Camus's L'étranger and the first description of a man with Asperger's syndrome.

The continued discussion about the meaning of Camus's famous novel, L'étranger, provoked a re-reading, and this, in turn, led to its clinical analysis and further investigation. The book rests entirely on the thoughts, words and actions of its central character, Meursault, and these were found to show impairment of social relationships, communication and interaction, with other traits diagnostic of the Asperger's subgroup of the autism spectrum disorder. It was then found that Camus had based Meursault on his close friend Galindo, and a search was therefore made for evidence of Galindo's character; this revealed him to be an intelligent but odd person, who exhibited the characteristic impairment of social and personal behavior of Asperger's syndrome. Thus, Camus had recognized and understood his friend's strange behavior before Asperger's syndrome had been defined; his use of it for the creation of Meursault is therefore the first published account of a man with this disorder. Many of the interpretations and ideas developed from Meursault's words, thoughts and actions must now be reconsidered, as they are a misreading of the words and behavior of a man with Asperger's syndrome. The outcome of this clinical examination of L'étranger is unique; it shows that a precise account of a person with a neurobehavioral disorder was made by a novelist before the disorder had been clinically defined.

The evolution of humor from male aggression.

The response to seeing a man riding a unicycle was reported to be consistently related to the viewer's sex and stage of physical development. To see if this observation was universal, observations of responses were collected from 23 male and 9 female unicyclists aged 15-69 years, with 2-40 years cycling experience across four continents. With two exceptions among men, the findings were the same as those originally reported: children showed interest and curiosity, young girls showed little interest, while adult women showed a kindly, concerned, praising response. By contrast, boys showed physical aggression, which became more verbal, merging in the later teens to the snide, aggressive, stereotyped humorous response shown by adult males, which became less frequent in elderly men. The universality of the response across different individuals, environments, and dates of observation suggests an endogenous mechanism, and the association with masculine development relates this to androgen. The theoretical consequences are discussed. It is concluded that humor develops from aggression in males and is evolutionarily related to sexual selection.

Characterization of neuropeptide Y2 receptor protein expression in the mouse brain. I. Distribution in cell bodies and nerve terminals.

Neuropeptide Y (NPY), a 36-amino-acid peptide, mediates biological effects by activating Y1, Y2, Y5, and y6 receptors. NPY neurons innervate many brain regions, including the hypothalamus, where NPY is involved in regulation of a broad range of homeostatic functions. We examined, by immunohistochemistry with tyramide signal amplification, the expression of the NPY Y2 receptor (Y2R) in the mouse brain with a newly developed rabbit polyclonal antibody. Y2R immunoreactivity was specific with its absence in Y2R knockout (KO) mice and in adjacent sections following preadsorption with the immunogenic peptide (10(-5) M). Y2R-positive processes were located in many brain regions, including the olfactory bulb, some cortical areas, septum, basal forebrain, nucleus accumbens, amygdala, hippocampus, hypothalamus, substantia nigra compacta, locus coeruleus, and solitary tract nucleus. However, colchicine treatment was needed to detect Y2R-like immunoreactivity in cell bodies in many, but not all, areas. The densest distributions of cell bodies were located in the septum basal forebrain, including the bed nucleus, and amygdala, with lower density in the anterior olfactory nucleus, nucleus accumbens, caudal striatum, CA1, CA2, and CA3 hippocampal fields, preoptic nuclei lateral hypothalamus, and A13 DA cells. The widespread distribution of Y2R-positive cell bodies and fibers suggests that NPY signaling through the Y2R is common in the mouse brain. Localization of the Y2R suggests that it is mostly presynaptic, a view supported by its frequent absence in cell bodies in the normal mouse and its dramatic increase in cell bodies of colchicine-treated mice.

An efficient intrathecal delivery of small interfering RNA to the spinal cord and peripheral neurons.

We have developed a highly effective method for in vivo gene silencing in the spinal cord and dorsal root ganglia (DRG) by a cationic lipid facilitated delivery of synthetic, small interfering RNA (siRNA). A siRNA to the delta opioid receptor (DOR), or a mismatch RNA, was mixed with the transfection reagent, i-Fect (vehicle), and delivered as repeated daily bolus doses (0.5 microg to 4 microg) via implanted intrathecal catheter to the lumbar spinal cord of rats. Twenty-four hours after the last injection, rats were tested for antinociception by the DOR selective agonist, [D-Ala(2), Glu(4)]deltorphin II (DELT), or the mu opioid receptor (MOR) selective agonist, [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO). Pretreatment with the siRNA, but not the mismatch RNA or vehicle alone, blocked DELT antinociception dose-dependently. The latter was concomitant with a reduction in the spinal immunoreactivity and receptor density of DOR, and in DOR transcripts in the lumbar DRG and spinal dorsal horn. Neither siRNA nor mismatch RNA pretreatment altered spinal immunoreactivity of MOR or antinociception by spinal DAMGO, and had no effect on the baseline thermal nociceptive threshold. The inhibition of function and expression of DOR by siRNA was reversed by 72 hr after the last RNA injection. The uptake of fluorescence-tagged siRNA was detected in both DRG and spinal cord. The low effective dose of siRNA/i-Fect complex reflects an efficient delivery of the siRNA to peripheral and spinal neurons, produced no behavioral signs of toxicity. This delivery method may be optimized for other gene targets.

Neuropeptide Y2 receptor protein is present in peptidergic and nonpeptidergic primary sensory neurons of the mouse.

The localization of the neuropeptide tyrosine (NPY) Y2 receptor (Y2R) protein was studied in mouse dorsal root ganglia (DRGs) and spinal cord, by using a recently developed rabbit anti-Y2R antibody and a sensitive immunohistochemical method. Y2R-like immunoreactivity (-LI) was observed in about 10% of the small/medium-sized lumbar DRG neurons. Among these, about 44% were calcitonin gene-related peptide-immunoreactive, and about 38% bound isolectin B4. In the dorsal horn of the spinal cord, an intense Y2R-LI was seen in the most superficial layers, mostly restricted to laminae I-II. This immunoreactivity was completely abolished by dorsal rhizotomy. Y2R-L1 was also detected on the skin, more abundantly in hairy than glabrous skin. Specificity experiments showed complete disappearance of the Y2R-LI described above after incubation with antibody preadsorbed with the immunogenic peptide. Furthermore, Y2R-LI was also absent in a Y2R knockout mouse. These results demonstrate that the NPY Y2R is associated mainly with both peptidergic and nonpeptidergic small, presumably nociceptive, neurons projecting to the superficial layers of the dorsal horn. The results also support a role for this receptor and NPY in pain mechanisms.

Two new XPD patients compound heterozygous for the same mutation demonstrate diverse clinical features.

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are both rare autosomal recessive disorders with defects in DNA repair. They are usually distinct both clinically and genetically but in rare cases, patients exhibit the clinical characteristics of both diseases concurrently. We report two new phenotypically distinct cases of XP with additional features of CS (xeroderma pigmentosum and Cockayne syndrome crossover syndrome (XP/CS)) carrying an identical mutation (G47R) in the XPD gene within the N terminus of the protein. Both patients had clinical features of XP and CS but only one fulfilled most criteria for diagnosing CS. Unusually, patient 1 developed early skin cancer, in contrast to patient 2, who never developed any malignancies. Cells from both these patients have repair defects typical of xeroderma pigmentosum complementation group D (XPD) cells, but also had the phenotype of uncontrolled DNA breakage found specifically in XPD/CS cells and similarly reduced levels of TFIIH. Despite these similarities between our two patients, their clinical features are quite different and the clinical severity correlates with other cellular responses to ultraviolet irradiation.