Differential influence of safe versus threatening facial expressions on decision-making during an inhibitory control task in adolescence and adulthood.

Social cognition matures dramatically during adolescence and into early adulthood, supported by continued improvements in inhibitory control. During this time, developmental changes in interpreting and responding to social signals such as facial expressions also occur. In the present study, subjects performed a Go No-Go task that required them to respond or inhibit responding based on threat or safety cues present in facial expressions. Subjects (N = 112) were divided into three age groups: adolescent (12-15 years), emerging adult (18-25 years) and adult (26-44 years). Analyses revealed a significant improvement in accuracy on No-Go trials, but not Go trials, during both safe and threat face conditions, with changes evident through early adulthood. In order to better identify the decision-making processes responsible for these changes in inhibitory control, a drift diffusion model (DDM) was fit to the accuracy and reaction time data, generating measures of caution, response bias, nondecision time (encoding + motor response), and drift rate (face processing efficiency). Caution and nondecision time both increased significantly with age while bias towards the Go response decreased. Drift rate analyses revealed significant age-related improvements in the ability to map threat faces to a No-Go response while drift rates on all other trial types were equivalent across age groups. These results suggest that both stimulus-independent and stimulus-dependent processes contribute to improvements in inhibitory control in adolescence with processing of negative social cues being specifically impaired by self-regulatory demands. Findings from this novel investigation of emotional responsiveness integrated with inhibitory control may provide useful insights about healthy development that can be applied to better understand adolescent risk-taking behavior and the elevated incidence of related forms of psychopathology during this period of life.

Irrigation of the wounds in open fractures.

Modern principles for the treatment of open fractures include stabilisation of the bone and management of the soft tissues. Wound debridement and irrigation is thought to be the mainstay in reducing the incidence of infection. Although numerous studies on animals and humans have focused on the type of irrigation performed, little is known of the factors which influence irrigation. This paper evaluates the evidence, particularly with regard to additives and the mode of delivery of irrigation fluid. Normal saline should be used and although many antiseptics and antibiotics have been employed, no consensus has been reached as to the ideal additive. Despite the advocates of high-pressure methods highlighting the improved dilutional ability of such techniques, the results are inconclusive and these irrigation systems are not without complications. New systems for debridement are currently being investigated, and an ideal method has yet to be determined.

Debridement and wound closure of open fractures: the impact of the time factor on infection rates.

Open fracture management represents an orthopaedic emergency. Early aggressive management of these debilitating injuries within the first 6h has been encouraged in order to minimise the risk of infection and long term sequelae. Debridement and wash-out of the wound, followed by stabilisation of the bony elements and closure of the soft-tissue envelope are all considered essential. However, the available scientific evidence supporting the timing of this multistage approach of open fracture management, and the "Six-hour rule" itself, are unclear. This review article analyses the available evidence regarding the impact of the timing of wound debridement and closure of open fractures of the lower extremity.

The SOS-dependent upregulation of uvrD is not required for efficient nucleotide excision repair of ultraviolet light induced DNA photoproducts in Escherichia coli.

We have shown previously that induction of the SOS response is required for efficient nucleotide excision repair (NER) of the major ultraviolet light (UV) induced DNA lesion, the cyclobutane pyrimidine dimer (CPD), but not for repair of 6-4 photoproducts (6-4PP) or for transcription-coupled repair of CPDs [1]. We have proposed that the upregulation of cellular NER capacity occurs in the early stages of the SOS response and enhances the rate of repair of the abundant yet poorly recognized genomic CPDs. The expression of three NER genes, uvrA, uvrB, and uvrD, is upregulated as part of the SOS response. UvrD differs from the others in that it is not involved in lesion recognition but rather in promoting the post-incision steps of NER, including turnover of the UvrBC incision complex. Since uvrC is not induced during the SOS response, its turnover would seem to be of great importance in promoting efficient NER. Here we show that the constitutive level of UvrD is adequate for carrying out efficient NER of both CPDs and 6-4PPs. Thus, the upregulation of uvrA and uvrB genes during the SOS response is sufficient for inducible NER of CPDs. We also show that cells with a limited NER capacity, in this case due to deletion of the uvrD gene, repair 6-4PPs but cannot perform transcription-coupled repair of CPDs, indicating that the 6-4PP is a better substrate for NER than is a CPD targeted for transcription-coupled repair.

Recovery of DNA replication in UV-irradiated Escherichia coli requires both excision repair and recF protein function.

After UV doses that disrupt DNA replication, the recovery of replication at replication forks in Escherichia coli requires a functional copy of the recF gene. In recF mutants, replication fails to recover and extensive degradation of the nascent DNA occurs, suggesting that recF function is needed to stabilize the disrupted replication forks and facilitate the process of recovery. We show here that the ability of recF to promote the recovery of replication requires that the disrupting lesions be removed. In the absence of excision repair, recF+ cells protect the nascent DNA at replication forks, but replication does not resume. The classical view is that recombination proteins operate in pathways that are independent from DNA repair, and therefore the functions of Rec proteins have been studied in repair-deficient cells. However, mutations in either uvr or recF result in failure to recover replication at UV doses from which wild-type cells recover efficiently, suggesting that recF and excision repair contribute to a common pathway in the recovery of replication.

Induction of the SOS response increases the efficiency of global nucleotide excision repair of cyclobutane pyrimidine dimers, but not 6-4 photoproducts, in UV-irradiated Escherichia coli.

Nucleotide excision repair (NER) is responsible for the removal of a variety of lesions from damaged DNA and proceeds through two subpathways, global repair and transcription-coupled repair. In Escherichia coli, both subpathways require UvrA and UvrB, which are induced following DNA damage as part of the SOS response. We found that elimination of the SOS response either genetically or by treatment with the transcription inhibitor rifampin reduced the efficiency of global repair of the major UV-induced lesion, the cyclobutane pyrimidine dimer (CPD), but had no effect on the global repair of 6-4 photoproducts. Mutants in which the SOS response was constitutively derepressed repaired CPDs more rapidly than did wild-type cells, and this rate was not affected by rifampin. Transcription-coupled repair of CPDs occurred in the absence of SOS induction but was undetectable when the response was expressed constitutively. These results suggest that damage-inducible synthesis of UvrA and UvrB is necessary for efficient repair of CPDs and that the levels of these proteins determine the rate of NER of UV photoproducts. We compare our findings with recent data from eukaryotic systems and suggest that damage-inducible stress responses are generally critical for efficient global repair of certain types of genomic damage.

Involvement of molecular chaperonins in nucleotide excision repair. Dnak leads to increased thermal stability of UvrA, catalytic UvrB loading, enhanced repair, and increased UV resistance.

UvrA is one of the key Escherichia coli proteins involved in removing DNA damage during the process of nucleotide excision repair. The relatively low concentrations (nanomolar) of the protein in the normal cells raise the potential questions about its stability in vivo under both normal and stress conditions. In vitro, UvrA at low concentrations is shown to be stabilized to heat inactivation by E. coli molecular chaperones DnaK or the combination of DnaK, DnaJ, and GrpE. These chaperone proteins allow sub-nanomolar concentrations of UvrA to load UvrB through >10 cycles of incision. Guanidine hydrochloride-denatured UvrA was reactivated by DnaK, DnaJ, and GrpE to as much as 50% of the native protein activity. Co-immunoprecipitation assays showed that DnaK bound denatured UvrA in the absence of ATP. UV survival studies of a DnaK-deficient strain indicated an 80-fold increased sensitivity to 100 J/m2 of ultraviolet light (254 nm) as compared with an isogenic wild-type strain. Global repair analysis indicated a reduction in the extent of pyrimidine dimer and 6-4 photoproduct removal in the DnaK-deficient cells. These results suggest that molecular chaperonins participate in nucleotide excision repair by maintaining repair proteins in their properly folded state.

Mismatch repair mutants in yeast are not defective in transcription-coupled DNA repair of UV-induced DNA damage.

Transcription-coupled repair, the targeted repair of the transcribed strands of active genes, is defective in bacteria, yeast, and human cells carrying mutations in mfd, RAD26 and ERCC6, respectively. Other factors probably are also uniquely involved in transcription-repair coupling. Recently, a defect was described in transcription-coupled repair for Escherichia coli mismatch repair mutants and human tumor cell lines with mutations in mismatch repair genes. We examined removal of UV-induced DNA damage in yeast strains mutated in mismatch repair genes in an effort to confirm a defect in transcription-coupled repair in this system. In addition, we determined the contribution of the mismatch repair gene MSH2 to transcription-coupled repair in the absence of global genomic repair using rad7 delta mutants. We also determined whether the Rad26-independent transcription-coupled repair observed in rad26 delta and rad7 delta rad26 delta mutants depends on MSH2 by examining repair deficiencies of rad26 delta msh2 delta and rad7 delta rad26 delta msh2 delta mutants. We found no defects in transcription-coupled repair caused by mutations in the mismatch repair genes MSH2, MLH1, PMS1, and MSH3. Yeast appears to differ from bacteria and human cells in the capacity for transcription-coupled repair in a mismatch repair mutant background.