Molecular modeling of a tandem two pore domain potassium channel reveals a putative binding Site for general anesthetics

[Image: see text] Anesthetics are thought to mediate a portion of their activity via binding to and modulation of potassium channels. In particular, tandem pore potassium channels (K2P) are transmembrane ion channels whose current is modulated by the presence of general anesthetics and whose genetic absence has been shown to confer a level of anesthetic resistance. While the exact molecular structure of all K2P forms remains unknown, significant progress has been made toward understanding their structure and interactions with anesthetics via the methods of molecular modeling, coupled with the recently released higher resolution structures of homologous potassium channels to act as templates. Such models reveal the convergence of amino acid regions that are known to modulate anesthetic activity onto a common three- dimensional cavity that forms a putative anesthetic binding site. The model successfully predicts additional important residues that are also involved in the putative binding site as validated by the results of suggested experimental mutations. Such a model can now be used to further predict other amino acid residues that may be intimately involved in the target-based structure–activity relationships that are necessary for anesthetic binding

Gender differences in the symptoms and physical and mental well-being of dyspeptics : a population based study

Purpose: To compare women and men with dyspepsia in terms of symptoms, physical and mental well-being and the relationships between individual symptoms and well-being. Methods: A cross-sectional random telephone survey of 2300 Australians identified 748 people with dyspepsia who were interviewed regarding the number, types and severity of symptoms and physical (PCS) and mental well-being (MCS) measured by the SF-12. Results: There were no significant gender differences in number or average severity of symptoms. Bloating, nausea, and early satiety were significantly more frequent among women; food regurgitation and heartburn in men. Dyspeptics (PCS = 47.1, MCS = 46.0) had poorer physical (p < 0.001) and mental well-being (p < 0.001) than did non-dyspeptics (PCS = 53.5, MCS = 55.3). Among dyspeptics, women (PCS = 46.4, MCS = 44.7) had poorer physical (p < 0.05) and mental well-being (p < 0.001) than males (PCS = 47.9, MCS = 47.5). Some symptoms were associated with low well-being for both sexes e.g. nausea. For women retching was related to poor physical well-being, and food regurgitation, dysphagia. bloating and epigastric pain to poor mental well-being. Among men epigastric pain and heartburn were associated with poor physical well-being, acid regurgitation with poor mental well-being, and vomiting with both. Conclusions: Dyspeptics report poorer physical and mental well-being than do non-dyspeptics. The difference between groups is greater for mental well-being, especially among women. Both physical and social factors may contribute to gender differences.9 page(s

The Impact of dyspepsia definition on prevalence estimates : considerations for future researchers

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Control of 5-hydroxytryptamine release in the dorsal raphe nucleus by the noradrenergic system in rat brain. Role of alpha-adrenoceptors

The interactions between the brainstem serotonergic (5-hydroxytryptamine, 5-HT) and noradrenergic (NA) systems are important for the pathophysiology and treatment of affective disorders. We examined the influence of -adrenoceptors on 5-HT and NA release in the rat dorsal raphe nucleus (DR) using microdialysis. 5-HT and NA concentrations in DR dialysates were virtually suppressed by TTX and increased by veratridine. The local and systemic administration of the 1-adrenoceptor antagonist prazosin reduced the DR 5-HT output but not that of NA. The maximal 5-HT reduction induced by local prazosin administration (-78% at 100 M) was more marked than by its systemic administration (-43% at 0.3 mg/kg). The local application of NA and desipramine, to increase the tone on DR 1-adrenoceptors, did not enhance 5-HT release. The local (100 M) or systemic (0.1–1 mg/kg s.c.) administration of clonidine reduced 5-HT and NA release (-48 and -79%, respectively, at 1 mg/kg), an effect reversed by RX-821002, which by itself increased both amines when given systemically. DSP-4 pretreatment prevented the effects of clonidine on 5-HT, suggesting the participation of 2-adrenoceptors on NA elements. Moreover, the systemic effect of clonidine on 5-HT (but not NA) was cancelled by lesion of the lateral habenula and by anesthesia, and was slightly enhanced by cortical transection. These data support the view that 1-adrenoceptors in the DR tonically stimulate 5-HT release, possibly at nearly maximal tone. Likewise, the 5-HT release is modulated by 2-adrenoceptors in NA neurons and in forebrain areas involved in the distal control of 5-HT neurons.Peer reviewe

Is health care seeking for irritable bowel syndrome and functional dyspepsia a socially learned response to illness?

In a population-based study of 207 subjects with irritable bowel syndrome (IBS) or functional dyspepsia (FD) and controls (n = 100), we aimed to determine whether dimensions of abnormal illness behavior from the Abnormal Illness Behaviour Questionnaire and aspects of social learning of illness behavior from the Social Learning of Illness Behaviour scale were independent predictors of health care seeking for IBS and FD. Results showed that dimensions of abnormal illness behavior and aspects of social learning of illness behavior (encouragement, reinforcement, and modeling) did not significantly differentiate between consulters and nonconsulters with IBS and/or FD. The Disease Conviction scale (OR = 1.55; 95% CI, 1.15-2.09) of the Abnormal Illness Behaviour Questionnaire was an independent predictor of having a diagnosis of IBS and/or FD, independent of age and gender, psychiatric diagnoses, and symptom severity. We conclude that a belief in the presence of serious pathology characterizes community subjects with IBS and FD, but not health care seeking

Cost of detecting malignant lesions by endoscopy in 2741 primary care dyspeptic patients without alarm symptoms.

Primary care dyspeptic patients without alarm symptoms rarely have serious underlying conditions at endoscopy. The costs associated with diagnosing an occult malignancy are large, but an age cut-off of 50 years for early endoscopy provides the best assurance that an occult malignancy will not be missed