Facial emotion recognition and eye movement behaviour in conduct disorder.

BACKGROUND: Conduct Disorder (CD) is associated with impairments in facial emotion recognition. However, it is unclear whether such deficits are explained by a failure to attend to emotionally informative face regions, such as the eyes, or by problems in the appraisal of emotional cues. METHOD: Male and female adolescents with CD and varying levels of callous-unemotional (CU) traits and age- and sex-matched typically developing (TD) controls (aged 13-18) categorised the emotion of dynamic and morphed static faces. Concurrent eye tracking was used to relate categorisation performance to participants' allocation of overt attention. RESULTS: Adolescents with CD were worse at emotion recognition than TD controls, with deficits observed across static and dynamic expressions. In addition, the CD group fixated less on the eyes when viewing fearful and sad expressions. Across all participants, higher levels of CU traits were associated with fear recognition deficits and reduced attention to the eyes of surprised faces. Within the CD group, however, higher CU traits were associated with better fear recognition. Overall, males were worse at recognising emotions than females and displayed a reduced tendency to fixate the eyes. DISCUSSION: Adolescents with CD, and particularly males, showed deficits in emotion recognition and fixated less on the eyes when viewing emotional faces. Individual differences in fixation behaviour predicted modest variations in emotion categorisation. However, group differences in fixation were small and did not explain the much larger group differences in categorisation performance, suggesting that CD-related deficits in emotion recognition were not mediated by abnormal fixation patterns.

Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer.

It may be possible to achieve insulin sensitivity through the recently identified mitochondrial target of thiazolidinediones (mTOT), thereby avoiding peroxisome proliferator-activated receptor-γ (PPAR-γ)-dependent side effects. In this phase IIb clinical trial, 258 patients with type 2 diabetes completed a 12-week protocol with 50, 100, or 150 mg of MSDC-0160 (an mTOT modulator), 45 mg pioglitazone HCl (a PPAR-γ agonist), or a placebo. The two active treatments lowered fasting glucose levels to the same extent. The decreases in glycated hemoglobin (HbA1c) observed with the two higher doses of MSDC-0160 were not different from those associated with pioglitazone. By contrast, fluid retention as evidenced by reduction in hematocrit, red blood cells, and total hemoglobin was 50% less in the MSDC-0160-treated groups. There was also a smaller increase in high-molecular-weight (HMW) adiponectin with MSDC-0160 than with pioglitazone (P < 0.0001), suggesting that MSDC-0160 produces less expansion of white adipose tissue. Thus, mTOT modulators may have glucose-lowering effects similar to those of pioglitazone but without the adverse effects associated with PPAR-γ agonists.

Laparoscopic hand-assisted extended right hemicolectomy for cancer management.

UNLABELLED: Laparoscopic extended right hemicolectomy for cancer management is an uncommon operation because it is difficult to divide the middle colic vessels laparoscopically in an oncologic resection. Furthermore, some surgeons believe a left hemicolectomy is an adequate alternative. This study aimed to evaluate the feasibility of performing a laparoscopic hand-assisted extended right hemicolectomy for cancer located between the distal transverse colon and the proximal descending colon. The technique was described and demonstrated with a video presentation. The clinical outcome was recorded for four consecutive patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi: 10.1007/s00464-006-9128-1) contains supplementary material, which is available to authorized users.

Effects of copper, cadmium, and zinc on the hatching success of brine shrimp (Artemia franciscana).

Previous studies indicate that the hatching success of brine shrimp (Artemia franciscana) cysts is surprisingly sensitive to ambient metal concentrations. These studies estimated median effective concentrations (EC50s) of 7, 5, and 28 microg l-1 for Cd, Cu, and Zn, suggesting that the hatching end point for A. franciscana is the most sensitive tested to date for Cd and Zn in saline environments and comparable in sensitivity with the most sensitive tested to date for Cu. Furthermore, these data suggest that brine shrimp are at significant risk from Cu and Zn in Great Salt Lake (GSL), UT, where ambient concentrations as high as 10 and 14 microg l-1, respectively, have been measured. Given that brine shrimp appear to be successfully reproducing in GSL, we hypothesized that these toxicity values were either biased low as a result of an artifact of the test method used or that site-specific water-quality conditions in the lake had decreased metal bioavailability such that brine shrimp could successfully reproduce. To test these hypotheses, we initiated a step-wise series of experiments. First we investigated the effects of pretreatment of brine shrimp cysts with antibiotics on brine shrimp sensitivity to metals because previous investigators as part of their test methods have used antibiotics. Next we considered the effect of ionic composition of the artificial test media on sensitivity. Finally, we evaluated the effects of the site-specific water quality of the GSL on metal bioavailability and toxicity. Results indicate that pretreatment of cysts with antibiotics had no effect on sensitivity. However, we were unable to repeat the previous values for Cd and Zn, obtaining EC50s of 11,859 and 289 microg l-1 for Cd and Zn, respectively. For Cu, however, we estimated an EC50 of 12 microg l-1, so we conducted further testing on the artificial media, adjusting the media composition to better reflect the Ca2+ and HCO3- concentration of normal seawater. This increased the EC50 to 28 microg l-1. Finally we evaluated the toxicity of Cu in GSL water and obtained an EC50 of 68 microg l-1, suggesting that the increased dissolved organic carbon in GSL has a significant protective effect. Overall, the results of this study suggest that brine shrimp hatching success is not particularly sensitive to Cd and Zn, but it is sensitive to Cu. However, site-specific water-quality conditions ensure that brine shrimp cyst hatching success is not significantly affected by any of these metals at the normal background concentrations that occur in GSL (<15 microg l-1).

Assessing acute and chronic copper risks to freshwater aquatic life using species sensitivity distributions for different taxonomic groups.

Using copper as an example, we present a method for assessing chemical risks to an aquatic community using species sensitivity distributions (SSDs) for different taxonomic groups. This method fits probability models to chemical exposure and effects data to estimate the percentage of aquatic species potentially at risk and expands on existing probabilistic risk assessment methodologies. Due to a paucity of chronic toxicity data for many chemicals, this methodology typically uses an acute-chronic ratio (ACR) to estimate the chronic effects distribution from the acute effects distribution. We expanded on existing methods in two ways. First, copper SSDs were developed for different organism groups (e.g., insects, fish) that share similar sensitivities or ecological functions. Integration of exposure and effects distributions provides an estimate of which organism groups may be at risk. These results were then compared with a site-specific food web, allowing an estimation of whether key food web components are potentially at risk and whether the overall aquatic community may be at risk from the perspective of ecosystem function. Second, chronic SSDs were estimated using the relationship between copper ACRs and acute toxicity (i.e., the less acutely sensitive a species, the larger the ACR). This correction in the ACR removes concerns previously identified with use of the ACR and allows evaluation of a significantly expanded chronic data set with the same approach as that for assessing acute risks.

Acute toxicity of sodium selenate to two daphnids and three amphipods.

This study evaluated the acute toxicity of sodium selenate to two daphnid and three gammarid amphipod species. The daphnids, Ceriodaphnia dubia and Daphnia pulex, were evaluated in 48-hour static tests and the amphipods, Gammarus pseudolimnaeus, Gammarus lacustris, and Hyalella azteca, were evaluated in 96-hour static and flow-through tests. Tests resulted in mean LC50's of 1.92, 9.12, 1.82, 3.05, and 1.95 mg/L selenium for C. dubia, D. pulex, G. pseudolimnaeus, G. lacustris, and H. azteca, respectively. The LC50's for the G. pseudolimnaeus tests are more than 30-fold higher than previously reported LC50's for the same or similar species. The explanation for these differing results appears to be partially, but not entirely, explained by differences in ambient pH between the new studies and previous ones. Depending on how the new data are included in U.S. EPA's selenium freshwater quality criterion data set, the selenate acute water quality criterion (i.e., Criterion Maximum Concentration) increases from 12.8 to as high as 583 microg/L selenium.

Effects of sulfate on the acute toxicity of selenate to freshwater organisms.

This study evaluated the relationship between ambient sulfate concentrations and acute selenate toxicity to freshwater aquatic life. Previous studies indicated that increasing sulfate concentrations reduced selenate bioconcentration and toxicity. However, these studies generally were not conducted in a manner that was conducive to their use in deriving a water quality criterion. We compiled results from previous studies and generated additional data to help define a selenate-sulfate relationship for acute toxicity. Selenate toxicity was determined in standardized test waters with varying sulfate concentrations using Ceriodaphnia dubia, Gammarus pseudolimnaeus, Hyalella azteca, and Pimephales promelas as the test organisms. Analysis of test results indicated that a significant relationship does exist between acute selenate toxicity and ambient sulfate concentrations. Data from these tests and previous studies were combined to develop a statistical relationship sufficiently robust to derive a sulfate-dependent water quality criterion for selenate. The relationship is similar to those commonly derived between divalent metals and hardness to adjust water quality criteria.

Adverse developmental and reproductive effects of copper deficiency in Xenopus laevis.

The effect of copper (Cu) deficiency on the reproduction and development in Xenopus laevis was evaluated, culminating in the development of a defined concentration-response relationship. Separate groups of four adult frog pairs were fed one of three diets for 28 d: (1) low-copper (-Cu); (2) copper supplemented (+Cu); and (3) ASTM standard beef liver and lung (BLL). Embryos collected from frogs administered the -Cu diet had markedly decreased egg masses and viability rates and an increased rate of necrosis when compared to the other dietary treatments. Malformations in -Cu larvae included maldevelopment of the heart, eye, craniofacial region, brain, and notochord. Larvae from adults administered the -Cu diet showed delayed abnormal hindlimb development, characterized as selective reductive deficiencies distal to the femur, with poor cartilaginous development. A U-shaped dose-response curve characteristic of nutritional essentiality was developed for Cu. Overall, these studies indicated that embryos produced from frogs administered a -Cu diet are substantially less viable than embryos from frogs administered a +Cu or copper-adequate (BLL) diet.

Synthesis and structure-activity relationships of the (alkylamino)piperidine-containing BHAP class of non-nucleoside reverse transcriptase inhibitors: effect of 3-alkylpyridine ring substitution.

Development of resistance to currently approved HIV therapies has continued to fuel research efforts to improve the metabolic stability and spectrum of activity of the (alkylamino)piperidine-containing bis(heteroaryl)piperazine (AAP-BHAP) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis of analogues in which the usual 3-alkylamino substituent on the pyridine ring is replaced by a 3-alkyl substituent led to compounds which retained activity against recombinant P236L and wild-type (WT) reverse transcriptase (RT), while inhibition of the Y181C mutant RT was reduced relative to the activity of the 3-alkylamino-substituted congeners. Testing of representative analogues in an in vitro liver microsome assay indicated that the alkyl substituent would not appreciably improve the metabolic stability of the AAP-BHAP template. In vivo pharmacokinetic evaluation of three compounds confirmed these results in that high systemic clearances were observed. Nevertheless, one compound (13), PNU-103657, possessed oral bioavailability in rats approaching that of the structurally related NNRTI drug delavirdine which is currently on the market for the treatment of HIV infection.

Randomized trial of preoperative cimetidine in patients with colorectal carcinoma with quantitative assessment of tumor-associated lymphocytes.

BACKGROUND: Previous studies have suggested that cimetidine, a histamine-2 receptor antagonist with immunostimulatory effects, may improve survival in patients with colorectal carcinoma. This effect may be apparent by an increase in the number of peritumoral lymphocytes. A prospective, double blind, randomized, placebo-controlled trial of a short course of preoperative treatment with cimetidine in patients with colorectal carcinoma was performed to assess the effect of cimetidine on survival and on the number of peritumoral lymphocytes. METHODS: One hundred and twenty-five patients who were scheduled to undergo elective colon or rectal excision for carcinoma were randomized to receive either placebo or cimetidine preoperatively for 5 days. In addition to standard histopathology, immunohistochemistry and computer video image analysis were used to assess the number of peritumoral lymphocytes in an objective manner. Interim survival analysis according to the Kaplan-Meier method was performed. RESULTS: A trend toward a survival advantage in the group of patients receiving cimetidine (800 mg twice daily) compared with the placebo group was observed (P = 0.20, log rank test) that was most marked in patients with replication error negative tumors (P = 0.04). Similarly, in these two groups there was a trend toward an increase in the number of patients with a conspicuous lymphocytic infiltration (P = 0.10, chi-square test). However, there was no difference in the number of peritumoral lymphocytes as measured by image analysis. CONCLUSIONS: Based on the results of the current study, a short course of preoperative treatment with cimetidine does appear to have an effect on patient survival; however, the exact mechanism is unknown. The failure of this study to demonstrate a clear increase in the local lymphocyte response does not exclude an immunologic mechanism of action.

Robust and optimal use of information in stereo vision.

Differences between the left and right eye's views of the world carry information about three-dimensional scene structure and about the position of the eyes in the head. The contemporary Bayesian approach to perception implies that human performance in using this source of eye-position information can be analysed most usefully by comparison with the performance of a statistically optimal observer. Here we argue that the comparison observer should also be statistically robust, and we find that this requirement leads to qualitatively new behaviours. For example, when presented with a class of stereoscopic stimuli containing inconsistent information about eccentricity of gaze, estimates of this gaze parameter recorded from one robust ideal observer bifurcate at a critical value of stimulus inconsistency. We report an experiment in which human observers also show this phenomenon and we use the experimentally determined critical value to estimate the vertical acuity of the visual system. The Bayesian analysis also provides a highly reliable and biologically plausible algorithm that can recover eye positions even before the classic stereo-correspondence problem is solved, that is, before deciding which features in the left and right images are to be matched.

Histamine in human breast cancer.

BACKGROUND: Histamine inhibits lymphocyte function in vitro at concentrations of greater than 10(-6) mol/l. The aim of this study was to determine whether histamine concentrations in breast cancers were sufficient to produce an immunological effect. METHODS: Tumour and adjacent normal breast content of histamine was measured using a radioenzymatic assay in 29 patients having surgery for breast cancer. RESULTS: The median content of histamine in breast cancer tissue was 5.4 (range 0.9-27.3) microg/g (median concentration 4.5 x 10(-5) mol/l), and was significantly greater than that in adjacent breast tissue (P = 0.007). CONCLUSION: The concentration of histamine in breast cancer was sufficient to inhibit lymphocyte function and could be locally immunosuppressive.

Pilot study--cimetidine enhances lymphocyte infiltration of human colorectal carcinoma: results of a small randomized control trial.

BACKGROUND: Cimetidine preserves postoperative immune function and inhibits the growth of some cancers. In this study, the effect of cimetidine on the local immune response to colorectal carcinoma was investigated. METHODS: Forty-two patients scheduled for elective resection of colorectal carcinoma were randomized either to receive cimetidine for 1 week perioperatively or to act as controls. A lymphocyte density of 50 cells per high-power field (approximately 50% of the tumor/tissue interface) was considered a positive response. Patient survival was determined by Kaplan-Meier life table analysis. The effects of histamine and cimetidine on normal subject lymphocyte function was determined in a mitogen-stimulated proliferation assay. RESULTS: A positive lymphocyte response was observed in 5 of 24 control carcinoma patients (21%) and 10 of 18 cimetidine-treated carcinoma patients (56%) (P = 0.03). The presence of a lymphocyte response correlated with a better survival (P = 0.02). Histamine had an inhibitory effect on lymphocyte proliferation with a median effective dose of 5 x 10(-7) M. Cimetidine antagonized this effect with a negative logarithm of the cimetidine molar concentration required to reduce the effect of histamine in half of 6.55. CONCLUSIONS: Histamine inhibits normal lymphocyte function, antagonized by cimetidine at a histamine type 2 receptor. Cimetidine increases lymphocyte infiltration of primary colorectal carcinoma, possibly by overcoming the immunosuppressive effects of high local histamine concentrations. The presence of a local lymphocyte response correlates with an improved 3-year survival.

Histamine content in colorectal cancer. Are there sufficient levels of histamine to affect lymphocyte function?

Histamine has been found to stimulate growth of colorectal cancer in vitro and in vivo. Histamine has also been found to inhibit lymphocyte activity in vitro at concentrations greater than 10(-7) M. The aim of our study was to determine if the histamine concentrations in human colorectal cancer were sufficient to achieve these effects. We measured the histamine content in 31 colorectal cancer specimens using a radioenzymatic assay. Results were expressed as microgram histamine per gram of fresh tissue weight. Recovery and reproducibility studies were also carried out. The median histamine concentration in colorectal cancer tissue was 8.4 micrograms/g [7.6 x 10(-5)M], ranging from 0.3 microgram/g to 20.6 micrograms/g. The high concentration of histamine in colon cancer is enough to be locally immunosuppressive.

Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships and increased metabolic stability of novel substituted pyridine analogs.

The major route of metabolism of the bis(heteroaryl)piperazine (BHAP) class of reverse transcriptase inhibitors (RTIs), atevirdine and delavirdine, is via oxidative N-dealkylation of the 3-ethyl- or 3-isopropylamino substituent on the pyridine ring. This metabolic pathway is also the predominant mode of metabolism of (alkylamino)piperidine BHAP analogs (AAP-BHAPs), compounds wherein a 4-(alkylamino)piperidine replaces the piperazine ring of the BHAPs. The novel AAP-BHAPs possess the ability to inhibit non-nucleoside reverse transcriptase inhibitor (NNRTI) resistant recombinant HIV-1 RT and NNRTI resistant variants of HIV-1. This report describes an approach to preventing this degradation which involves the replacement of the 3-ethyl- or 3-isopropylamino substituent with either a 3-tert-butylamino substituent or a 3-alkoxy substituent. The synthesis, bioactivity and metabolic stability of these analogs is described. The majority of analogs retain inhibitory activities in enzyme and cell culture assays. In general, a 3-ethoxy or 3-isopropoxy substituent on the pyridine ring, as in compounds 10, 20, or 21, resulted in enhanced stabilities. The 3-tert-butylamino substituent was somewhat beneficial in the AAP-BHAP series of analogs, but did not exert a significant effect in the BHAP series. Lastly, the nature of the indole substitution sometimes plays a significant role in metabolic stability, particularly in the BHAP series of analogs.