Heterochromatin is a higher order assembly that is characterized by a genome-wide distribution, gene-repression, durability and potential to spread. In this light, it is an appealing mechanism to interpret the neurobiology of complex brain disorders such as schizophrenia where downregulation of expression appears to be the norm. H3K9 methylation (H3K9me) can initiate the seeding of a heterochromatin assembly on an inactive or poorly coordinated promoter as a consequence of a decline in transactivators either from disuse or from misuse. H3K9me can extend its influence by spatial spreading through the mechanism of recursively recruiting adapters, such as heterochromatin protein 1 (HP1) homodimers. HP1 itself serves as a platform for other repressive proteins such as DNA methyltransferases. In full color, heterochromatin can occupy genome-wide gene networks, tissue specific ontologies and even rearrange the nuclear architecture. Heterochromatin in the brain is modified by small molecule pharmacology and serves a physiological role in the functioning of dopamine neurons and the construction of memory. From a therapeutic perspective, the durable nature of heterochromatin implies that it may require disassembly before the full genomic-potential of standard pharmacotherapies is achieved, especially in treatment resistant patients.The Pharmacogenomics Journal advance online publication, 17 January 2012; doi:10.1038/tpj.2011.64.

OBJECTIVES: To understand nurse and other staff perceptions about care activities in labor and delivery (L&D) that were performed with high frequency, required high exertion, and had the greatest potential to cause injury and to determine what personal characteristics might be related to the caregiving tasks with potential for injury. DESIGN: This exploratory study employed a mixed methods design using qualitative open-ended questions and quantitative surveys administered in three different times (n = 56, 58, and 58). SETTING: A 22-room L&D unit in a women's hospital with 8,500 annual deliveries. PARTICIPANTS: Nurses and assistive staff. RESULTS: High-risk tasks were classified in three categories. High-exertion tasks included (a) moving patients in labor, delivery, recovery (LDR) beds to other locations;(b) breaking delivery beds and applying stirrups;(c) assisting dependent patients with mobility in bed; and (d) pushing medical equipment and delivery carts. Awkward posture tasks during patient care included (a) listening for heart tones;(b) performing difficult vaginal exams;(c) keeping the fetal head off of the cord during cord prolapse; and (d) assisting with epidurals. Culture of safety tasks included (a) physician requests to conduct patient care tasks that put staff at risk for injury;(b) providers ignoring broken equipment in the environment;(c) responding to emergent/urgent situations without regard to self-posturing to prevent injury; and (d) holding patients' legs during delivery at the physician's direction. Several significant correlations were noted between demographic variables and high potential for risk items. CONCLUSIONS: This study provides the first information about the caregiving tasks L&D nurses perceive to be risky for personal injury because of their high frequency and exertion or breaches in the culture of safety.

Aberrant neocortical DNA methylation has been suggested to be a pathophysiological contributor to psychotic disorders. Recently, a growth arrest and DNA-damage-inducible, beta (GADD45b) protein-coordinated DNA demethylation pathway, utilizing cytidine deaminases and thymidine glycosylases, has been identified in the brain. We measured expression of several members of this pathway in parietal cortical samples from the Stanley Foundation Neuropathology Consortium (SFNC) cohort. We find an increase in GADD45b mRNA and protein in patients with psychosis. In immunohistochemistry experiments using samples from the Harvard Brain Tissue Resource Center, we report an increased number of GADD45b-stained cells in prefrontal cortical layers II, III, and V in psychotic patients. Brain-derived neurotrophic factor IX (BDNF IXabcd) was selected as a readout gene to determine the effects of GADD45b expression and promoter binding. We find that there is less GADD45b binding to the BDNF IXabcd promoter in psychotic subjects. Further, there is reduced BDNF IXabcd mRNA expression, and an increase in 5-methylcytosine and 5-hydroxymethylcytosine at its promoter. On the basis of these results, we conclude that GADD45b may be increased in psychosis compensatory to its inability to access gene promoter regions.

Recent evidence suggests that covalent modifications to the genomic platform in the brain, that is DNA and its surrounding histones, provide a stable potentially lifelong mechanism for remembrance. Consequently, the making and unmaking of memories is accessible through pharmacological manipulations of these modifications. This has implications for psychotherapy and long-term rehabilitation of CNS disorders. We hypothesize that by enhancing learning through pharmacologically manipulating 'epigenetic' parameters, the effects of psychotherapies and rehabilitation can be enhanced.

We recently showed that genes at 3 loci account for the majority of variation in canine fur. Allelic variation at genes controlling length of fur, texture, and curl is responsible for the striking phenotypic variety observed among purebred dogs in the United States today. In this paper, we investigate the phenomenon of "improper coat"(IC) or a coat that is not typical of the breed. IC is occasionally observed among specific breeds, such as the Portuguese Water Dog (PWD), and is characterized by short hair on the head, face, and lower legs, rather than a thick and even coat covering the whole body. The IC is reminiscent of that observed on the curly or flat-coated retriever, thus making such dogs unable to compete effectively in conformation events. We have found that the presence of the wild-type allele, rather than the expected variant allele at the R-spondin 2 (RSPO2) gene, accounts for this phenotype. The development of a genetic test that distinguishes these 2 allelic types would allow breeders to easily avoid producing PWD with ICs.

Adolescent hallux valgus deformity is a complex surgical condition. Although several techniques have been described to correct this deformity in adults, limitations exist for adolescents because of the presence of open growth plates and high recurrence rates. This retrospective study reports results of 7 patients (14 feet) using the Scarf osteotomy for correction of adolescent hallux valgus deformity. All patients underwent concomitant bilateral hallux valgus surgery. Radiographic evaluation measures included intermetatarsal 1-2 angle, hallux valgus angle, and distal metatarsal articular angle. Data recorded from the lateral radiograph evaluated the first metatarsal declination angle. Postoperative patient satisfaction was assessed using a standard patient satisfaction survey. Postoperative, subjective, and objective measurements were calculated using the American College of Foot and Ankle Surgeons (ACFAS) Scoring Scale for the First Metatarsophalangeal Joint and First Ray and the American Orthopaedic Foot & Ankle Society (AOFAS) Hallux Metatarsophalangeal-Interphalangeal Scoring Scale. Average patient age and follow-up were 14.43 years and 57 months, respectively. There was 100% maternal inheritance of hallux valgus deformity. The average postoperative ACFAS Metatarsophalangeal Joint and First Ray Scale (module 1) score was 94.72, and the average AOFAS Hallux Metatarsophalangeal-Interphalangeal Scale score was 96.43. Complications included 1 patient who underwent revision surgery on 1 foot 18 years after the date of index surgery because of painful recurrence of the deformity. The authors believe the Scarf osteotomy is a safe, effective, and versatile procedure for the correction of juvenile and adolescent hallux valgus deformity.

Huntingtin (Htt) localizes to endosomes but its role in the endocytic pathway is not established. Recently we found that Htt is important for the activation of Rab11, a GTPase involved in endosomal recycling. Here we studied fibroblasts of normal individuals and patients with Huntington's disease (HD), which is a movement disorder caused by polyglutamine expansion in Htt. Formation of endocytic vesicles containing transferrin at plasma membranes was the same in control and HD patient fibroblasts. However, HD fibroblasts were delayed in recycling biotin-transferrin back to the plasma membrane. Membranes of HD fibroblasts supported less nucleotide exchange on Rab11 than did control membranes. Rab11 positive vesicular and tubular structures in HD fibroblasts were abnormally large, suggesting they were impaired in forming vesicles. We used Total Internal Reflection Fluorescence (TIRF) imaging in living fibroblasts to monitor fluorescent labeled transferrin-carrying transport intermediates that emerged from recycling endosomes. HD fibroblasts had fewer small vesicles and more large vesicles and long tubules than control fibroblasts. Dominant active Rab11 expressed in HD fibroblasts normalized recycling of biotin-transferrin. We propose a novel mechanism for cellular dysfunction by the HD mutation arising from inhibition of Rab11 activity and a deficit in vesicle formation at recycling endosomes.

The domestic dog offers a remarkable opportunity to disentangle the genetics of complex phenotypes. Here, we explore a locus, previously identified in the Portuguese water dog (PWD), associated with PC2, a morphological principal component characterized as leg width versus leg length. The locus was initially mapped to a region of 26 Mb on canine chromosome 12 (CFA12) following a genome-wide scan. Subsequent and extensive genotyping of single-nucleotide polymorphisms (SNPs) and haplotype analysis in both the PWD and selected breeds representing phenotypic extremes of PC2 reduced the region from 26 Mb to 500 kb. The proximity of the critical interval to two collagen genes suggests that the phenotype may be controlled by cis-acting mechanisms.

Coat color and type are essential characteristics of domestic dog breeds. While the genetic basis of coat color has been well characterized, relatively little is known about the genes influencing coat growth pattern, length, and curl. We performed genome-wide association studies of more than 1000 dogs from 80 domestic breeds to identify genes associated with canine fur phenotypes. Taking advantage of both inter- and intrabreed variability, we identified distinct mutations in three genes, RSPO2, FGF5, and KRT71 (encoding R-spondin-2, fibroblast growth factor-5 and keratin-71, respectively), which together account for the majority of coat phenotypes in purebred dogs in the United States. This work illustrates that an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only a few genes.