Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid,uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: A potential drug for bipolar disorder

Background

Mood stabilizers used for treating bipolar disorder (BD) selectively downregulate arachidonic acid (AA) turnover (deacylation–reacylation) in brain phospholipids, when given chronically to rats. In vitro studies suggest that one of these, valproic acid (VPA), which is teratogenic, reduces AA turnover by inhibiting the brain long-chain acyl-CoA synthetase (Acsl)4 mediated acylation of AA to AA-CoA. We tested whether non-teratogenic VPA analogues might also inhibit Acsl4 catalyzed acylation, and thus have a potential anti-BD action.

Methods

Rat Acsl4-flag protein was expressed in Escherichia coli, and the ability of three VPA analogues, propylisopropylacetic acid (PIA), propylisopropylacetamide (PID) and N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (MTMCD), and of sodium butyrate, to inhibit conversion of AA to AA-CoA by Acsl4 was quantified using Michaelis–Menten kinetics.

Results

Acsl4-mediated conversion of AA to AA-CoA in vitro was inhibited uncompetitively by PIA, with a K_i of 11.4 mM compared to a published K_i of 25 mM for VPA, while PID, MTMCD and sodium butyrate had no inhibitory effect.

Conclusions

PIA's ability to inhibit conversion of AA to AA-CoA by Acsl4 in vitro suggests that, like VPA, PIA may reduce AA turnover in brain phospholipids in unanesthetized rats, and if so, may be effective as a non-teratogenic mood stabilizer in BD patients.     

Aquatic biodiversity and saline lakes: Lake Bogoria National Reserve,Kenya

Lake Bogoria, in the Rift Valley of Kenya is an extreme saline lake (conductivity 40–80 mS cm^–1, alkalinity 1500 m equ l^–1). It is hydrologically more stable than the other, endorheic lakes in Kenya, because it is deep – maximum depth at present just over 10 m in an area of 3000 ha – and so does not have periods when it is dry. It is ecologically simple, with only one species dominating the phytoplankton – the cyanobacterium `spirulina', Arthrospira fusiformis. Its biomass and productivity were very high – biomass between 38 and 365 g l<sup>–1</sup> chlorophyll `a' and 3.4–21 × 10³ coils ml^–1 and net production between 0.24 and 1 gm C m³ h, the latter in a narrow zone of less than a metre. There were no macro-zooplankton in the plankton and the only grazer of A. fusiformis was the lesser flamingo, Phoeniconaias minor,which occurred irregularly in very high concentrations (in excess of 1 × 10⁶). Detritivory in the benthos was effected by a single chironomid species, Paratendipes sp., at a maximum density of 4 × 10⁴ m^–2. The mean daily emergence of adult chironomids was estimated to be 1 × 10³ m^–2, the maximum 3. There was no littoral plant community within the lake but 44 dicotyledonous and 31 monocotyledonous plant species in the drawn-down zone and adjacent to it. A diverse draw-down terrestrial invertebrate fauna, only superficially described here, processed the flamingo feathers and carcasses, with other detritus such as chironomid pupal exuviae and decaying A. fusiformis scum. About 50 bird species depended upon the chironomids, either as they emerged through the water column as flying adults or later on the shoreline as floating pupal exuvia and dead adults. The lake has high conservation value because of three bird species in particular – lesser flamingo, Cape teal and black-necked grebe. The former provides real economic value in a region otherwise impoverished, because of the spectacle of tens of thousands of flamingos set against the landscape of hot springs and fumaroles at the lake edge, which draws 15000 visitors per annum. P. minor has experienced three periods during the past ten years when major mortalities have occurred, the last of which killed 700 birds day^–1. This could have involved as many as 200000 birds (about 1/5th of the maximum population at this lake) if mortality was at a constant rate for the nine months it was observed. Causes of mortality have been suggested as avian tuberculosis, poisoning from cyanobacterial toxins or from heavy metal contamination at Lake Nakuru, but it is still not yet clear what contribution each makes to the problem.     

Communication about Children's Clinical Trials as Observed and Experienced: Qualitative Study of Parents and Practitioners

Background

Recruiting children to clinical trials is perceived to be challenging. To identify ways to optimise recruitment and its conduct, we compared how parents and practitioners described their experiences of recruitment to clinical trials.

Methods and Findings

This qualitative study ran alongside four children''s clinical trials in 11 UK research sites. It compared analyses of semi-structured interviews with analyses of audio-recordings of practitioner-family dialogue during trial recruitment discussions. Parents from 59 families were interviewed; 41 had participated in audio-recorded recruitment discussions. 31 practitioners were interviewed. Parents said little in the recruitment discussions contributing a median 16% of the total dialogue and asking a median of one question. Despite this, parents reported a positive experience of the trial approach describing a sense of comfort and safety. Even if they declined or if the discussion took place at a difficult time, parents understood the need to approach them and spoke of the value of research. Some parents viewed participation as an ‘exciting’ opportunity. By contrast, practitioners often worried that approaching families about research burdened families. Some practitioners implied that recruiting to clinical trials was something which they found aversive. Many were also concerned about the amount of information they had to provide and believed this overwhelmed families. Whilst some practitioners thought the trial information leaflets were of little use to families, parents reported that they used and valued the leaflets. However, both parties agreed that the leaflets were too long and wanted them to be more reader-friendly.

Conclusions

Parents were more positive about being approached to enter their child into a clinical trial than practitioners anticipated. The concerns of some practitioners, that parents would be overburdened, were unfounded. Educating practitioners about how families perceive clinical trials and providing them with ‘moral’ support in approaching families may benefit paediatric research and, ultimately, patients.     

Olfactory Behavioral Testing in the Adult Mouse

The rodent olfactory system is of increasing interest to scientists, studied, in part, in systems biology because of its stereotyped, yet accessible circuitry. In addition, this area''s unique ability to generate new neurons throughout an organism''s lifetime makes it an attractive system for developmental and regenerative biologists alike. Such interest necessitates a means for a quick, yet reliable assessment of olfactory function. Many tests of olfactory ability are complex, variable or not specifically designed for mice. Also, some tests are sensitive to memory deficits as well as defects in olfactory abilities, confounding obtained results.Here, we describe a simple battery of tests designed to identify defects in olfactory sensitivity and preference. First, an initial general health assessment allows for the identification of animals suitable for further testing. Second, mice are exposed to various dilutions of scents to ascertain whether there is a threshold difference. Third, mice are presented with various scents, both attractive and aversive, that allow for the assessment of olfactory preference. These simple studies should make the initial characterization of olfactory behavior accessible for labs of varied resources and expertise.Download video file.^{(52M, flv)}