The transcription factor NF-B (NF-B) plays a pivotal role in regulating inflammatory gene expression. Its effects are optimized by various coactivators including histone acetyltransferases (HATs) such as CBP/p300 and p/CAF. Evidence shows that high glucose (HG) conditions mimicking diabetes can activate the transcription of NF-B-regulated inflammatory genes. However, the underlying in vivo transcription and nuclear chromatin remodeling events are unknown. We therefore carried out chromatin immunoprecipitation (ChIP) assays in monocytes to identify 1) chromatin factors bound to the promoters of tumor necrosis factor-␣ (TNF-␣) and related NF-B-regulated genes under HG or diabetic conditions, 2) specific lysine (Lys (K)) residues on histone H3 (HH3) and HH4 acetylated in this process. HG treatment of THP-1 monocytes increased the transcriptional activity of NF-B p65, which was augmented by CBP/ p300 and p/CAF. ChIP assays showed that HG increased the recruitment of NF-B p65, CPB, and p/CAF to the TNF-␣ and COX-2 promoters. Interestingly, ChIP assays also demonstrated concomitant acetylation of HH3 at Lys 9 and Lys 14 , and HH4 at Lys 5 , Lys 8 , and Lys 12 at the TNF-␣ and COX-2 promoters. Overexpression of histone deacetylase (HDAC) isoforms inhibited p65-mediated TNF-␣ transcription. In contrast, a HDAC inhibitor stimulated gene transcription and histone acetylation. Finally, we demonstrated increased HH3 acetylation at TNF-␣ and COX-2 promoters in human blood monocytes from type 1 and type 2 diabetic subjects relative to nondiabetic. These results show for the first time that diabetic conditions can increase in vivo recruitment of NF-B and HATs, as well as histone acetylation at the promoters of inflammatory genes, leading to chromatin remodeling and transcription.

Klinefelter syndrome (KS) is a sex chromosome abnormality associated with male infertility and mild cognitive deficits. Individuals with KS have been reported to have impaired verbal ability, as well as deficits in executive function. To further understand the nature of their deficits, we assessed specific elements of frontal lobe function such as working memory and relational reasoning. Men with KS exhibited a deficit in a transitive inference task in which participants ordered a set of names based on a list of propositions about the relative heights of the people named. This deficit was present even for items in which the propositions were given in order, so a chaining strategy could be used. Men with KS are also impaired on the n-back task, which uses letters as stimuli. In contrast, these men performed as well as controls in nonverbal reasoning (Raven's Progressive Matrices). These results suggest that men with KS have intact nonverbal reasoning abilities, but that a difficulty in encoding verbal information into working memory may underlie their executive and linguistic impairments. (JINS, 2003, 9, 839-846.)

Children and adolescents with Klinefelter syndrome (XXY) have been reported to show deficits in language processing including VIQ , PIQ and a learning disability in reading and spelling. However, whether this is characteristic of adults with Klinefelter syndrome has not been established. Thirty-five men with Klinefelter syndrome, aged 16 to 61, and 22 controls were evaluated with a comprehensive neuropsychological battery. The Klinefelter patients scored significantly below controls in language skills, verbal processing speed, verbal and nonverbal executive abilities, and motor dexterity. Within the Klinefelter sample, three cognitive subgroups were identified: VIQ 7 or more points below PIQ (n 5 10), VIQ within 6 points of PIQ (n 5 12), and PIQ 7 or more points below VIQ (n 5 12). The deficits detected in language, verbal processing speed, and verbal executive skills were found to be isolated to the VIQ , PIQ subgroup, while the abnormalities in motor dexterity and nonverbal executive skills were confined to the PIQ , VIQ subgroup. Older age was significantly correlated with increases in VIQ relative to PIQ in the patient group, which suggests the intriguing possibility that the PIQ , VIQ subgroup primarily emerges in young adulthood, perhaps in response to the reported hormonal abnormalities detected in Klinefelter syndrome patients during puberty. (JINS, 2001, 7, 446-456)