Citations

Objective— Tissue factor pathway inhibitor (TFPI) is the primary regulator of the tissue factor (TF) coagulation pathway. As such, TFPI may regulate the proangiogenic effects of TF. TFPI may also affect angiogenesis independently of TF, through sequences within its polybasic carboxyl terminus (TFPI C terminus [TFPIct]). We aimed to determine the effects of TFPI on angiogenesis and the role of TFPIct. Methods and Results— Transgenic overexpression of TFPI attenuated angiogenesis in the murine hindlimb ischemia model and an aortic sprout assay. In vitro, TFPI inhibited endothelial cell migration. Peptides within the human TFPIct inhibited endothelial cell cord formation and migration in response to vascular endothelial growth factor (VEGF) 165 but not VEGF121. Furthermore, exposure to human TFPIct inhibited the phosphorylation of VEGF receptor 2 at residue Lys951, a residue known to be critical for endothelial cell migration. Finally, systemic delivery of a murine TFPIct peptide inhibited angiogenesis in the hindlimb model. Conclusion— These data demonstrate an inhibitory role for TFPI in angiogenesis that is, in part, mediated through peptides within its carboxyl terminus. In addition to its known role as a TF antagonist, TFPI, via its carboxyl terminus, may regulate angiogenesis by directly blocking VEGF receptor 2 activation and attenuating the migratory capacity of endothelial cells.

Abstract Background: Multiple genome-wide and candidate gene association studies have been conducted in search of common risk variants for breast cancer. Recent large meta analyses, consolidating evidence from these studies, have been consistent in highlighting the caspase-8 (CASP8) gene as important in this regard. To define a risk haplotype and map the CASP8 gene region with respect to underlying susceptibility variant/s, we screened four genes in the CASP8 region on 2q33-q34 for breast cancer risk. Methods: Two independent data sets from the United Kingdom and the United States, including 3,888 breast cancer cases and controls, were genotyped for 45 tagging single nucleotide polymorphisms (tSNP) in the expanded CASP8 region. SNP and haplotype association tests were carried out using Monte Carlo-based methods. Results: We identified a three-SNP haplotype across rs3834129, rs6723097, and rs3817578 that was significantly associated with breast cancer (P < 5 × 10−6), with a dominant risk ratio and 95% CI of 1.28 (1.21–1.35) and frequency of 0.29 in controls. Evidence for this risk haplotype was extremely consistent across the two study sites and also consistent with previous data. Conclusion: This three-SNP risk haplotype represents the best characterization so far of the chromosome upon which the susceptibility variant resides. Impact: Characterization of the risk haplotype provides a strong foundation for resequencing efforts to identify the underlying risk variant, which may prove useful for individual-level risk prediction, and provide novel insights into breast carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(1); 176–81. ©2011 AACR.

ABSTRACT Antimicrobial susceptibility testing (AST) of clinical isolates of Nocardia is recommended to detect resistance to commonly used antimicrobial agents; such testing is complicated by difficulties in inoculum preparation and test interpretation. In this study, six laboratories performed repetitive broth microdilution testing on single strains of Nocardia brasiliensis , Nocardia cyriacigeorgica , Nocardia farcinica , Nocardia nova , and Nocardia wallacei . For each isolate, a total of 30 microdilution panels from three different lots were tested at most sites. The goal of the study was to determine the inter- and intralaboratory reproducibility of susceptibility testing of this group of isolates. Acceptable agreement (>90% agreement at ±1 dilution of the MIC mode) was found for amikacin, ciprofloxacin, clarithromycin, and moxifloxacin. After eliminating MIC values from single laboratories whose results showed the greatest deviation from those of the remaining laboratories, acceptable agreement was also found for amoxicillin-clavulanic acid, linezolid, minocycline, and tobramycin. Results showed unsatisfactory reproducibility of broth microdilution testing of ceftriaxone with N. cyriacigeorgica and N. wallacei , tigecycline with N. brasiliensis and N. cyriacigeorgica , and sulfonamides with N. farcinica and N. wallacei. N. nova ATCC BAA-2227 is proposed as a quality control organism for AST of Nocardia sp., and the use of a disk diffusion test for sulfisoxazole is proposed as a check of the adequacy of the inoculum and to confirm sulfonamide MIC results.

We undertook this study to determine the minimum amount of coronoid necessary to stabilise an otherwise intact elbow joint. Regan–Morrey types II and III, plus medial and lateral oblique coronoid fractures, collectively termed type IV fractures, were simulated in nine fresh cadavers. An electromagnetic tracking system defined the three-dimensional stability of the ulna relative to the humerus. The coronoid surface area accounts for 59% of the anterior articulation. Alteration in valgus, internal and external rotation occurred only with a type III coronoid fracture, accounting for 68% of the coronoid and 40% of the entire articular surface. A type II fracture removed 42% of the coronoid articulation and 25% of the entire articular surface but was associated with valgus and external rotational changes only when the radial head was removed, thereby removing 67% of the articular surface. We conclude that all type III fractures, as defined here, are unstable, even with intact ligaments and a radial head. However, a type II deficiency is stable unless the radial head is removed. Our study suggests that isolated medial-oblique or lateral-oblique fractures, and even a type II fracture with intact ligaments and a functional radial head, can be clinically stable, which is consistent with clinical observation.

We report the effectiveness of revision of total elbow replacement by re-cementing. Between 1982 and 2004, 53 elbows in 52 patients were treated with re-cementing of a total elbow replacement into part or all of the existing cement mantle or into the debrided host-bone interface, without the use of structural bone augmentation or a custom prosthesis. The original implant revision was still in situ and functional in 42 of 53 elbows (79%) at a mean of 94.5 months (26 to 266) after surgery. In 31 of these 42 elbows (74%) the Mayo Elbow Performance Score was good or excellent. Overall, of the 53 elbows, 18 (34%) required re-operation, ten (19%) for loosening. A classification system was developed to identify those not suitable for revision by this technique, and using this we have showed that successful re-implantation is statistically correlated to properly addressing the bone deficiency for both the humeral (p = 0.005) and the ulnar (p = 0.039) components.

With the passage of time, certain hand surgery procedures are anecdotally dubbed “workhorse” techniques. These are procedures that are extremely reliable and have repeatedly demonstrated good results. However, with time, paradigms undergo shifts, and this is as true for hand surgery as any other field. In this article, we will describe the use of three new “workhorse” flaps that we have found to have reliable results in complex hand reconstruction: the pedicled radial forearm fascia flap for dorsal hand reconstruction, the free anterolateral thigh flap for mangled hand reconstruction, and the medial femoral condyle vascularized bone graft for scaphoid fracture nonunion reconstruction.

Background and Purpose— American Indians have high rates of stroke. Improved risk stratification could enhance prevention, but the ability of biochemical and echocardiographic markers of preclinical disease to improve stroke prediction is not well-defined. Methods— We evaluated such markers as predictors of ischemic stroke in a community-based cohort of American Indians without prevalent cardiovascular or renal disease. Laboratory markers included C-reactive protein, fibrinogen, urine albumin-to-creatinine ratio, and glycohemoglobin (HbA1c), whereas echocardiographic parameters comprised left atrial diameter, left ventricular mass, mitral annular calcification, and the ratio of early to late mitral diastolic velocities. Predictive performance was judged by indices of discrimination, reclassification, and calibration. Results— After adjustment for standard risk factors, only HbA1c, albuminuria, and left atrial diameter were significantly associated with first ischemic stroke. Addition of HbA1c, although not urine albumin-to-creatinine ratio, to a basic clinical model significantly improved the C-statistic (0.714 versus 0.695; P =0.044), whereas left atrial diameter modestly enhanced integrated discrimination improvement (0.90%; P =0.004), but not the C-statistic (0.701; P =0.528). When combined with HbA1c, left atrial diameter further increased integrated discrimination improvement (1.81%; P <0.001) but not the C-statistic (0.716). No marker achieved significant net reclassification improvement. Conclusions— In this cohort at high cardiometabolic risk, HbA1c emerged as the foremost predictor of ischemic stroke when added to traditional risk factors, affording substantially improved discrimination, with a more modest contribution for left atrial diameter. These findings bolster the role of HbA1c in cardiovascular risk assessment among persons with glycometabolic disorders and provide impetus for further study of the incremental value of echocardiography in high-risk populations.

Background— We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality. Methods and Results— Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different ( P >0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P =0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation ( P =0.05) and improved positive vascular remodeling ( P =0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P =0.006), as was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P =0.002). Conclusions— Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.