Impairment in the recognition of facial expression: a case study.

In this study, a case (HY) is described. This man, now 25 yr. old, lived in a persistent vegetative state for 6 yr. after encephalitis at the age of 10 yr. He was reportedly impaired at recognizing fear, and in everyday life, apparently had impaired recognition of anger as well. In testing with facial expressions, no obvious differences between HY and normal controls in anger perceptions were found. In this study, Japanese and Caucasian models of facial expression were used; on these tests, HY was impaired at recognizing facial expressions of anger only in the Japanese models.

A case report of compensation in daily life of a person with memory problems: detailed functional use of memory aids over a five-year period.

Numerous studies have been conducted on memory aids for memory-impaired people. However, it is not known how they use these memory aids in a functional, practical way. A 20-year-old patient (MH) was monitored for five years to identify what memory aids or other means she used and how she used them to compensate for her memory problems, e.g., forgetting what was said by others in a few minutes and getting lost or turning in the wrong direction on a walk or in a building. Results indicated MH did not necessarily always use memory aids such as a notebook or calendar to compensate for her memory problems, although MH and her mother reported that she frequently used them in daily life. She coped with memory problems by using various "resources" besides the memory aid. These facts suggest that it may be necessary to redefine functionally useful compensations, which include both memory aids and resources in daily life.

Is processing emotional signals necessary for performance on tasks requiring understanding a "theory of mind".

In this case study, HY had lived in a persistent vegetative state for 6 years after onset of encephalitis at age 10. His processing of emotionally and socially meaningful information was impaired by the age of 20, as it is in individuals with amygdala damage; however, his performance on tasks requiring understanding a "theory of mind" improved by age 22. A series of responses to photographs of facial expressions and to a gambling task were obtained to evaluate his functioning related to the amygdala. He was particularly impaired in recognizing fear. One may tentatively suggest that processing emotional signals, i.e., functioning related to the amygdala, may not play an important role in the neural systems supporting development of understanding a "theory of mind".

Recognition and its impairment regarding autobiographical memories in a patient with hippocampal amnesia.

Autobiographical memories of one case (Y.K.) were assessed before and after onset of hippocampal amnesia. He was a 56-yr.-old male patient who used to work in an office. The findings can be described as follows. First, Y.K.'s recognition performance regarding his premorbid and postmorbid personal semantics along with premorbid autobiographical incidents was significantly greater than chance, and recognition of premorbid autobiographical incidents was within chance. Given information before onset, a relationship was suspected between frontal lobe dysfunction and Y.K.'s autobiographical problem. The possibility that an amnesic patient could acquire semantic information after onset is discussed.

Identification of a novel 4-aminomethylpiperidine class of M3 muscarinic receptor antagonists and structural insight into their M3 selectivity.

Identification of a novel class of potent and highly selective M(3) muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M(3) selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M(3) antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M(3) selective antagonist that had >100-fold selectivity versus the M(1), M(2), M(4), and M(5) receptors (M(3): K(i) = 0.30 nM, M(1)/M(3) = 570-fold, M(2)/M(3) = 1600-fold, M(4)/M(3) = 140-fold, M(5)/M(3) = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M(3) antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M(3) receptors.

Developmental order driving the relationship between executive functions and theory of mind: a case study.

Several studies have suggested there is a developmental link between executive functions and theory of mind. However, the developmental order driving the relationship is not well understood. The main reason is that the development of executive function parallels the development of theory of mind in normally developing children. In this paper, a case (H.Y.) is reported. H.Y. had lived in a persistent vegetative state for 6 years after encephalitis at the age of 10. He showed a developmental order driving the relationship between executive functions and theory of mind. These findings are consistent with recent suggestions that development of executive function might be important as a predecessor of either the ability to understand false beliefs or the ability to express that understanding.

Preferential inhibition of human phosphodiesterase 4 by ibudilast.

Ibudilast ophthalmic solution exhibited an improved clinical efficacy over cromoglycate in the treatment of allergic conjunctivitis. To further characterize its principal mode of action, the phosphodiesterase (PDE) inhibitory profile of ibudilast has been examined using human recombinant enzymes. Ibudilast, but not the other commonly used anti-allergic ophthalmic solutions including cromoglycate, ketotifen, tranilast and levocabastine, potently inhibits purified human PDE4A, 4B, 4C and 4D with IC50 values at 54, 65, 239 and 166 nM, respectively. Ibudilast effectively blocks lipopolysaccharide (LPS)-induced tumor necrosis factor (TNFalpha, IC50 = 6.2 microM) and N-formyl-Met-Leu-Phe (fMLP)-induced leukotriene (LT) B4 biosynthesis (IC50 = 2.5 microM) in human whole blood, which are 3 and 6-fold more potent than cilomilast, respectively. The attenuated inflammatory and allergic responses from the potent and preferential PDE4 inhibition of ibudilast may have contributed significantly to its beneficial pharmacological responses and distinguishes ibudilast from the other ophthalmic solutions in the treatment of ocular allergy.

Structure-activity relationships of 2-(benzothiazolylthio)acetamide class of CCR3 selective antagonist.

The structure activity relationships of novel selective CCR3 receptor antagonists, 2-(benzothiazolylthio)acetamimde derivatives were described. A lead structure (1a) was discovered from the screening of the focused library that was based on the structure of our dual antagonists for the human CCR1 and CCR3 receptors. Derivatization of 1a including incorporation of substituent(s) into each benzene ring of the benzothiazole and piperidine side chain resulted in the identification of potent and selective compounds (1b, r, s) exhibiting nano-molar binding affinity (IC(50)s: 1.5-3.0 nM) and greater than 800-fold selectivity for the CCR3 receptor over the CCR1 receptor.

Muscarinic M(3) receptor antagonists with (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxyphenylacetamide Structures. Part 2.

Optimization of the amine part of our original muscarinic M(3) receptor antagonist 1 was performed to identify M(3) receptor antagonists that are superior to 1. Compounds carrying a variety of diamine moieties without hydrophobic substituent on the nitrogen atom were screened against the binding affinity for the M(3) receptor and the selectivity for M(3) over the M(1) and M(2) receptors. This process led to a 4-aminopiperidinamide (2l) with a K(i) value of 5.1 nM and with a selectivity of the M(3) receptor that was 46-fold greater than that of the M(2) receptor. Further derivatization of 2l by inserting a spacer group or by incorporating alkyl group(s) into the amine part resulted in the identification of an 4-(aminoethyl)piperidinamide 2l-b with a K(i) value of 3.7 nM for the M(3) receptor and a selectivity for the M(3) receptor that was 170-fold greater than that of the M(2) receptor.

Structure-activity relationships of xanthene carboxamides, novel CCR1 receptor antagonists.

The structure-activity relationships of xanthene carboxamide derivatives on the CCR1 receptor binding affinity and the functional antagonist activity were described. Previously, we reported a quaternarized xanthen-9-carboxamide 1 as a potent human CCR1 receptor antagonist that was derived from a xanthen-9-carboxamide lead 2a. Further derivatization of 2a focusing on installing an additional substituent into the xanthene ring resulted in the identification of 2b-1 with IC(50) values of 1.8nM and 13nM in the binding assay using human CCR1 receptors transfected CHO cells and in the functional assay using U937 cells expressing human CCR1 receptors, respectively.

Identification of novel muscarinic M(3) selective antagonists with a conformationally restricted Hyp-Pro spacer.

The identification of potent and selective muscarinic M(3) antagonists that are based on the recently discovered triphenylpropioamide derivative, 1, and have a unique amino acid spacer group is described. The introduction of a hydroxyproline-proline group to the spacer site and the use of a propyl or cyclopropylmethyl group as the piperidine N-substituent led to the discovery of the novel M(3) selective antagonists [8c, 8g; K(i)<2 nM (M(3)), M(1)/M(3)>700-fold, M(2)/M(3)>180-fold], which have a more rigid structure than 1.

The subtypes of muscarinic receptors for neurogenic bladder contraction in rats.

We evaluated in vivo functional selectivity profiles for muscarinic M(2) and M(3) subtypes of four muscarinic antagonists: Compound A (a novel muscarinic receptor antagonist with M(2)-sparing antagonistic activity), darifenacin, (a muscarinic M(3) receptor antagonist); methoctramine (a muscarinic M(2) receptor antagonist) and tolterodine (a nonselective muscarinic receptor antagonist), and compared the inhibition potency on distention-induced bladder contraction in rats. In an in vivo functional study, Compound A (0.03-10 mg/kg, i.v.) showed antimuscarinic activity with high selectivity for M(3) (salivation) over M(2) (bradycardia) (>100-fold). Darifenacin (0.01-0.3 mg/kg, i.v.) showed only slight selectivity for M(3) over M(2) (3.7-fold). Methoctramine (0.003-1 mg/kg, i.v.) showed the reverse selectivity profile (0.077-fold). Tolterodine (0.003-0.3 mg/kg, i.v.) showed less selectivity (1.2-fold). Compound A at M(3) inhibitory doses (0.1 and 0.3 mg/kg, i.v.) showed inhibition in a distention-induced neurogenic bladder contraction model, and its maximal inhibitory effects were about 60% at an even higher dose (3 mg/kg). Methoctramine at M(2) inhibitory doses (0.03 and 0.1 mg/kg, i.v.) did not significantly affect distention-induced bladder contraction. When tolterodine and darifenacin caused inhibition of distention-induced bladder contraction, its maximal inhibitory effects were similar to that of Compound A. Therefore, these findings suggest that Compound A would be an excellent pharmacological tool to give a better understanding of which subtypes of muscarinic receptors act in bladder function so far, and muscarinic M(3), but not M(2), receptors mainly mediate the cholinergic component of distention-induced bladder contraction.

I cannot remember, but I know my past events: remembering and knowing in a patient with amnesic syndrome.

Case Y.K. has severe anterograde amnesia and a selective loss of specific personal episodes in his remote memories (Hirano & Noguchi, 1998). In this paper, we attempted to analyze remembering (R) and knowing (K) responses, that is, the relationship between autobiographical remembering and remembering accompanied by subjective experience. Although the rate of R responses was significantly higher than that of K responses in control subjects, Y.K.'s R responses were rare in all subtypes of remote memories. Based on these results, we conclude that Y.K.'s memories on autobiographical incident task were not based on episodic memory but rather on semantic memory. Thus, the autobiographical incidents he could recall were not episodic memory, and his semantic memory made him recall information as fact rather than episode.

6-Carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine derivatives: a novel class of endothelin receptor antagonists.

Compounds (2-5) with a 6-carboxy-5,7-diarylcyclopentenopyridine skeleton were designed, synthesized, and identified as a new class of potent non-peptide endothelin receptor antagonists. The regio-isomer 2 was found to show potent inhibitory activity with an IC(50) value of 2.4 nM against (125)I-labeled ET-1 binding to human ET(A) receptors and a 170-fold selectivity for ET(A) over ET(B) receptors. Furthermore, 2 displayed more potent in vivo activity than did the indan-type compound 1 in a mouse ET-1 induced lethality model, suggesting the potential of 2 as a new lead structure. Derivatization on substituted phenyl groups at the 5- and 7-positions of 2 revealed that a 3,4-methylenedioxyphenyl group at the 5-position and a 4-methoxyphenyl group at the 7-position were optimal for binding affinity. Further derivatization of 2 by incorporating a substituent into the 2-position of the 4-methoxyphenyl group led to the identification of a more potent ET(A) selective antagonist 2p with an IC(50) value of 0.87 nM for ET(A) receptors and a 470-fold selectivity. In addition, 2p showed highly potent in vivo efficacy (AD(50): 0.04 mg/kg) in the lethality model.

Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes.

To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).