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.

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.

Pharmacokinetics and systemic bioavailability of menogaril, an anthracycline antitumor agent, in the mouse, dog, and monkey.

Menogaril is an antitumor agent of the anthracycline type which is less cardiotoxic than doxorubicin in a chronic rabbit model and is active in experimental tumor systems when given by p.o. or parenteral routes. It is currently undergoing i.v. and p.o. Phase II clinical evaluation. We report here the results of pharmacokinetic and systemic bioavailability studies of menogaril in three species (mouse, dog, and monkey). Upon i.v. administration, menogaril plasma concentration-time curves declined in a biexponential (dog) or triexponential (mouse and monkey) manner, with the terminal disposition half-life (t1/2) being considerably shorter in the dog (2.86 +/- 0.47 h) than in the mouse and monkey (21.6 and 19.0 +/- 3.7 h, respectively). The systemic clearance (CL, in liters/h/kg) was highest in mouse (6.2), followed by dog (2.9) and then monkey (1.4). The drug was extensively distributed in all three species, with steady state volumes of distribution being 88.5, 9.8, and 27.9 liters/kg in the mouse, dog, and monkey, respectively. One, two, and three metabolites were detected in the plasma of mice, monkeys, and dogs, respectively, using reverse phase high performance liquid chromatography. The major fluorescent metabolite in all species coeluted with authentic N-demethyl-menogaril; the other two metabolites were present at low concentrations relative to unchanged menogaril and its putative N-demethylated metabolite. One of these metabolites, which was found in both the dog and monkey, eluted with authentic (7R)-nogarol. Mean maximum plasma concentrations of the putative N-demethylmenogaril metabolite were approximately one-tenth those of menogaril in all three species following i.v. drug administration. Upon p.o. treatment, first-pass metabolism or incomplete absorption reduced the systemic bioavailability to 12% in the dog and 33% in the mouse and monkey. N-Demethylmenogaril was the major fluorescent metabolite observed in the plasma of p.o. treated animals. Interspecies comparison of menogaril pharmacokinetic parameters in mice, dogs, monkeys, and humans using allometric techniques indicated that the parameters for mice, monkeys, and humans were highly correlated; in each of these species presystemic metabolism of p.o. administered menogaril reduced its systemic bioavailability to an equivalent extent (30-35%). To determine if metabolically formed N-demethylmenogaril might contribute to the overall antitumor activity of menogaril, we determined the effect of synthetic N-demethylmenogaril on the life span of mice bearing P388 leukemia. Results indicated that the metabolite is marginally active compared to menogaril itself.

Phase I study of intravenous menogaril administered intermittently.

Thirty-three adult patients with solid tumors were treated with menogaril, a new anthracycline antibiotic. The drug was given as a two-hour infusion every 4 to 5 weeks at doses ranging from 17 to 250 mg/m2. The maximum tolerated dose was 250 mg/m2. Reversible and dose-related leukopenia was the dose-limiting toxicity. Thrombocytopenia was less frequent. Hematologic toxicity was maximal 2 weeks after treatment, and recovery usually occurred within 4 weeks. There was no dissociation between WBC and neutrophil counts, and myelosuppression did not appear to be cumulative up to 200 mg/m2. Myelosuppression was more severe for patients with heavy pretreatment and/or bone marrow involvement. Local toxicity consisting of phlebitis and/or erythema was the most common nonhematologic toxicity, especially at 250 mg/m2 (eight out of nine patients). Usually, erythema appeared within 24 hours after treatment at or near the infusion site and resolved within a few days. Occasionally, a more persistent (several weeks) orange discoloration suggesting cutaneous deposits of menogaril was observed. Nausea and vomiting were uncommon and never severe. Alopecia and mucositis were rare. Minor arrhythmias were seen in several patients during treatment, but their relationship with menogaril therapy was unclear, and in no patient did heart failure develop. Plasma concentrations were best described by a tricompartmental model with a mean terminal half-life of 29.5 hours and a mean total-body clearance of 20.2 L/h/m2. Doses of 160 and 200 mg/m2 are recommended for phase II trials in poor- and good-risk patients, respectively.

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.

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.

Targeting delavirdine/atevirdine resistant HIV-1: identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors.

A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted screening. Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions). Further structural modifications were required to inhibit metabolism and modulate solubility in order to obtain compounds with the desired biological profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most suitable characteristics were compounds 7, 15, and 36.

Influence of H2 receptor antagonists on the disposition of flurbiprofen enantiomers.

The effect of oral cimetidine or ranitidine on the pharmacokinetics of the R and S enantiomers of the nonsteroidal anti-inflammatory drug flurbiprofen and its major metabolite, 4'-hydroxyflurbiprofen, was evaluated. Nine healthy volunteers participated in a randomized crossover design study with the following treatments: (A) flurbiprofen 200 mg; (B) flurbiprofen 200 mg plus ranitidine 150 mg bid for 7 days before and for 2 days after receiving flurbiprofen and (C) flurbiprofen 200 mg plus cimetidine 300 mg qid for 7 days before and for 2 days after receiving flurbiprofen. Blood and urine samples were collected at various intervals during a 48-hour period. These samples were assayed stereospecifically for flurbiprofen and its metabolite. Small but statistically significant differences in the terminal elimination rate constant (K), maximum peak serum drug concentration (Cmax), time to reach peak concentration (tmax), oral clearance (Cl/F) and area under the curve (AUC) were noted for flurbiprofen enantiomers. No significant treatment*isomer interactions were observed, indicating that neither cimetidine nor ranitidine interacted stereospecifically with flurbiprofen. Cimetidine, but not ranitidine, resulted in small (less than or equal to 15%) but statistically significant changes in flurbiprofen pharmacokinetic parameters. The interaction between H2-antagonists and flurbiprofen is unlikely to be clinically important.

Toward an automated analysis system for nuclear magnetic resonance imaging. II. Initial segmentation algorithm.

Image segmentation algorithms based on hierarchical clustering have been developed for analysis of T1 and T2 nuclear magnetic resonance images. Application of these algorithms to simultaneous T1-T2 images of healthy volunteers extracted fundamental tissue types in the brain. These algorithms also were used both to identify the extent of the region of involvement of a subject with a history of a grade 3 astrocytoma of the right frontal lobe of the brain, and to characterize the tissue within the region of involvement. These results suggest that a simple segmentation algorithm can produce reasonable clustering of tissue types within the brain.

Toward an automated analysis system for nuclear magnetic resonance imaging. I. Efficient pulse sequences for simultaneous T1-T2 imaging.

Simultaneous T1 and T2 images have been obtained using multiple-echo self-normalizing sequences. Differential T1 and T2 discrimination for two of these sequences, double saturation recovery and inversion-saturation recovery, have been explored in detail. The inversion-saturation recovery sequence exhibits T1 discrimination comparable to, and in many cases better than, that of optimal T1 weighted conventional pulse sequences, but is poor for T2 imaging. The double saturation recovery sequence yields comparable tissue discrimination for T1 and T2 imaging, but is poor compared to optimal T1 weighted and T2 weighted conventional pulse sequences. Simultaneous T1 and T2 images represent quantitative maps of intrinsic tissue properties, and hence form a natural basis for an automated image analysis and tissue classification system.

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.

The growth of carcinogen-induced colon cancer in rats is inhibited by cimetidine.

Colon cancer was induced in 40 Sprague Dawley rats using a 10-week course of 1,2 dimethylhydrazine (DMH). Twenty animals received cimetidine in their drinking water, commencing 5 weeks after concluding the course of DMH. After five weeks treatment of the animals were sacrificed and the colon and rectum excised. Tumours were assessed histologically for depth of invasion, inflammatory cell response and stained for Proliferating Cell Nuclear Antigen (PCNA), as a measure of tumour proliferative index. PCNA staining was measured using a computerized image analysis system. There were 25 tumours in the cimetidine treated group and 20 in controls. In the control group, 10% of the tumours were benign, 35% malignant polyps, 40% invading through submucosa and 15% invading through the bowel wall, as opposed to 40%, 44%, 8% and 8%, respectively in the cimetidine group (Chi squared test: P = 0.002). The mean proliferative index for control tumours was 27.9% and for the cimetidine tumours 23.1% t test: P = 0.002). It is concluded that cimetidine inhibits colon cancer cellular proliferation and slows early tumour invasion in this animal model.

A randomized trial of cimetidine with 5-fluorouracil and folinic acid in metastatic colorectal cancer.

Cimetidine has demonstrated a survival benefit in a randomized trial as adjuvant therapy for gastric cancer. We have demonstrated expression of histamine receptors on colon cancer cell lines and inhibition of their growth with cimetidine. Cimetidine also activates suppressor T cells and stimulates cell-mediated immunity. We therefore performed a randomized controlled clinical trial to determine the effect of cimetidine 400 mg given twice daily in conjunction with chemotherapy vs chemotherapy alone. Thirty-eight patients were randomized and 35 patients were eligible for further analysis. Both groups were well matched for pre-treatment characteristics. There was no difference in overall response. There was, however, a significantly increased rate of CEA response in the cimetidine group. Four of 11 patients (36%) in the cimetidine group had a CEA response compared to none of eight in the control. Meaningful comparisons of overall survival cannot yet be made. This study demonstrates that cimetidine has encouraging activity in increasing CEA response in patients with metastatic colorectal cancer treated with chemotherapy. This observation needs to be extended in a larger randomized study, which is currently underway.

The Allen Brown shunt: a useful option for vascular access.

This study analyzes the performance of 273 Allen Brown arteriovenous shunts inserted in the thigh and anastomosed to the superficial femoral artery and either the superficial femoral vein or the long saphenous vein. The median duration of shunt function was 9 weeks (range: 0 to 175 weeks). A significantly longer median function time of 22 weeks was found in patients who had had more than five previous access procedures (p less than 0.02). No other independent variable affecting shunt function time was identified. There were 84 complications (56 due to infection) and 2 deaths in the series. The infection rate was not improved by the use of perioperative antibiotics, with most infections occurring more than 6 weeks after insertion. Since the complication rate for Allen Brown shunts was no greater than that reported for subclavian catheters, and their function no less reliable than that reported for Quinton-Scribner shunts, the Allen Brown shunt is a useful option for short- and medium-term vascular access. It may also be useful for longer-term access in the patient in whom failure of multiple previous access procedures has occurred.

Acute toxicity and urinary excretion of diphenyldiselenide.

The acute toxicity of diphenyldiselenide (DPDS) in the male Swiss mouse was found to be enhanced by pretreatment with phenobarbital of SKF-525A. DPDS decreased hepatic glutathione content by 50% at 1 h after administration. Following administration of 14C-DPDS, labelled metabolites were found in urine but not in bile or feces. Analysis of the urinary metabolites of 14C-DPDS showed that selenium-containing metabolites elute from a DEAE-Sephadex column in two fractions: the first has not been chemically characterized, while the second peak contained the glucuronide conjugates of C6H4(OH)SeH and C6H5SeH. Virtually all of the administered selenium is excreted within 5 days, while only about 36% of the 14C is excreted in the same time period. This discrepancy indicates metabolic scission of the carbon-selenium bond.

Specific and sensitive high-performance liquid chromatographic determination of glyburide.

A specific and sensitive high-performance liquid chromatographic method has been developed for the rapid determination of intact glyburide in dog serum. With butylparaben as an internal standard, 1 ml of acid-buffered serum was extracted with toluene and an aliquot of the toluene was evaporated to dryness. The redissolved residue was chromatographed on a microparticulate reversed-phase column, and quantitation was achieved by monitoring the UV absorbance of the eluate at 228 nm. The response was linear, and the lower detection limit was approximately 20 ng/ml. Assay precision, as estimated by analyzing replicate samples of a laboratory standard, was better than 6% (CV). The utility of the analytical methodology for the determination of this highly potent sulfonylurea in pharmacokinetic studies in the dog was demonstrated.

Absorption of triazolam from pelleted drug-diet mixtures by the mouse: quantitation of alpha-hydroxytriazolam in urine.

The absorption of triazolam from pelleted drug-diet mixtures by mice under steady-state conditions was determined for doses up to 150 mg/kg/day by measuring alpha-hydroxytriazolam, the principal urinary metabolite of triazolam in the mouse, in urine samples collected over a 24-hour period. Following beta-glucuronide glucuronosohydrolase hydrolysis of the urine, quantitation of alpha-hydroxytriazolam was accomplished using a specific reverse-phase liquid chromatographic method which utilized UV detection at 214 nm. Assay precision was greater than 2.7% (CV) over the concentration range of interest. Statistical analysis of the excretion data indicated that the mathematical relationship between the triazolam dose and the quantity of alpha-hydroxytriazolam excreted was linear for female mice and nonlinear for male mice. Triazolam absorption, as reflected by alpha-hydroxytriazolam urinary excretion data, increased with triazolam dose.

Selective time-reversal pulses for NMR imaging.

Using a nonlinear systems approach, a selective time-reversal pulse for multiple-slice-multiple-echo NMR imaging sequences has been developed. The results of both computer simulation and experiments on a 1.5 T imaging system demonstrate the markedly improved selectivity of the pulse compared to conventional time-reversal pulses.