Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior.

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=-0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

Growth phase and metal-dependent regulation of the dpsA gene in Synechococcus sp. strain PCC 7942, USA.

The Synechococcus sp. strain PCC 7942 dpsA gene encodes a stress-inducible DNA-binding protein whose transcription increases in the stationary phase. Such transcription is likely under the control of an alternative sigma factor. Our current work indicated that dpsA transcription is also important under metal-ion limitation, because dpsA mRNA levels increased 12-fold under low-iron conditions, and that dpsA function is essential for growth under iron-limiting conditions. Promoter activity of the dpsA-promoter-lacZ reporter gene constructs implied that a region of dyad symmetry centered 28 nucleotides from the transcription start is required for metal-dependent repression, as judged by the level of lacZ induction following treatment of cultures with the chelator 2,2'-dipyridyl. This potential operator sequence is distinct from the site recognized by the cyanobacterial Fur repressor homologue. No other nutrient stresses (nitrogen, sulfur, phosphorus) yielded the high level of induction seen following chelator treatment. These studies suggest that there may be more than one class of metal-dependent repressor in cyanobacteria.

A nonlinear method for estimating nucleotide polymorphism from restriction maps.

Restriction mapping is used to estimate nucleotide sequence polymorphism when the regions to be studied are too long or too numerous to be sequenced. Restriction mapping is less costly than DNA sequencing, but it does not allow direct measurement of underlying nucleotide polymorphism. It is therefore useful to be able to estimate underlying nucleotide polymorphism from observations of polymorphism in restriction maps, as this offers some of the resolution afforded by DNA sequencing at a reduced cost. Previous estimators of underlying nucleotide polymorphism have assumed that each restriction-enzyme-binding site contains, at most, a single polymorphic nucleotide position (the low-polymorphism-frequency assumption), and this assumption has placed an upper limit on the level of polymorphism that can be resolved by these estimators. The present study documents an estimator which allows relaxation of this assumption. The new estimator more accurately estimates underlying nucleotide polymorphism when the polymorphism level is high enough to falsify the low-polymorphism-frequency assumption. The new estimator therefore yields good results for data sets that are too divergent for analysis by present methods.

Trustee development comes of age.

Cursory and sporadic attempts to educate trustees are giving way in many hospitals to systematic programs of board development, encompassing traditional facility orientation, continuing education and information programs, and other efforts to contribute to improved board performance. This article suggests steps for boards to follow in launching a board development program: vehicles for board development: and the composition and responsibilities of the board development committee.