Large, binge-type meals of high fat diet change feeding behaviour and entrain food anticipatory activity in mice.

Male C57BL/6 mice fed ad libitum on control diet but allowed access to a palatable high fat diet (HFD) for 2 h a day during the mid-dark phase rapidly adapt their feeding behaviour and can consume nearly 80% of their daily caloric intake during this 2 h-scheduled feed. We assessed food intake microstructure and meal pattern, and locomotor activity and rearing as markers of food anticipatory activity (FAA). Schedule fed mice reduced their caloric intake from control diet during the first hours of the dark phase but not during the 3-h period immediately preceding the scheduled feed. Large meal/binge-like eating behaviour during the 2-h scheduled feed was characterised by increases in both meal number and meal size. Rearing was increased during the 2-h period running up to scheduled feeding while locomotor activity started to increase 1 h before, indicating that schedule-fed mice display FAA. Meal number and physical activity changes were sustained when HFD was withheld during the anticipated scheduled feeding period, and mice immediately binged when HFD was represented after a week of this "withdrawal" period. These findings provide important context to our previous studies suggesting that energy balance systems in the hypothalamus are not responsible for driving these large, binge-type meals. Evidence of FAA in HFD dark phase schedule-fed mice implicates anticipatory processes in binge eating that do not involve immediately preceding hypophagia or regulatory homeostatic signalling.

Brain pyruvate dehydrogenase: phosphorylation and enzyme activity altered by a training experience.

The active portion of the alpha subunit of pyruvate dehydrogenase in rat frontal cortex was elevated after a training experience. No change in total pyruvate dehydrogenase activity was observed. The phosphorylation in vitro of pyruvate dehydrogenase (band F-2) was also elevated after training. Since activation of pyruvate dehydrogenase requires its dephosphorylation, the following sequence is proposed. Training alters frontal cortex and reduces the phosphate content of pyruvate dehydrogenase in vivo; this leads to enzyme activation; and an increase in back-titration of sites available for phosphorylation in vitro.

The bacterial flagellar cap as the rotary promoter of flagellin self-assembly.

The growth of the bacterial flagellar filament occurs at its distal end by self-assembly of flagellin transported from the cytoplasm through the narrow central channel. The cap at the growing end is essential for its growth, remaining stably attached while permitting the flagellin insertion. In order to understand the assembly mechanism, we used electron microscopy to study the structures of the cap-filament complex and isolated cap dimer. Five leg-like anchor domains of the pentameric cap flexibly adjusted their conformations to keep just one flagellin binding site open, indicating a cap rotation mechanism to promote the flagellin self-assembly. This represents one of the most dynamic movements in protein structures.

An important role of heparan sulfate proteoglycan (Perlecan) in a model system for the deposition and persistence of fibrillar A beta-amyloid in rat brain.

A consistent rat model for the study of the consequences of congophilic and fibrillar A beta-amyloid in brain has been developed. One hundred percent of animals receiving infusions of synthetic beta-amyloid protein (A beta 1-40) plus a specific heparan sulfate proteoglycan (HSPG) for 1 week or 7 weeks (following 2 week infusions) demonstrated Congo red and thioflavin S-positive deposits adjacent to the infusion site. Extracellular amyloid fibrils were identified by electron microscopy and were immunogold decorated with A beta antibody. Significant increases in Congo red staining were observed in animals infused with A beta plus HSPG versus those infused with only A beta. Infusion of A beta alone was variable with respect to congophilic amyloid persistence, which occurred in 50% of animals and only when endogenous HSPGs accumulated at A beta deposition sites. By 7 weeks, only animals infused with A beta plus HSPG demonstrated compaction of the Congo red material from amorphous, wispy deposits (at 1 week) to stellate deposits resembling a Maltese cross. These spherical amyloid deposits were very similar to Congo red-stained amyloid plaques in human Alzheimer's disease brain, and in vitro data suggest that they were probably formed in vivo following interactions with endogenous brain components.

Glucagon-like peptide-1 stimulates luteinizing hormone-releasing hormone secretion in a rodent hypothalamic neuronal cell line.

To examine the influence of the putative satiety factor (GLP-1) on the hypothalamo-pituitary-gonadal axis, we used GT1-7 cells as a model of neuronal luteinizing hormone- releasing hormone (LHRH) release. GLP-1 caused a concentration-dependent increase in LHRH release from GT1-7 cells. Specific, saturable GLP-1 binding sites were demonstrated on these cells. The binding of [125I]GLP-1 was time-dependent and consistent with a single binding site (Kd = 0.07+/-0.016 nM; binding capacity = 160+/-11 fmol/mg protein). The specific GLP-1 receptor agonists, exendin-3 and exendin-4, also showed high affinity (Ki = 0.3+/-0.05 and 0.32+/-0.06 nM, respectively) as did the antagonist exendin-(9-39) (Ki = 0.98+/-0.24 nM). At concentrations that increased LHRH release, GLP-1 (0.5-10 nM) also caused an increase in intracellular cAMP in GT1-7 cells (10 nM GLP-1: 7.66+/-0.4 vs. control: 0.23+/-0.02 nmol/mg protein; P < 0.001). Intracerebroventricular injection of GLP-1 at a single concentration (10 microg) produced a prompt increase in the plasma luteinizing hormone concentration in male rats (GLP-1: 1.09+/-0.11 vs. saline: 0.69+/-0.06 ng/ml; P < 0.005). GLP-1 levels in the hypothalami of 48-h-fasted male rats showed a decrease, indicating a possible association of the satiety factor with the low luteinizing hormone levels in animals with a negative energy balance.

The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin.

Prolonged fasting is associated with a downregulation of the hypothalamo-pituitary thyroid (H-P-T) axis, which is reversed by administration of leptin. The hypothalamic melanocortin system regulates energy balance and mediates a number of central effects of leptin. In this study, we show that hypothalamic melanocortins can stimulate the thyroid axis and that their antagonist, agouti-related peptide (Agrp), can inhibit it. Intracerebroventricular (ICV) administration of Agrp (83-132) decreased plasma thyroid stimulating hormone (TSH) in fed male rats. Intraparaventricular nuclear administration of Agrp (83-132) produced a long-lasting suppression of plasma TSH, and plasma T4. ICV administration of a stable alpha-MSH analogue increased plasma TSH in 24-hour-fasted rats. In vitro, alpha-MSH increased thyrotropin releasing hormone (TRH) release from hypothalamic explants. Agrp (83-132) alone caused no change in TRH release but antagonized the effect of alpha-MSH on TRH release. Leptin increased TRH release from hypothalami harvested from 48-hour-fasted rats. Agrp (83-132) blocked this effect. These data suggest a role for the hypothalamic melanocortin system in the fasting-induced suppression of the H-P-T axis.

Maintenance treatment of gastroesophageal reflux disease: an evaluation of continuous and on-demand therapy with rabeprazole 20 mg.

OBJECTIVE: To evaluate continuous therapy (COT) and on-demand therapy (ODT) with rabeprazole 20 mg for maintenance in uninvestigated gastroesophageal reflux disease (GERD). METHODS: This randomized, open-label study enrolled 331 GERD (heartburn-predominant) patients with a pre-existing proton pump inhibitor history of one month or longer, to an acute four-week trial with 20 mg rabeprazole daily for heartburn management. Patients who achieved satisfactory heartburn control during the acute phase (three days or less of heartburn, with no more than one episode rated as moderate, and heartburn rated satisfactorily or completely controlled with minimal rescue antacid use in the seven days preceding randomization) were randomly assigned to six months of rabeprazole 20 mg given as either daily COT or daily ODT, which was initiated upon symptom recurrence and stopped upon symptom resolution. Rescue antacid usage was permitted and tracked. Primary efficacy was measured as the proportion of heartburn-free days over six months. RESULTS: For the 268 patients, the mean percentage of heartburn-free days for the COT group and for the ODT group were 90.3%+/-14.8% and 64.8%+/-22.3%, respectively (P<0.0001). COT was associated with an increased number of medication intake days (154+/-40.2) versus ODT (68+/-46.1), with less heartburn episodes observed with COT versus ODT, respectively (n=7, n=26, P<0.0001). Ninety-two per cent of COT patients and 79% of ODT patients were either 'satisfied' or 'very satisfied' with treatment. The mean usage of antacids was low and similar in both groups. COT and ODT regimens were safe and well-tolerated, with a similar incidence of adverse events. CONCLUSION: Results based on symptom assessments favour COT with rabeprazole 20 mg for maintenance therapy in patients with uninvestigated GERD; however, both therapy types are safe and acceptable treatment options for selected patients.

Arcuate nucleus homeostatic systems reflect blood leptin concentration but not feeding behaviour during scheduled feeding on a high-fat diet in mice.

Hypothalamic homeostatic and forebrain reward-related genes were examined in the context of scheduled meal feeding without caloric restriction in C57BL/6 mice. Mice fed ad libitum but allowed access to a palatable high-fat (HF) diet for 2 hours a day rapidly adapted their feeding behaviour and consumed approximately 80% of their daily caloric intake during this 2-hour scheduled feed. Gene expression levels were examined during either the first or second hour of scheduled feeding vs 24 hours ad libitum feeding on the same HF diet. Gene expression of neuropeptide Y, agouti-related peptide, cocaine- and amphetamine-regulated transcript, pro-opiomelanocortin, long-form leptin receptor and suppressor of cytokine signalling-3 in the hypothalamic arcuate nucleus (ARC), as well as enkephalin, dynorphin, dopamine-2-receptor and dopamine-3-receptor in the nucleus accumbens (NAcc) in the forebrain, were measured by in situ hybridisation. Mice fed ad libitum on a HF diet had the highest total caloric intake, body weight gain, fat mass and serum leptin, whereas schedule-fed mice had a mild obese phenotype with intermediate total caloric intake, body weight gain, fat mass and serum leptin. The effects of feeding regime on ARC gene expression were emphasised by significant positive or negative correlations with body weight gain, fat mass and blood leptin, although they did not appear to be related to feeding behaviour in the schedule-fed groups (ie, the large, binge-type meals) and did not reveal any potential candidates for the regulation of these meals. Mechanisms underlying large meal/binge-type eating may be regulated by nonhomeostatic hedonic processes. However, assessment of opioid and dopamine receptor gene expression in the NAcc did not reveal evidence of involvement of these genes in regulating large meals. This complements our previous characterisation of ARC and NAcc genes in schedule-fed mice and rats, although it still leaves open the fundamental question about the underlying mechanisms of meal feeding.

Poor predictive value of lower gastrointestinal alarm features in the diagnosis of colorectal cancer in 1981 patients in secondary care.

BACKGROUND: Clinicians are advised to refer patients with lower gastrointestinal (GI) alarm features for urgent colonoscopy to exclude colorectal cancer (CRC). However, the utility of alarm features is debated. AIM: To assess whether performance of alarm features is improved by using a symptom frequency threshold to trigger referral, or by combining them into composite variables, including minimum age thresholds, as recommended by the National Institute for Health and Care Excellence (NICE). METHODS: We collected data prospectively from 1981 consecutive adults with lower GI symptoms. Assessors were blinded to symptom status. The reference standard to define CRC was histopathological confirmation of adenocarcinoma in biopsy specimens from a malignant-looking colorectal lesion. Controls were patients without CRC. Sensitivity, specificity, positive predictive values (PPVs) and negative predictive values were calculated for individual alarm features, as well as combinations of these. RESULTS: In identifying 47 (2.4%) patients with CRC, individual alarm features had sensitivities ranging from 11.1% (family history of CRC) to 66.0% (loose stools), and specificities from 30.5% (loose stools) to 75.6% (family history of CRC). Using higher symptom frequency thresholds improved specificity, but to the detriment of sensitivity. NICE referral criteria also had higher specificities and lower sensitivity, with PPVs above 4.8%. More than 80% of those with CRC met at least one of the NICE referral criteria. CONCLUSIONS: Using higher symptom frequency thresholds for alarm features improved specificity, but sensitivity was low. NICE referral criteria had PPVs above 4.8%, but sensitivities ranged from 2.2% to 32.6%, meaning many cancers would be missed.

Melatonin for cognitive impairment.

BACKGROUND: There are a number of studies that suggest a relationship between decline of melatonin function and the symptoms of dementia. OBJECTIVES: The review assessed the evidence of clinical efficacy and safety of melatonin in the treatment of manifestations of dementia or cognitive impairment (CI). SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched for trials involving melatonin on 5 October 2005. The search terms used were MELATONIN, and N-ACETYL-5-METHOXYTRYPTAMINE. This Register contains records from all major health care databases as well as many ongoing trials databases and is updated regularly. SELECTION CRITERIA: All relevant, randomized controlled trials in which orally administered melatonin in any dosage was compared with a control group for the effect on managing cognitive, behavioural (excluding sleep), and/or affective disturbances of people with dementia of any degree of severity. DATA COLLECTION AND ANALYSIS: Two to three reviewers independently assessed the retrieved articles for relevance and methodological quality, and extracted data from the selected studies. Statistically significant differences in changes in outcomes from baseline to end of treatment between the melatonin and control groups were examined. Each study was summarized using a measure of effect (e.g. mean difference) and meta-analyses were conducted when appropriate. MAIN RESULTS: Three studies met the inclusion criteria. This review revealed non-significant effects from the pooled estimates of MMSE cognitive, and ADAS-cognitive change scores. Individual study estimates for treatment effect demonstrated a significant improvement for melatonin compared with placebo in behavioural and affective symptoms as measured by the ADAS non-cognitive scale in a study of 20 patients, and the Neuropsychiatric Inventory (NPI) following treatment with 2.5 mg/day (SR) melatonin, but not with 10mg/day (IR) melatonin in a larger study of 157 patients. The remainder of the treatment effects for affect, behaviour and activities of daily living were non-significant. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the effectiveness of melatonin in managing the cognitive and non-cognitive sequelae of dementia.

Effects of chronic central nervous system administration of agouti-related protein in pair-fed animals.

The melanocortin receptor (MC3-R and MC4-R) antagonist, agouti-related protein (AGRP), is a potent stimulant of food intake. We examined the effect of chronic intracerebroventricular (ICV) AGRP treatment on energy metabolism and pituitary function in ad libitum fed rats and rats administered AGRP and then pair-fed to a saline control group. Chronic ICV AGRP (83-132) administration (1 nmol/day for 7 days) significantly increased food intake and body weight in ad libitum fed animals compared with saline-treated controls (body weight on day 7: 272 +/- 6 [saline] vs. 319 +/- 8 g [AGRP ad libitum fed]; P < 0.001). A significant increase in the epididymal fat pad weight, interscapular brown adipose tissue (BAT) weight, and plasma leptin was also observed in the ad libitum fed group. In the AGRP pair-fed group, a significant increase in the epididymal fat pad weight, BAT weight, and plasma leptin was again observed, suggesting that AGRP caused metabolic changes independent of increased food intake. BAT uncoupling protein 1 (UCP-1) content was significantly decreased compared with saline controls in both the AGRP ad libitum fed (21 +/- 8% of saline control; P < 0.01) and AGRP pair-fed groups (24 +/- 7% of saline control; P < 0.01). Plasma thyroid-stimulating hormone (TSH) was significantly suppressed compared with saline controls in both the AGRP ad libitum fed and AGRP pair-fed groups (3.5 +/- 0.3 [saline] vs. 2.7 +/- 0.4 [AGRP ad libitum fed] vs. 2.1 +/- 0.2 ng/ml [AGRP pair-fed]; P < 0.01). This study demonstrates that independent of its orexigenic effects, chronic AGRP treatment decreased BAT UCP-1, suppressed plasma TSH, and increased fat mass and plasma leptin, suggesting that it may play a role in energy expenditure.

Hypothalamic localization of the feeding effect of agouti-related peptide and alpha-melanocyte-stimulating hormone.

The melanocortin-4 receptor (MC4R) in the hypothalamus is thought to be important in physiological regulation of food intake. We investigated which hypothalamic areas known to express MC4R are involved in the regulation of feeding by using alpha-melanocyte-stimulating hormone (alpha-MSH), an endogenous MC4R agonist, and agouti-related peptide (Agrp), an endogenous MC4R antagonist. Cannulae were inserted into the rat hypothalamic paraventricular (PVN), arcuate (Arc), dorsomedial (DMN), and ventromedial (VMN) nuclei; the medial preoptic (MPO), anterior hypothalamic (AHA), and lateral hypothalamic (LHA) areas; and the extrahypothalamic central nucleus of the amygdala (CeA). Agrp (83-132) (0.1 nmol) and [Nle4, D-Phe7]alpha(-MSH (NDP-MSH) (0.1 nmol), a stable alpha-MSH analog, were administered to fed and fasted rats, respectively. The PVN, DMN, and MPO were the areas with the greatest response to Agrp and NDP-MSH. At 8 h postinjection, Agrp increased feeding in the PVN by 218 +/- 23% (P < 0.005), in the DMN by 268 +/- 42% (P < 0.005), and in the MPO by 236 +/- 31% (P < 0.01) compared with a saline control group for each nucleus. NDP-MSH decreased food intake in the PVN by 52 +/- 6% (P < 0.005), in the DMN by 44 +/- 6% (P < 0.0001), and in the MPO by 55 +/- 6% (P < 0.0001) at 1 h postinjection. Injection into the AHA and CeA resulted in smaller alterations in food intake. No changes in feeding were seen after the administration of Agrp into the Arc, LHA, or VMN, but NDP-MSH suppressed food intake in the Arc and LHA. This study indicates that the hypothalamic nuclei expressing MC4R vary in their sensitivity to Agrp and alpha-MSH with regard to their effect on feeding.

Structure of bacterial flagellar filaments at 11 A resolution: packing of the alpha-helices.

Recent advances in the analysis of electron micrographs of frozen, hydrated bacterial filaments have allowed us to average data from more than 150 images and to reconstruct the bacterial flagellar filament of Salmonella typhimurium at a resolution of approximately 11 A. In addition to the outermost features seen in earlier lower resolution maps of the filament, we find a pair of concentric tubes which surround a approximately A diameter channel at the center of the structure. The walls of these tubes are composed of rod-like features which we have interpreted as columns of individual alpha-helices stacked end-to-end. Each column runs approximately parallel to the helix axis. The wall of the innermost tube, at a radius of approximately 20 A, is formed from 11 such columns. The wall of the second tube is formed from 22 columns which occur alternately at radii of approximately 43 and approximately 47 A. The two concentric tubes are held apart by spacers. These are short, rod-like features, which run approximately parallel to the helix axis. We have interpreted these as additional alpha-helices. By symmetry, each flagellin monomer contributes an alpha-helix to the inner tube, two alpha-helices to the outer tube and a fourth alpha-helix to the spacer. We have tentatively assigned one type of alpha-helix in the outer tube to the approximately 30 C-terminal residues of flagellin while the remaining three alpha-helices are assigned to the approximately 70 N-terminal residues. This interpretation of the reconstruction is consistent with available biochemical, biophysical and amino acid sequence information. We also present details of improved methodology to extract and evaluate the original data and also to assess the statistical significance of features in the three-dimensional map.

Three-dimensional structural analysis of tetanus toxin by electron crystallography.

Two-dimensional crystalline arrays of native tetanus toxin have been formed at the interface between a solution of the toxin and a phospholipid monolayer containing a ganglioside. Electron crystallographic analysis has been used to study these periodic arrays. The arrays obey the symmetry of plane group p12(1), with a = 126 A and b = 84 A, and a thickness of 90 A (1 A = 0.1 nm). The three-dimensional structure of tetanus toxin in negative stain is reconstructed to a nominal resolution of 14 A from multiple tilt images. The molecule presents an asymmetric three-lobed structure and could interact with the monolayer in two possible orientations.

Domain organization of the subunit of the Salmonella typhimurium flagellar hook.

The deduced amino acid sequences of the family of axial proteins of the bacterial flagellum possess N and C-terminal heptad repeats of hydrophobic amino acid residues, which suggests that these proteins all fold to form bundles of alpha-helices (e.g. coiled coils). There is evidence that flagellin, which is one of the axial proteins, has an axially oriented bundle of alpha-helices that gives rise to the inner, rod-shaped domains seen in electron density maps. We present evidence that a second member of the family, the hook subunit, also has such an axially oriented, rod-shaped domain. In three-dimensional reconstructions from electron micrographs of the helical hook of Salmonella typhimurium, the rod-shaped domain has a diameter of 18 A, which is that expected for a coiled coil. The corresponding domain in the flagellin subunit of the filament, however, is larger, having a diameter of 24 A suggesting a bundle of three or more alpha-helices. In addition to the rod-shaped domain, the hook has two other domains. At a radius of 55 A is the middle spheroidal domain about 25 A in diameter and at a radius of 75 A is the outer ellipsoidal domain about 20 A by 30 A by 40 A. The flagellin subunit also has a middle and an outer domain although they appear different from those of the hook. This is no doubt a result of the lack of any sequence similarity of the hook and flagellin subunits, apart from the N and C-terminal heptad repeats. Along the hook axis, there is a 25 A wide channel, which presumably serves in the export of hook and flagellin subunits in the assembly of the filament. There is a comparably sized channel in the filaments as deduced from electron micrographs. Thus, electron microscopy consistently finds a small channel, whereas in X-ray diffraction studies of the filament, the channel size appeared to be about 60 A. At a diameter of 60 A, the channel could pass the flagellin or hook subunit in its completely folded state, but if the channel is only 25 A in diameter, the subunit would have to be at least partially unfolded in order to pass through the channel.

A comparison of the yeast and rabbit 80 S ribosome reveals the topology of the nascent chain exit tunnel, inter-subunit bridges and mammalian rRNA expansion segments.

Protein synthesis in eukaryotes is mediated by both cytoplasmic and membrane-bound ribosomes. During the co-translational translocation of secretory and membrane proteins, eukaryotic ribosomes dock with the protein conducting channel of the endoplasmic reticulum. An understanding of these processes will require the detailed structure of a eukaryotic ribosome. To this end, we have compared the three-dimensional structures of yeast and rabbit ribosomes at 24 A resolution. In general, we find that the active sites for protein synthesis and translocation have been highly conserved. It is interesting that a channel was visualized in the neck of the small subunit whose entrance is formed by a deep groove. By analogy with the prokaryotic small subunit, this channel may provide a conserved portal through which mRNA is threaded into the decoding center. In addition, both the small and large subunits are built around a dense tubular network. Our analysis further suggests that the nascent chain exit tunnel and the docking surface for the endoplasmic reticulum channel are formed by this network. We surmise that many of these features correspond to rRNA, based on biochemical and structural data. Ribosomal function is critically dependent on the specific association of small and large subunits. Our analysis of eukaryotic ribosomes reveals four conserved inter-subunit bridges with a geometry similar to that found in prokaryotes. In particular, a double-bridge connects the small subunit platform with the interface canyon on the large subunit. Moreover, a novel bridge is formed between the platform and the base of the L1 domain. Finally, size differences between mammalian and yeast large subunit rRNAs have been correlated with five expansion segments that form two large spines and three extended fingers. Overall, we find that expansion segments within the large subunit rRNA have been incorporated at positions distinct from the active sites for protein synthesis and translocation.

Work stress and physical assault of nursing aides in rural nursing homes with and without dementia special care units.

PURPOSE: This study compared nursing aides (NAs) employed in rural nursing homes with and without dementia special care units (SCUs) on (1) exposure to and distress from disruptive behaviours exhibited by residents, (2) job strain and (3) physical assault. DESIGN AND METHODS: The data were drawn from a larger study conducted in Saskatchewan, Canada, in which all rural nursing homes of < or = 100 beds that had an SCU were matched to same-sized rural facilities with no SCU. Nursing aides (n = 355) completed a mailed survey questionnaire. RESULTS: Nursing aides employed in nursing homes with an SCU reported significantly less frequent exposure to disruptive behaviours (including aggressive and aversive behaviours) than NAs in non-SCU facilities, less distress when these behaviours were directed toward them, less exposure to aggressive behaviour during caregiving, lower job demands and lower job strain. There was a trend toward increased risk of being assaulted in the last year associated with being in a non-SCU facility. Having a permanent position, increased job strain, and feeling inadequately prepared for dementia care were significantly associated with higher risk of being assaulted. In the SCU facilities, NAs who worked more time on the SCU reported more assaults but less distress from disruptive behaviour, lower psychological job demands, lower job strain and greater work autonomy. IMPLICATIONS: Providing more dementia care training and reducing job demands and job strain may help to reduce work-related stress and physical assault of nursing aides employed in nursing homes.

Irritable bowel syndrome is significantly associated with somatisation in 840 patients, which may drive bloating.

BACKGROUND: Psychological factors may influence persistence and perceived severity of symptoms in irritable bowel syndrome (IBS). Literature suggests that somatisation is associated with IBS. However, the relationship between IBS subtype, symptoms of IBS and somatisation is unclear. AIM: To examine this issue in a large cohort of secondary care patients. METHODS: Demographic and gastrointestinal (GI) symptom data were collected from 4224 adult patients via the Rome III questionnaire. Somatisation data were collected using the patient health questionnaire-12. Mean somatisation score and number of somatic symptoms were compared between IBS patients and controls with minimal GI symptoms, and between IBS subtypes using analysis of variance. Effect of level of somatisation on symptom frequency was compared according to IBS subtype using a χ(2) test. RESULTS: 840 patients met Rome III criteria for IBS, controls were 2137 patients with GI symptoms without IBS. Mean somatisation scores and number of somatic symptoms were higher in IBS vs. controls (P < 0.001), and in mixed stool pattern IBS (IBS-M), vs. IBS with constipation (IBS-C) or diarrhoea (IBS-D) (P < 0.001). High levels of somatisation were more prevalent in IBS-M (31.7%) vs. IBS-C (22.5%) or IBS-D (20.8%) (P = 0.003). For all IBS subtypes, high levels of somatisation were associated with a greater frequency of bloating or abdominal distension prior to logistic regression. CONCLUSIONS: IBS is strongly associated with higher levels of somatisation, particularly IBS-M. Bloating may be associated with higher levels of somatisation, perhaps explaining why it can be difficult to treat.

No increase in prevalence of somatization in functional vs organic dyspepsia: a cross-sectional survey.

BACKGROUND: Psychological factors are associated with functional gastrointestinal (GI) disorders. Literature suggests that somatization is associated with functional dyspepsia (FD). However, the relationship between organic dyspepsia (OD), FD, and FD subtypes and somatization is poorly described. We aimed to examine this issue in a cross-sectional study of secondary care patients. METHODS: Demographic and GI symptom data were collected from 4224 adult patients via the Rome III questionnaire. Somatization data were collected using the patient health questionnaire-12. Mean somatization score and number of somatic symptoms were compared between patients with organic and FD, and between FD subtypes using analysis of variance. The same comparison was undertaken for the proportion of patients reporting individual somatic symptoms. KEY RESULTS: Exactly, 783 patients met criteria for dyspepsia, of whom 231 (29.5%) had organic disease following upper GI endoscopy. Mean somatization scores and number of somatic symptoms were no higher in functional vs OD (p = 0.23; p = 0.19). In addition, while the prevalence of somatization in FD was relatively high, there was no difference in severity of somatization in FD subgroups. CONCLUSIONS & INFERENCES: Somatization is associated with functional and OD to the same degree. Overall severity of somatization did not appear to vary according to FD subtype.

Expression of a novel receptor for the calcitonin peptide family and a salmon calcitonin-like peptide in the alpha-thyrotropin thyrotroph cell line.

We have previously shown an increased incidence of alpha-subunit-producing thyrotroph tumors after salmon calcitonin (sCT) injection into rats. However, it is not clear whether the effects of CT are direct or indirect. Our hypothesis was that for sCT to act directly, it must have a binding site on thyrotrophs. The alpha TSH cell line was used as a model for thyrotrophs. Receptor binding studies using alpha TSH membranes revealed a high affinity binding site for sCT [IC50 = 0.97 +/- 0.18 nM (n = 4); Kd = 5.45 +/- 0.43 nM (n = 3); binding capacity = 6.6 pmol/mg protein (n = 3)]. Rat CT did not compete with binding at this site. Receptor screening for other CT peptide family members revealed high specific binding for CT gene-related peptide (CGRP; IC50 = 0.25 +/- 0.08 nM; n = 3) and islet amyloid polypeptide (IC50 = 4.36 +/- 1.1 nM; n = 3). This together with the absence of rat CT binding excluded a conventional CT-binding site, and we propose a site similar to the CGRP subtype III receptor described in the rat nucleus accumbens. Guanosine 5'O-(3-thiotriphosphate) (GTP gamma S) (20 microM), reduced [125I]CGRP binding to 38% of maximal, indicating that this site is G-protein coupled. Immunocytochemically, all of the cells displayed intense sCT-like immunoreactivity, which was totally abolished by preabsorption of the antibody with sCT. The presence of this receptor supports the hypothesis that sCT mediates tumorigenesis via a direct pituitary action and, together with the coexistence of a sCT-like peptide in these cells, provides evidence for a possible autocrine role of this peptide in the control of thyrotroph function.