Investigation of feeding behaviour in C. elegans reveals distinct pharmacological and antibacterial effects of nicotine.

Caenorhabditis elegans is an informative model to study the neural basis of feeding. A useful paradigm is one in which adult nematodes feed on a bacterial lawn which has been pre-loaded with pharmacological agents and the effect on pharyngeal pumping rate scored. A crucial aspect of this assay is the availability of good quality bacteria to stimulate pumping to maximal levels. A potential confound is the possibility that the pharmacological agent impacts bacterial viability and indirectly influences feeding rate. Here, the actions of nicotine on pharyngeal pumping of C. elegans and on the Escherichia coli bacterial food source were investigated. Nicotine caused an immediate and concentration-dependent inhibition of C. elegans pharyngeal pumping, IC50 4 mM (95% CI = 3.4 mM to 4.8 mM). At concentrations between 5 and 25 mM, nicotine also affected the growth and viability of E. coli lawns. To test whether this food depletion by nicotine caused the reduced pumping, we modified the experimental paradigm. We investigated pharyngeal pumping stimulated by 10 mM 5-HT, a food 'mimic', before testing if nicotine still inhibited this behaviour. The IC50 for nicotine in these assays was 2.9 mM (95% CI = 3.1 mM to 5.1 mM) indicating the depletion of food lawn does not underpin the potency of nicotine at inhibiting feeding. These studies show that the inhibitory effect of nicotine on C. elegans pharyngeal pumping is mediated by a direct effect rather than by its poorly reported bactericidal actions.

Molecules of the mind: integrating synaptic biochemistry to understand brain function.

The focused meeting entitled 'Molecular Determinants of Synaptic Function: Molecules and Models' brought together several molecules and experimental models that are furthering our understanding of the biochemical basis of integrative brain function. Invited speakers and short communications from more junior scientists highlighted how individual molecules or protein networks underlie defined subcellular functions (e.g. transmitter release, receptor activation and transmitter uptake) can be used to unravel integrative function at cellular, systems and behavioural levels.

Increased expression of glial fibrillary acidic protein fragments and mu-calpain activation within the hippocampus of prion-infected mice.

Prion diseases are characteristically accompanied by marked astrocytic activation, which is initiated relatively early in the disease process. Using the intracerebrally injected ME7 strain of prion agent to model disease, we identified an expected increase in GFAP (glial fibrillary acidic protein) but additionally noted an accumulation of GFAP cleavage fragments in hippocampal homogenates. A time-dependent increase in hippocampal mu-calpain immunoreactivity within astrocytes suggests that its proteolytic activity may account for the cleavage of GFAP that is observed in the ME7 model. It may therefore contribute to the reactive gliosis that is characteristic of prion diseases.

Predictors of hysterectomy: an Australian study.

OBJECTIVE: We evaluated the relative importance of predictors of hysterectomy. STUDY DESIGN: A questionnaire survey of an Australia-wide sample of adult female twins was conducted; self-report data were validated against reports from treating physicians. RESULTS: A total of 3096 women (94%) and 366 physicians (87%) responded. The sensitivity of patient report of hysterectomy was 98.2%. Best predictors of hysterectomy were endometriosis (odds ratio 4.85, 95% confidence interval 3.17-7.43), medical consultation for menorrhagia (odds ratio 3.55, 95% confidence interval 2.47-5.12), joint effects of fibroids with medical consultation for chronic or persisting pelvic pain (odds ratio 3.34, 95% confidence interval 1. 42 to 7.87), having smoked >40 cigarettes per day (odds ratio 3.24, 95% confidence interval 1.10-9.55), joint effects of fibroids with consultation for menstrual problems (odds ratio 2.61, 95% confidence interval 1.36-5.01), and tubal ligation (odds ratio 1.77, 95% confidence interval 1.31-2.39). Less-important predictors were age and higher education level (protective). CONCLUSION: Consulting a physician about pelvic pain and menstrual problems, especially heavy bleeding, are recognized steps toward hysterectomy. Of particular interest for future genetic analyses are the high odds of hysterectomy for women with endometriosis, fibroids, or menorrhagia.

Genetic influences on endometriosis in an Australian twin sample. sueT@qimr.edu.au.

OBJECTIVE: To investigate the prevalence of and twin pair concordance for endometriosis. DESIGN: A questionnaire survey incorporating validation. SETTING: An Australia-wide volunteer sample of female monozygotic (MZ) and dizygotic (DZ) twin pairs from the Australian National Health and Medical Research Council Twin Register. PATIENT(S): Twins were selected only on the basis of previous participation in twin research. INTERVENTION(S): Questionnaires were sent to 3,298 individuals. Information was requested from physicians named by consenting twins. MAIN OUTCOME MEASURE(S): Reported endometriosis, validated where possible by pathology or surgical report. RESULT(S): Three thousand ninety-six (94%) of the twins and 145 (82%) of the physicians responded to the survey. Two hundred fifteen twins reported endometriosis, for a prevalence rate of .07 among question respondents. Tetrachoric twin pair correlations for self-reported endometriosis (MZ: n = 854 and DZ: n = 493) were rMz = .46+/-.09 and rDz = .28 +/-.13. When available medical and pathology reports were included, they changed to rMz =.52 +/-.08 and rDZ = .19+/-.16, suggesting that 51% of the variance of the latent liability to endometriosis may be attributable to additive genetic influences. CONCLUSION(S): These findings support the hypothesis that genes influence liability to endometriosis.

Do psycho-social factors contribute more to symptom reporting by middle-aged women than hormonal status?

Six hundred women aged between 45 and 54 were randomly selected from the electoral roll in Brisbane, Australia. A questionnaire addressing their symptoms, hormone status and psycho-social factors was successfully administered to 381 women (64% of the original sample; 83% of those contactable). Although cardiovascular symptoms were experienced by 25% of the sample, the most common (hot flushes) ranked only tenth on a list of recently experienced symptoms. The association of hormone status with symptoms was weak in comparison with other factors. Most symptoms were reported by women who were perimenopausal, had undergone a hysterectomy, or were currently using hormone replacement therapy. A poor mental health index was strongly associated with all groups reporting symptoms. It is concluded that clinicians responding to symptoms from middle-aged women should continue to address psychosocial factors just as vigorously as those related to their hormone status.

On the structure of the 'synaptosecretosome'. Evidence for a neurexin/synaptotagmin/syntaxin/Ca2+ channel complex.

Recent experiments have identified interactions between presynaptic and synaptic vesicle membrane proteins, that might be important in organizing the components of the fast neurotransmitter release mechanism to ensure that the process follows a rapid time course. Here we extend previous investigations to show that in addition to the alpha-latrotoxin receptor (neurexin) and synaptotagmin another presynaptic protein, syntaxin, co-purifies on a alpha-latrotoxin affinity column. This implies that syntaxin is associated with these two molecules in a complex; a conclusion supported by the immunoprecipitation of [125I]latrotoxin binding by syntaxin antibodies. In addition, antibodies against syntaxin and the alpha-latrotoxin receptor immunoprecipitate [125I]omega-conotoxin binding sites, indicating that calcium channels are associated with this complex. Thus, neurexin, synaptotagmin, syntaxin, and calcium channels can be found in a structure we propose to call the 'synaptosecretosome'. The components of the synaptosecretosome, in association with additional proteins, are postulated to organize the process of neurotransmitter release.