Purification and characterization of a novel excitatory peptide from Conus distans venom that defines a novel gene superfamily of conotoxins.

An excitatory peptide, di16a, with 49 amino acids and 10 cysteine residues was purified and characterized from the venom of Conus distans. Five AA residues were modified: one gamma-carboxyglutamate (Gla), and four hydroxyproline (Hyp) residues. A cDNA clone encoding the precursor for the peptide was characterized; the peptide has a novel cysteine framework and a distinctive signal sequence that differs from any other conotoxin superfamily. The peptide was chemically synthesized and folded, and synthetic and native materials were shown to co-elute. Injection of the synthetic peptide causes a hyperexcitable phenotype in mice greater than 3 weeks of age at lower doses, and lethargy at higher doses. The peptide defines both a previously uncharacterized gene superfamily of conopeptides, and a new Cys pattern with three vicinal Cys residues.     

A cell-based approach to the minimization of immunosuppression in renal transplantation.

Five renal transplant recipients were preoperatively treated with transplant acceptance-inducing cells (TAICs) in a Phase-I safety study of TAICs as an adjunct immune-conditioning therapy in living-donor kidney transplantation. Initially, patients received anti-thymocyte globulin induction therapy in combination with tacrolimus and steroid immunosuppression. Over the course of 12 weeks, steroids were withdrawn and tacrolimus therapy was minimized. Three of the five patients were able to tolerate low-dose tacrolimus monotherapy and one patient was withdrawn from all immunosuppression for over 8 months. No acute or delayed adverse events were associated with the infusion of TAICs. Monitoring of the recipient anti-donor reactivity of TAIC-treated patients in mixed lymphocyte cultures demonstrated that, during periods of clinically stable graft function, recipient T-cell proliferation and cytokine secretion in response to stimulation with donor alloantigen was relatively suppressed. Therefore, although the TAIC-II trial did not provide conclusive evidence of a beneficial effect of preoperative TAIC treatment, the results were encouraging because they suggest that TAICs promote a state of alloantigen-specific unresponsiveness, which might allow safe minimization of pharmacological immunosuppression.     

Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives

On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis bioassay. Of these six (5, 6, 9a, 10, 11a, 11b), the most effective compound was found to be 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene (RS-43179, lonapalene, 11a). An extensive series of 1,2,3,4-tetraoxygenated naphthalenes (16-74) incorporating variations of the ester, ether, and aryl substituents were prepared as analogues of 11a to examine the structural requirements for activity and were screened in vivo as inhibitors of arachidonic acid induced mouse ear edema, a topical bioassay capable of detecting 5-lipoxygenase inhibitors. Net lipophilicity, hydrolytic stability, and ring substitution play significant roles in determining the observed in vivo activity. Lonapalene (11a) is currently in clinical development as a topically applied nonsteroidal antipsoriatic agent.     

Lower Lateral Orbitofrontal Cortex Density Associated With More Frequent Exposure to Television and Movie Violence in Male Adolescents

The relationship between cortical grey matter density and media violence exposure in healthy male adolescents was investigated using voxel-based morphometry and the Childrens' Report of Exposure to Violence. Adolescents with more frequent exposure have lower left lateral orbitofrontal cortex density—a possible risk factor for altered socioemotional functioning.     

Psychometric Evaluation of the Rasch-Based Depression Screening in Patients With Neurologic Disorders

Forkmann T, Norra C, Wirtz M, Gauggel S, Boecker M. Psychometric evaluation of the Rasch-based depression screening in patients with neurologic disorders.

Objectives

To provide a first evaluation of the Rasch-Based Depression Screening (DESC) in consecutive patients with neurologic disorders.

Design

Cross-sectional study.

Setting

Hospital specializing in neurologic disorders.

Participants

Eligible patients (N=323; mean age ± SD, 53.4±17.2y; 49.3% women) age 18 years and older.

Interventions

Not applicable.

Main outcome Measures

DESC with 2 parallel versions.

Results

Both versions of the DESC showed good item separation (DESC-I=4.96; DESC-II=4.94) and person separation (DESC-I=2.01; DESC-II=2.14) as well as item separation reliability (DESC-I=.96; DESC-II=.96) and person separation reliability (DESC-I=.80; DESC-II=.82). All items fit the Rasch model (infit and outfit mean squares ≤1.3). There were no signs of violation of unidimensionality. One item of DESC-I showed differential item functioning because of age and 1 item because of sex. Parallel test reliability of the 2 DESC forms was r equal to .92.

Conclusions

The DESC shows good psychometric characteristics that suggest high psychometric quality of the instrument in patients with neurologic disorders. Differential item functioning on single items needs further examination but should not substantially interfere with the valid interpretation of DESC sum scores.     

Long-term potentiation in the amygdala: a mechanism for emotional learning and memory

In the mammalian brain, LTP is an enduring form of synaptic plasticity that is posited to have a role in learning and memory. Compelling new evidence for this view derives from studies of LTP in the amygdala, a brain structure that is essential for simple forms of emotional learning and memory, such as Pavlovian fear conditioning in rats. More specifically, antagonists of the NMDA receptor block both amygdaloid LTP induction and fear conditioning, fear conditioning induces increases in amygdaloid synaptic transmission that resemble LTP, and genetic modifications that disrupt amygdaloid LTP eliminate fear conditioning. Collectively, these results provide the most-convincing evidence to date that LTP mediates learning and memory in mammals.