T cells detect intracellular DNA but fail to induce type I IFN responses: implications for restriction of HIV replication.

HIV infects key cell types of the immune system, most notably macrophages and CD4+ T cells. Whereas macrophages represent an important viral reservoir, activated CD4+ T cells are the most permissive cell types supporting high levels of viral replication. In recent years, it has been appreciated that the innate immune system plays an important role in controlling HIV replication, e.g. via interferon (IFN)-inducible restriction factors. Moreover, innate immune responses are involved in driving chronic immune activation and the pathogenesis of progressive immunodeficiency. Several pattern recognition receptors detecting HIV have been reported, including Toll-like receptor 7 and Retinoic-inducible gene-I, which detects viral RNA. Here we report that human primary T cells fail to induce strong IFN responses, despite the fact that this cell type does express key molecules involved in DNA signaling pathways. We demonstrate that the DNA sensor IFI16 migrates to sites of foreign DNA localization in the cytoplasm and recruits the signaling molecules stimulator of IFN genes and Tank-binding kinase, but this does not result in expression of IFN and IFN-stimulated genes. Importantly, we show that cytosolic DNA fails to affect HIV replication. However, exogenous treatment of activated T cells with type I IFN has the capacity to induce expression of IFN-stimulated genes and suppress HIV replication. Our data suggest the existence of an impaired DNA signaling machinery in T cells, which may prevent this cell type from activating cell-autonomous anti-HIV responses. This phenomenon could contribute to the high permissiveness of CD4+ T cells for HIV-1.

A biomechanical comparison of headless tapered variable pitch compression and ao cortical bone screws for fixation of a simulated midbody transverse fracture of the proximal sesamoid bone in horses.

OBJECTIVE: To compare mechanical properties and failure characteristics of 2 methods of fixation for repair of a transverse, midbody fracture of the proximal sesamoid bone (PSB): 4.5-mm AO cortical bone screw (AO) placed in lag fashion and 4/5-mm Acutrak (AT) self-compressing screw. STUDY DESIGN: An in vitro biomechanical evaluation of intact forelimb preparations and forelimb preparations with a simulated midbody PSB fracture stabilized by a bone screw. SAMPLE POPULATION: Sixteen paired and 8 unilateral cadaveric equine forelimbs. METHODS: A midbody transverse osteotomy was created in the medial PSB of bilateral forelimbs of 8 equine cadavers. The osteotomized PSB in 1 forelimb from each cadaver was repaired with an AO screw. The osteotomized PSB in each contralateral limb was repaired with an AT screw. Eight unilateral intact control limbs were also studied. Mechanical properties were determined from axial compression, single cycle to failure, load-deformation curves. Failure characteristics were determined by evaluation of video images and radiographs. RESULTS: No statistically significant differences were found between repair groups. Both AO and AT groups had significantly lower mechanical properties than intact limbs except for stiffness. CONCLUSION: AO and AT constructs were mechanically comparable when used to stabilize a simulated midbody fracture of the medial PSB. Both constructs were mechanically inferior to intact limbs. Clinical Relevance- The AT screw should be considered for clinical use because of the potential for less soft tissue impingement and superior biocompatibility compared with the stainless-steel AO screw. However, postoperative external coaptation is necessary to augment initial fracture stability for either fixation method, and to maintain a standing metacarpophalangeal joint dorsiflexion angle between 150 degrees and 155 degrees.

A biomechanical comparison of headless tapered variable pitch and AO cortical bone screws for fixation of a simulated slab fracture in equine third carpal bones.

OBJECTIVE: To compare the mechanical shear strengths and stiffnesses obtained from in vitro testing of a simulated complete third carpal bone (C3) frontal plane radial facet slab fracture (osteotomy) stabilized with either a 4/5 Acutrak (AT) compression screw or a 4.5-mm AO cortical bone (AO) screw inserted in lag fashion. Drilling, tapping, and screw insertion torques, forces, and times also were compared between AT and AO implants. STUDY DESIGN: In vitro biomechanical assessment of site preparation, screw insertion, and shear failure test variables of bone screw stabilized simulated C3 slab fracture in paired cadaveric equine carpi. SAMPLE POPULATION: Eight pairs of cadaveric equine C3 without orthopedic abnormalities. METHODS: Standardized simulated C3 slab fractures were repaired with either AO or AT screws (AO/C3 and AT/C3 groups, respectively). Drilling, tapping, and screw insertion torques, forces, and times were measured with a materials testing machine for each screw type. Repaired specimens were tested in axially oriented shear until failure. Paired Students t-tests were used to assess differences between site preparation, screw insertion, and shear testing variables. Significance was set at P <.05. RESULTS: There were no significant differences in bone fragment measurements of the standardized simulated C3 slab fractures created for AO or AT screws. There were no significant differences for mean and maximum drilling torques; however, the tapered AT drill had greater maximum drilling force compared with the 3.2-mm and 4.5-mm AO drill bits. Mean insertion torque and force measured from the self-tapping AT screw were not significantly different compared with the 4.5-mm AO tap. There were no significant differences in maximum screw torque among constructs. Total procedure time was significantly longer for the AT group (5.8 +/- 1.6 minutes) compared with the AO group (2.9 +/- 1.1 minutes; P =.001). AT stabilized specimens had significantly greater mean +/- SD initial shear stiffness (3.64 +/- 1.08 kN/mm) than AO specimens (1.64 +/- 0.73 kN/mm; P =.005). All other shear mechanical testing variables were not statistically different among screw types. CONCLUSION: The 4/5 Acutrak insertion technique was accurate and safe, and the AT screw effectively stabilized simulated equine C3 frontal plane slab fractures. When tested in shear, this screw type was mechanically comparable to the 4.5-mm AO screw; however, AT constructs had greater initial shear stiffness. Initial shear stiffness was likely an indirect measure of interfragmentary compression, and thus may indicate that the AT screw provides a more rigid fixation for frontal plane C3 slab fractures in horses. CLINICAL RELEVANCE: Considering the comparable mechanical behavior, greater initial shear stiffness for AT screw stabilized C3 slab fracture fragments, the ability to accurately insert the screw with the aid of a guide pin, and the potential for less persistent soft tissue irritation with the headless screw design, the 4/5 tapered AT screw is an attractive alternative for repair of C3 slab fractures in horses.

Goal-directedness and personal identity as correlates of life outcomes.

Although much research has been conducted on goal setting, researchers have not examined goal-directedness or propensity to set goals as a stable human characteristic in adults. In this study, a survey was developed and distributed to 104 adult participants to assess their goal-directedness, personal identity, and various life outcomes. A theoretical model was developed and tested using structural equation modeling that proposed that both goal-directedness and personal identity should positivcly influence important life outcomes. Analysis showed that goal-directedness and personal identity are positively related to personal well-being, salary, and marital satisfaction. Further, personal identity was positively related to job satisfaction but, contrary to related research, goal-directedness did not predict job satisfaction.

A biomechanical comparison of equine third metacarpal condylar bone fragment compression and screw pushout strength between headless tapered variable pitch and AO cortical bone screws.

OBJECTIVES: To compare bone fragment compression and the mechanical pushout strength and stiffness of 6.5-mm Acutrak Plus (AP) and 4.5-mm AO cortical (AO) bone screws after stabilization of a simulated equine third metacarpal (MC3) bone complete lateral condylar fracture. STUDY DESIGN: In vitro biomechanical paired study of screw insertion variables, bone fragment compression, and screw pushout tests using a bone screw stabilized simulated lateral condylar fracture model. SAMPLE POPULATION: Six pairs of cadaveric equine MC3s. METHODS: Metacarpi were placed in a fixture and centered on a biaxial load cell in a materials testing system to measure torque, compressive force, and time for drilling, tapping, and screw insertion. Fragment compression was measured with a pressure-sensing device placed between the simulated fracture fragments during screw insertion for fragment stabilization. Subsequently, screws were pushed out of the stabilized bone fragments in a single cycle to failure. A paired t test was used to assess differences between site preparation, screw insertion, fragment compression, and screw pushout variables, with significance set at P <.05. RESULTS: Measured drilling variables were comparable for AO and AP specimens. However, the AP tap had significantly greater insertion torque and force. Mean maximum screw insertion torque was significantly greater for AO screws. For fragment compression, AP screws generated 65% and 44% of the compressive pressure and force, respectively, of AO screws. AP screws tended to have higher overall pushout strength. Pushout stiffness was similar between both screw types. CONCLUSION: The 6.5-mm tapered AP screw generated less interfragmentary compressive pressure and force but had similar pushout stiffness. Evaluation of failure patterns demonstrated that AP screws had greater pushout strength compared with 4.5-mm AO screws for fixation of a simulated complete lateral condylar fracture. CLINICAL RELEVANCE: The 6.5-mm tapered AP screw should provide ample holding strength but would provide less interfragmentary compression than 4.5-mm AO screws for repair of complete lateral condylar fractures in horses.