Because T cells act primarily through short-distance interactions, homing receptors can identify colocalizing cells that serve common functions. Expression patterns for multiple chemokine receptors ...on CD4(+) T cells from human blood suggested a hierarchy of receptors that are induced and accumulate during effector/memory cell differentiation. We characterized CD4(+)CD45RO(+) T cells based on expression of two of these receptors, CCR5 and CCR2, the principal subsets being CCR5(-)CCR2(-) (∼70%), CCR5(+)CCR2(-) (∼25%), and CCR5(+)CCR2(+) (∼5%). Relationships among expression of CCR5 and CCR2 and CD62L, and the subsets' proliferation histories, suggested a pathway of progressive effector/memory differentiation from the CCR5(-)CCR2(-) to CCR5(+)CCR2(-) to CCR5(+)CCR2(+) cells. Sensitivity and rapidity of TCR-mediated activation, TCR signaling, and effector cytokine production by the subsets were consistent with such a pathway. The subsets also showed increasing responsiveness to IL-7, and the CCR5(+)CCR2(+) cells were CD127(bright) and invariably showed the greatest response to tetanus toxoid. CCR5(+)CCR2(+) cells also expressed the largest repertoire of chemokine receptors and migrated to the greatest number of chemokines. By contrast, the CCR5(+)CCR2(-) cells had the greatest percentages of regulatory T cells, activated/cycling cells, and CMV-reactive cells, and were most susceptible to apoptosis. Our results indicate that increasing memory cell differentiation can be uncoupled from susceptibility to death, and is associated with an increase in chemokine responsiveness, suggesting that vaccination (or infection) can produce a stable population of effector-capable memory cells that are highly enriched in the CCR5(+)CCR2(+) subset and ideally equipped for rapid recall responses in tissue.
Venous thromboembolism is the most common reason for readmission after total knee arthroplasty. Prospective contrast venography was conducted from 1984 to 2003 in 1321 patients undergoing total knee ...arthroplasty. Patients with deep venous thrombosis or pulmonary embolism were treated with warfarin; those with negative venograms received no further anticoagulation. From 1984 to 1992, patients not completing venography were discharged without warfarin; since 1993 patients without venography received warfarin for 6 weeks. Readmission for deep venous thrombosis, pulmonary embolism, or bleeding was tracked for 6 months. Venography was completed in 810 patients; 343 (42.3%) had deep venous thrombosis. Readmission for venous thromboembolism occurred in 0.6% of patients after total knee compared with 1.62% after total hip arthroplasty. Following total knee arthroplasty, patients discharged on warfarin (target INR 2.0) had a 0.21% readmission rate compared with 1.05% for patients with negative venograms discharged without further anticoagulation. One patient suffered a fatal pulmonary embolism after negative venography and no outpatient prophylaxis. Secondary prophylaxis with extended warfarin therapy reduced venous thromboembolism-related readmission. Surveillance venograms were a poor predictor of ultimate thromboembolism risk and need for extended anticoagulation therapy. We therefore recommend extended warfarin prophylaxis for all patients after hospital discharge following total knee arthroplasty.
The topological complexity $\mathsf {TC}(X)$ is a numerical homotopy invariant of a topological space X which is motivated by robotics and is similar in spirit to the classical Lusternik–Schnirelmann ...category of X. Given a mechanical system with configuration space X, the invariant $\mathsf {TC}(X)$ measures the complexity of motion planning algorithms which can be designed for the system. In this paper, we compute the topological complexity of the configuration space of n distinct ordered points on an orientable surface, for both closed and punctured surfaces. Our main tool is a theorem of B. Totaro describing the cohomology of configuration spaces of algebraic varieties. For configuration spaces of punctured surfaces, this is used in conjunction with techniques from the theory of mixed Hodge structures.
Venous thromboembolic disease remains the most common reason for readmission after total hip arthroplasty. Prospective analysis of screening contrast venography was done from 1984 to 2003 in 1972 ...patients having elective total hip arthroplasty. Patients with deep venous thrombosis or pulmonary embolism received warfarin therapy; those with negative venograms received no further anticoagulation. From 1984 to 1992, patients not completing venography were discharged without warfarin; since 1993, patients without venography received warfarin for 6 weeks. Readmission for deep venous thrombosis, pulmonary embolism, or bleeding was tracked for 6 months. Venograms were completed in 1032 patients; 175 (16.9%) had deep venous thrombosis. Deep venous thrombosis was reduced by a clinical pathway that included continuous epidural anesthesia (14.2% versus 22.5%). The overall readmission rate for venous thromboembolic disease was 1.62%, including 14 pulmonary emboli (three fatal) and 18 femoral deep venous thrombosis. Readmission occurred in 0.27% (1 of 360) patients on continued warfarin, compared with 2.2% (19 of 880) with negative venograms discharged without further anticoagulation. Three patients (0.15%) suffered fatal pulmonary emboli; all had negative venograms and received no outpatient prophylaxis. Extended outpatient warfarin therapy provided effective protection against venous thromboembolic disease readmission. Surveillance venography was a poor predictor of need for continued prophylaxis; all patients should have extended anticoagulation after total hip arthroplasty.
Therapeutic study, Level I-1 (high-quality randomized trial with statistically significant difference or no statistically significant difference but narrow confidence intervals). See the Guidelines for Authors for a complete description of levels of evidence.
Background. Foot and ankle surgeons are in a unique position to educate patients about the importance of proper footwear. Neither their recommendations regarding shoe selection nor their own footwear ...patterns have previously been reported. Methods. A total of 866 members of the American Orthopaedic Foot & Ankle Society (AOFAS) were asked to complete a survey via the Internet. Topics included specific shoe brands recommended to patients, how attributes of footwear are communicated, and respondents’ footwear habits. Results. In all, 276 (32%) surgeons responded, and 64% recommended New Balance athletic shoes to patients; 26% did not recommend specific brands. It was found that 50% wear New Balance athletic shoes; 25% wear Nike. Rockport (27%) and SAS (27%) were the most recommended dress shoes. In all, 76% are familiar with AOFAS guidelines for proper shoe fit, but only 56% educated their patients about the guidelines; 43% do not consider what patients might think of their shoes when selecting what to wear in the clinical setting. Conclusions. Despite the multitude of different brands, several were commonly recommended. Respondents seem to be aware of the impact of their own shoe selection on patients’ perspectives of footwear, but many do not consider themselves role models for proper footwear.
Level of Evidence: Internet survey
The ulcerated foot in individuals with Charcot neuroarthropathy presents a complex problem when correction of the deformity is necessary but the presence of infection precludes the use of internal ...fixation. We reviewed 11 patients with midfoot Charcot neuroarthropathy, collapse, and ulceration who were at risk for amputation. These patients underwent operative debridement, corrective osteotomy, external skeletal fixation and culture-directed antibiotic therapy as a limb salvage procedure. Patients were transitioned from the external fixator (average 57 days) to total contact casting (average 131 days) and all subsequently progressed to therapeutic footwear in 12 to 49 months of follow-up (average 24 months), except one patient whose medical decline resulted in bedrest. We believe that when performed in properly selected patients, this procedure presents an alternative to amputation and, via corrective osteotomy, results in a shoe-able, functional foot that is potentially less prone to ulceration.
Diabetic foot problems are significant cause of morbidity. With good medical care, the progression of neuropathy and vascular disease can be slowed but not stopped. Effective diabetic foot care ...requires screening to detect the at-risk foot, prevention to avoid the occurrence of ulcers, and treatment to heal ulcers quickly before they become more significant problems. Screening comprises assessment of patient behaviors and skin, neurologic, and vascular examinations. Prevention is accomplished by patient education and appropriate footwear or bracing. Recognition of Charcot's arthropathy can greatly reduce the risk of later problems. If problems progress beyond the scope of basic treatment by the primary care physician, referral to other members of the diabetic team is indicated.
The optimal management of chronic Achilles tendon injuries continues to be debated. The tension-length relationship and intrinsic viscoelasticity of the native tendon that allows efficient propulsion ...during ambulation are difficult to restore once the tendon has been injured. Missed or misdiagnosed injuries or failure of surgical or nonsurgical management of acute Achilles tendon ruptures can lead to the tendon healing in an elongated position or lack of healing altogether. This condition results in persistent weakness, pain, and functional debilitation for the patient. Understanding the tendon and muscle properties will inform the choice of treatment. Nonsurgical treatment options are primarily bracing treatment and physical therapy. Surgical treatment options involve direct repair, reconstruction with local tissue, allograft or autograft, and tendon transfer. Various options and techniques for reconstruction are described to assist in optimizing management of this challenging clinical problem.
Abstract
Th17 and related (type 17) cells have been investigated in mice for their contributions to autoimmune diseases and have demonstrated roles in immune-mediated disorders and host defense in ...humans. However, the pathways of differentiation of type 17 cells and the structure and heterogeneity of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cells in vivo. By exploiting differences in levels of surface CCR6 and analyzing cells in bulk and as single cells, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing the signature regulator, RORγt. On this continuum, cells are marked by extensive but progressively diminishing co-expression of genes of alternative lineages. Single-cell analysis of cytokine gene expression also revealed that Th cells initially undergo pan-activation of effector pathways rather than choose one lineage, and that these pan-activated cells persist in the memory population with multi-lineage character - reflecting both an efficient mechanism for jump starting an initial immune response and the availability of multi-potential cells in case of a repeat challenge. Along the type 17 continuum, the cells’ phenotypes and epigenomes are stable across cell divisions under homeostatic-like conditions. Nonetheless, strong activation in non-polarizing and polarizing environments can induce additional functionalities by both previously imprinted and environment-induced mechanisms that contribute differentially across the continuum to yield the unusual plasticity ascribed to even highly differentiated type 17 cells.
This study was supported by the Intramural Research Program of NIAID, NIH.
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