Several lines of evidence have led us to postulate that afferent vagal hyperactivity could be an important factor in the pathophysiology of the eating disorder bulimia nervosa. Ondansetron is a ...peripherally active antagonist of the serotonin receptor 5-HT3, and is marketed for prevention of vagally-mediated emesis caused by cancer chemotherapeutic agents. We investigated the effects of ondansetron on bulimic behaviours in patients with severe and chronic bulimia nervosa in a randomised, double-blind, placebo-controlled study.
We enrolled patients with severe bulimia nervosa (at least seven coupled binge/vomit episodes per week). The patients were otherwise healthy, their weight was normal, and they were not receiving medical or psychiatric treatment. During the first week of the study, patients recorded all eating-behaviour events to establish a baseline. In the second week, all patients received placebo, but were told that they were receiving either placebo or active drug. At the end of this single-blind phase, patients were randomly assigned placebo or ondansetron (24 mg daily) for a further 4 weeks. The primary outcome measure was the number of binge/vomit episodes per week. Data were analysed by intention to treat.
29 patients met the inclusion criteria, of whom 28 completed the baseline study, and 26 completed the single-blind placebo week. 12 patients were assigned placebo, and 14 ondansetron; one patient in the ondansetron group dropped out owing to accidental injury. During the 4th week of double-blind treatment, mean binge/vomit frequencies were 13·2 per week (SD 11·6) in the placebo group, versus 6·5 per week (3·9) in the ondansetron group (estimated difference 6·8 95% CI 4·0–9·5; p<0·0001). The ondansetron group also showed significant improvement, compared with the placebo group, in two secondary indicators of disease severity. The amount of time spent engaging in bulimic behaviours was decreased on average by 7·6 h per week in the ondansetron group, compared with 2·3 h in the placebo group (estimated difference 5·1 0·6–9·7). Similarly, the number of normal meals and snacks increased on average by 4·3 normal eating episodes without vomiting per week in the ondansetron group, compared with 0·2 in the placebo group (estimated difference 4·1 1·0–7·2).
The decrease in binge-eating and vomiting under ondansetron treatment was not achieved by compensatory changes in eating behaviour such as by a smaller number of binges of longer duration, or by not eating, or by binge-eating without vomiting. Instead, our findings indicate a normalisation of the physiological mechanism(s) controlling meal termination and satiation. Since meal termination and satiety are mainly vagally mediated functions, since binge-eating and vomiting produce intense stimulation of vagal afferent fibres, and since ondansetron and other 5-HT3 antagonists decrease afferent vagal activity, the symptom improvement may result from a pharmacological correction of abnormal vagal neurotransmission.
The Generality of Working Memory Capacity Kane, Michael J; Hambrick, David Z; Tuholski, Stephen W ...
Journal of experimental psychology. General,
06/2004, Volume:
133, Issue:
2
Journal Article
Peer reviewed
Open access
A latent-variable study examined whether verbal and visuospatial working memory (WM) capacity measures reflect a primarily domain-general construct by testing 236 participants in 3 span tests each of ...verbal WM, visuospatial WM, verbal short-term memory (STM), and visuospatial STM, as well as in tests of verbal and spatial reasoning and general fluid intelligence (Gf). Confirmatory factor analyses and structural equation models indicated that the WM tasks largely reflected a domain-general factor, whereas STM tasks, based on the same stimuli as the WM tasks, were much more domain specific. The WM construct was a strong predictor of Gf and a weaker predictor of domain-specific reasoning, and the reverse was true for the STM construct. The findings support a domain-general view of WM capacity, in which executive-attention processes drive the broad predictive utility of WM span measures, and domain-specific storage and rehearsal processes relate more strongly to domain-specific aspects of complex cognition.
We present results from Chandra and XMM-Newton observations of Abell 98 (A98), a galaxy cluster with three major components: a relatively bright subcluster to the north (A98N), a disturbed subcluster ...to the south (A98S), and a fainter subcluster to the far south (A98SS). We find evidence for surface brightness and temperature asymmetries in A98N consistent with a shock-heated region to the south, which could be created by an early stage merger between A98N and A98S. Deeper observations are required to confirm this result. We also find that A98S has an asymmetric core temperature structure, likely due to a separate ongoing merger. Evidence for this is also seen in optical data. A98S hosts a wide-angle tail radio source powered by a central active galactic nucleus (AGN). We find evidence for a cavity in the intracluster medium that has been evacuated by one of the radio lobes, suggesting that AGN feedback is operating in this system. Examples of cavities in non-cool core clusters are relatively rare. The three subclusters lie along a line in projection, suggesting the presence of a large-scale filament. We observe emission along the filament between A98N and A98S, and a surface brightness profile shows emission consistent with the overlap of the subcluster extended gas halos. We find the temperature of this region is consistent with the temperature of the gas at similar radii outside this bridge region. Lastly, we examine the cluster dynamics using optical data. We conclude A98N and A98S are likely bound to one another with a 67% probability, while A98S and A98SS are not bound at a high level of significance.
Aims: In view of recent findings that a multidrug efflux pump CmeABC exists in Campylobacter jejuni, 391 C. jejuni and 52 Campylobacter coli of human and animal origin were examined for a multidrug ...resistance phenotype. Materials and methods: The MICs of ampicillin, chloramphenicol, ciprofloxacin, erythromycin, kanamycin, tetracycline, cetrimide, triclosan, acridine orange, paraquat and ethidium bromide were determined. Resistance to organic solvents and the effect of salicylate (known inducer of the marRAB operon in Escherichia coli and Salmonella) were also examined. Results: Two C. coli and 13 C. jejuni isolates, mainly from pigs or poultry, were resistant to three or more antibiotics and 12 of these strains had reduced susceptibility to acridine orange and/or ethidium bromide. Strains (n = 20) that were less susceptible to acridine orange, ethidium bromide and triclosan were significantly more resistant (P < 0.05) to ampicillin, chloramphenicol, ciprofloxacin, erythromycin, nalidixic acid and tetracycline, with two- to four-fold increases in MIC values compared with strains (n = 20) most susceptible to acridine orange, ethidium bromide and triclosan. Growth of strains with 1 mM salicylate caused a small (up to two-fold) but statistically significant (P ≤ 0.005) increase in the MICs of chloramphenicol, ciprofloxacin, erythromycin and tetracycline. Conclusions: These data indicate that multiple antibiotic resistant (MAR)-like Campylobacter strains occur and it may be postulated that these may overexpress cmeABC or another efflux system.
Dissection of the carotid artery can, in certain cases, lead to significant stenosis, occlusion, or pseudoaneurysm formation, with subsequent hemodynamic and embolic infarcts, despite anticoagulant ...therapy. We sought to determine the therapeutic value of stent-supported angioplasty retrospectively in this subset of patients who are poor candidates for medical therapy.
Five men and five women (age range, 37-83 years; mean age, 51.2 years) with dissection of the internal (n=9) and common (n=1) carotid artery were successfully treated with percutaneous endovascular balloon angioplasty and stent placement. The etiology was spontaneous in five, iatrogenic in three, and traumatic in two. Seven of the treated lesions were left-sided and three were right-sided.
The treatment significantly improved dissection-related stenosis from 74+/-5.5% to 5.5+/-2.8%. Two occlusive dissections were successfully recanalized using microcatheter techniques during the acute phase. Multiple overlapping stents were needed in four patients to eliminate the inflow zone and false lumen and establish an angiographically smooth outline within the true lumen. There was one case of retroperitoneal hemorrhage, but there were no procedural transient ischemic attacks (TIAs), minor or major strokes, or deaths (0%). Clinical outcome at latest follow-up (16.5+/-1.9 months) showed significant improvements compared with pretreatment modified Rankin score (0.7+/-0.3 vs 1.8+/-0.44) and Barthel index (99.5+/-0.5 vs 80.5+/-8.9). One delayed stroke occurred in a treated patient with contralateral carotid occlusion following a hypotensive uterine hemorrhage at 8 months; the remaining nine patients have remained free of TIA or stroke.
In select cases of carotid dissection associated with critical hemodynamic insufficiency or thromboembolic events that occur despite medical therapy, endovascular stent placement appears to be a safe and effective method of restoring vessel lumen integrity, with good clinical outcome.
Niemann-Pick type C (NPC) is a neurodegenerative disorder characterized by greatly altered somatic cholesterol metabolism. The
NPC1 gene has recently been cloned and shown to have sequence homology ...to other sterol-sensing proteins. We have used a mouse model with a disrupted
npc1 gene to study the effects of the cholesterol-mobilizing compound, 2-hydroxypropyl-β-cyclodextrins (HPBCD), on the clinical course of this disorder. Treatment with two HPBCDs, with varying levels of 2-hydroxypropyl substitution, had effects in delaying neurological symptoms and in decreasing liver cholesterol storage while a third HPBCD was without effect. The ameliorating effect was not improved by longer exposure times (commencement of exposure
in utero), however, it is not known if there is transplacental transfer of HPBCDs. The combination of HPBCD with probucol or nifedipine (which have previously been shown to lower liver cholesterol in this animal model) markedly decreased liver storage of unesterified cholesterol without altering the depressed levels of esterified cholesterol. The slight effects of the HPBCDs on neurological symptoms may be partially due to their apparent non-permeation of the blood-brain barrier (BBB). This non-permeation was assayed with radioactive tracers and was also present in the
mdr1a knockout mice which have greatly increased BBB permeability for many drugs. Intrathecal delivery of HPBCD by an Alzet
® osmotic minipump did not improve its efficacy in ameliorating neurological symptoms.
Objectives: To determine the mutant prevention concentrations (MPCs) of ciprofloxacin and enrofloxacin against four strains of Salmonella enterica serovar Enteritidis and four strains of S. ...Typhimurium including one fully susceptible, one multiply resistant (MAR), one GyrA mutant and one GyrA/MAR mutant. Further, to examine mutants arising after exposure to sub-MPC concentrations of the antibiotics for susceptibility to ciprofloxacin and enrofloxacin, and cyclohexane tolerance. Methods: MICs were determined using the agar dilution method of the BSAC. The MPC was recorded as the lowest concentration of antibiotic to inhibit growth from an inoculum of 1010 cfu. Results: The MPCs and resulting MPC/MIC ratios of enrofloxacin were generally two- to four-fold higher than for ciprofloxacin. At 24 h for both antibiotics, MPCs were lowest for the fully susceptible strains (0.25–0.5 mg/L), similar for the MAR (1–4 mg/L) and GyrA (2–4 mg/L) mutants and highest for the GyrA/MAR mutants (1–8 mg/L). MPC/MIC ratios at 24 h were 2–16 for all strains except those for the MAR strains without mutation in gyrA where the ratios were 8–64. Conclusions: The ability to eradicate Salmonella in vivo depends on many factors such as antibiotic susceptibility of the strain, dose and route of administration. It is suggested that these MPC values will be useful when considering dosing strategies. In view of the high MPC/MIC ratio, MAR strains with wild-type gyrA, although susceptible to ciprofloxacin (MICs 0.06–0.13 mg/L), may give rise to treatment failures.
ABSTRACT
Subsurface tile drains are a key source of nitrate N (NO3–N) losses to streams in parts of the north central USA. In this study, the Erosion Productivity Impact Calculator (EPIC) model was ...evaluated by comparing measured vs. predicted tile flow, tile NO3–N loss, soil profile residual NO3–N, crop N uptake, and yield, using 4 yr of data collected at a site near Lamberton, MN, for three crop rotations: continuous corn (Zea mays L.) or CC, corn–soybean Glycine max (L.) Merr. or CS, and continuous alfalfa (Medicago sativa L.) or CA. Initially, EPIC was run using standard Soil Conservation Service (SCS) runoff curve numbers (CN2) for CC and CS; monthly variations were accurately tracked for tile flow (r2 = 0.86 and 0.90) and NO3–N loss (r2 = 0.69 and 0.52). However, average annual CC and CS tile flows were underpredicted by −32 and −34%, and corresponding annual NO3–N losses were underpredicted by −11 and −52%. Predicted average annual tile flows and NO3–N losses generally improved following calibration of the CN2; tile flow underpredictions were −9 and −12%, whereas NO3–N losses were 0.6 and −54%. Adjusting a N parameter further improved predicted CS NO3–N losses. Predicted monthly tile flows and NO3–N losses for the CA simulation compared poorly with observed values (r2 values of 0.27 and 0.19); the annual drainage volumes and N losses were of similar magnitude to those measured. Overall, EPIC replicated the relative impacts of the three cropping systems on N fate.
Hereditary hemochromatosis (HH) is a common autosomal recessive disease characterized by increased iron absorption and progressive iron storage that results in damage to major organs in the body. ...Recently, a candidate gene for HH called HFE encoding a major histocompatibility complex class I-like protein was identified by positional cloning. Nearly 90% of Caucasian HH patients have been found to be homozygous for the same mutation (C282Y) in the HFE gene. To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, we studied the effects of a targeted disruption of the murine homologue of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates (96 ± 5% vs. 77 ± 3%, P < 0.007), and hepatic iron concentration was 8-fold higher than that of wild-type littermates (2,071 ± 450 vs. 255 ± 23 μ g/g dry wt, P < 0.002). Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. This study shows that the HFE protein is involved in the regulation of iron homeostasis and that mutations in this gene are responsible for HH. The knockout mouse model of HH will facilitate investigation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for prevention or correction of iron overload.
We present an XMM-Newton X-ray observation of the X-ray-bright E2 elliptical galaxy NGC 4649. In addition to bright diffuse emission, we resolve 158 discrete sources, 650 of which are likely to be ...LMXBs associated with NGC 4649. We find evidence for variability in three sources between this observation and a previous Chandra observation. Additionally, we detect five sources that were not detected with Chandra despite its better detection limit, suggesting that these sources have since brightened. The total X-ray spectrum of the resolved sources is well fit by a hard power law, while the diffuse spectrum requires a hard and a soft component, presumably due to the relatively soft diffuse gas and the harder unresolved sources. A deprojection of the diffuse emission revealed a radial temperature gradient that is hot in the center, drops to a minimum at about 20"-50" (1.6-4.1 kpc), and rises again in the outer regions. The diffuse emission appears to require a two-temperature model with heavy-element abundance ratios that differ from the solar values. We have verified the existence of faint radial features extending out from the core of NGC 4649 that had previously been seen with Chandra. The fingers are morphologically similar to radial features seen in hydrodynamic simulations of cooling flows in elliptical galaxies, and although their other properties do not match the predictions of the particular simulations used, we conclude that the radial fingers might be due to convective motions of hot outflowing gas and cooler inflowing gas. We also find evidence for a longer, previously undetected filament that extends to the northeastern edge of NGC 4649. The diffuse gas in the region of the filament appears to have a lower temperature and may also have a higher abundance as compared to nearby regions. There also appears to be an excess of X-ray sources along the filament, although the excess is not statistically significant. We conclude that the filament may be the result of a tidal interaction, possibly with NGC 4647, although more work is necessary to verify this conclusion.
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