leptin. These data indicate that leptin, via PI 3-kinase-driven activation of BK channels, elicits a novel mechanism for controlling neuronal excitability. As uncontrolled excitability in the hippocampus is one underlying cause of temporal lobe epilepsy, this novel action of leptin could provide an alternative therapeutic target in the management of epilepsy.

Racial bias and the MCMI.

We studied the scores obtained on the Millon Clinical Multiaxial Inventory (MCMI) by Black and White male psychiatric inpatients to determine the presence or absence of racial bias. In predicting psychopathology for the two races, comparisons of MCMI performance indicated significant differences for all diagnoses except the personality disorders. The subjects were then matched into two groups of 209 patients each, according to DSM-III psychiatric diagnoses. The data were analyzed at the item, scale, and structural levels. At the item level, application of the Mantel-Haenszel Procedure revealed that 45 of the 175 items of the inventory were answered significantly different by the two racial groups. Because this number was higher than what could be expected by chance, the finding suggested possible deficiencies in terms of the culture-fairness of the items used in the test. At the scale level, an analysis of variance (ANOVA) demonstrated that the scores obtained by the Black and White groups were significantly different in 9 of the 20 scales (Histrionic, Narcissistic, Antisocial, Paraphrenia, Hypomania, Dysthymia, Alcohol Abuse, Drug Abuse, and Psychotic Delusion). With the exception of the Dysthymic scale, all of the differences were in the direction of the Blacks obtaining a higher score than the Whites. At the structural level, however, a principal components factor analysis performed on each group resulted in factor structures that looked identical.