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A novel, hand-held Reference Point Indentation (RPI) instrument, measures how well the bone of living patients and large animals resists indentation. The results presented here are reported in terms of Bone Material Strength, which is a normalized measure of how well the bone resists indentation, and is inversely related to the indentation distance into the bone. We present examples of the instrument's use in: (1) laboratory experiments on bone, including experiments through a layer of soft tissue, (2) three human clinical trials, two ongoing in Barcelona and at the Mayo Clinic, and one completed in Portland, OR, and (3) two ongoing horse clinical trials, one at Purdue University and another at Alamo Pintado Stables in California. The instrument is capable of measuring consistent values when testing through soft tissue such as skin and periosteum, and does so handheld, an improvement over previous Reference Point Indentation instruments. Measurements conducted on horses showed reproducible results when testing the horse through tissue or on bare bone. In the human clinical trials, reasonable and consistent values were obtained, suggesting the Osteoprobe® is capable of measuring Bone Material Strength in vivo, but larger studies are needed to determine the efficacy of the instrument's use in medical diagnosis.

Objectives: Peroneal nerve injuries are not uncommon with multiligament (ML) knee dislocations. However, there remains little information on outcome of these injuries. Therefore, the purpose of this study was to (1) report the clinical and functional outcomes after ML knee injury with concomitant peroneal nerve palsy, (2) compare recovery and outcome with partial versus complete peroneal nerve injury, (3) compare outcomes to a matched cohort of ML knee injuries without concomitant peroneal nerve palsy. Methods: Patients that underwent surgical reconstruction of a ML knee injury from 1993 to 2010 were reviewed and concomitant nerve injuries were identified, forming the peroneal nerve injury group (PI). Patient demographics, injury mechanism, modified Schenck classification, and peroneal nerve function, treatment, and recovery were documented. Patients were divided into two sub-groups: complete peroneal nerve palsy (CNP) and partial peroneal nerve palsy (PNP). A second group of patients with ML knee injury without peroneal nerve injury were identified, forming the no nerve injury group (NI). The PI and NI groups were matched based on Modified Schenck Classification, age, and gender. Peroneal nerve motor grade was assessed at last clinical follow-up and outcome scores were obtained using the International Knee Documentation Committee (IKDC) and Lysholm forms at a minimum of 2 years post-op. Data was analyzed using univariate and multivariate models to assess for predictive factors between the groups. Results: 27 patients (24 males, 3 females) met inclusion criteria for the PI group (9 CNP and 18 PNP). Treatment for CNP included an AFO for all patients, non-operative (1), neurolysis (2), tendon transfer (3), nerve transfer (1), and combined nerve/tendon transfer (1). One patient in the CNP group required additional surgery, undergoing below knee amputation. Treatment for PNP included non-op (12), neurolysis (4), nerve transfer (1), and combined nerve/tendon transfer (1). 2 patients with incomplete nerve palsy required additional surgery, undergoing an arthrodesis and a total knee arthroplasty. 3 CNP (37.5%) and 15 PNP (83.3%) regained 3/5 or greater tibialis anterior (TA) strength. PNP was associated with increased recovery of 3/5 extensor hallucis longus (EHL) strength (p=0.0093). Outcome scores were obtained for 17 of the remaining patients at a mean 6.6 (range 2-18) years. Univariate analysis revealed no difference between the CNP and PNP groups. Final motor grade of 3/5 did not predict improved outcomes. Not undergoing a tendon transfer procedure predicted better outcomes on the IKDC score (70.5 vs 45.0; p=0.027). All other peroneal nerve interventions were not associated with improved motor or functional outcome. 20 patients formed the NI group. The PI and NI groups were matched on gender (18 M, 2 F), age (mean 30.8 vs 29.5 years), and Modified Schenck Classification (2 KD-I, 10 KD-IIIL, 5 KD-IV, 3 KD-V vs 2, 7, 8, and 3 respectively). In univariate analysis, the PI group had inferior outcomes on both the IKDC (64.5 vs 77.3; p=0.036) and Lysholm (67.1 vs 83.0; p=0.023) scores. Conclusion: Patients with partial peroneal nerve palsy are more likely to regain antigravity EHL strength, but not antigravity TA strength. There is no significant difference in outcomes between partial and complete peroneal nerve palsy. In ML knee injuries, patients with peroneal nerve injury have significantly worse outcomes than similar patients without peroneal nerve injury.

Background— A patent foramen ovale (PFO) may permit arterial embolization of thrombi that accumulate on the leads of cardiac implantable electronic devices in the right-sided cardiac chambers. We sought to determine whether a PFO increases the risk of stroke/transient ischemic attack (TIA) in patients with endocardial leads. Methods and Results— We retrospectively evaluated all patients who had endocardial leads implanted between January 1, 2000, and October 25, 2010, at Mayo Clinic Rochester. Echocardiography was used to establish definite PFO and non-PFO cohorts. The primary end point of stroke/TIA consistent with a cardioembolic etiology and the secondary end point of mortality during postimplantation follow-up were compared in PFO versus non-PFO patients with the use of Cox proportional hazards models. We analyzed 6075 patients (364 with PFO) followed for a mean 4.7±3.1 years. The primary end point of stroke/TIA was met in 30/364 (8.2%) PFO versus 117/5711 (2.0%) non-PFO patients (hazard ratio, 3.49; 95% confidence interval, 2.33–5.25; P <0.0001). The association of PFO with stroke/TIA remained significant after multivariable adjustment for age, sex, history of stroke/TIA, atrial fibrillation, and baseline aspirin/warfarin use (hazard ratio, 3.30; 95% confidence interval, 2.19–4.96; P <0.0001). There was no significant difference in all-cause mortality between PFO and non-PFO patients (hazard ratio, 0.91; 95% confidence interval, 0.77–1.07; P =0.25). Conclusions— In patients with endocardial leads, the presence of a PFO on routine echocardiography is associated with a substantially increased risk of embolic stroke/TIA. This finding suggests a role of screening for PFOs in patients who require cardiac implantable electronic devices; if a PFO is detected, PFO closure, anticoagulation, or nonvascular lead placement may be considered.

Transforming growth factor β (TGFβ) has significant profibrotic activity both in vitro and in vivo . This reflects its capacity to stimulate fibrogenic mediators and induce the expression of other profibrotic cytokines such as platelet‐derived growth factor (PDGF) and epidermal growth factor (EGF/ErbB) ligands. Here we address both the mechanisms by which TGFβ induced ErbB ligands and the physiological significance of inhibiting multiple TGFβ‐regulated processes. The data document that ErbB ligand induction requires PDGF receptor (PDGFR) mediation and engages a positive autocrine/paracrine feedback loop via ErbB receptors. Whereas PDGFRs are essential for TGFβ‐stimulated ErbB ligand up‐regulation, TGFβ‐specific signals are also required for ErbB receptor activation. Subsequent profibrotic responses are shown to involve the cooperative action of PDGF and ErbB signaling. Moreover, using a murine treatment model of bleomycin‐induced pulmonary fibrosis we found that inhibition of TGFβ/PDGF and ErbB pathways with imatinib plus lapatinib, respectively, not only prevented myofibroblast gene expression to a greater extent than either drug alone, but also essentially stabilized gas exchange (oxygen saturation) as an overall measure of lung function. These observations provide important mechanistic insights into profibrotic TGFβ signaling and indicate that targeting multiple cytokines represents a possible strategy to ameliorate organ fibrosis dependent on TGFβ.—Andrianifahanana, M., Wilkes, M. C., Gupta, S. K., Rahimi, R. R., Repellin, C. E., Edens, M., Wittenberger, J., Yin, X., Maidl, E., Becker, J., Leof, E. B. Profibrotic TGFβ responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases. FASEB J . 27, 4444‐4454 (2013). www.fasebj.org

Abstract To identify novel genetic loci influencing interindividual variation in red blood cell (RBC) traits in African-Americans, we conducted a genome-wide association study (GWAS) in 2315 individuals, divided into discovery (n = 1904) and replication (n = 411) cohorts. The traits included hemoglobin concentration (HGB), hematocrit (HCT), RBC count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Patients were participants in the electronic MEdical Records and GEnomics (eMERGE) network and underwent genotyping of ~1.2 million single-nucleotide polymorphisms on the Illumina Human1M-Duo array. Association analyses were performed adjusting for age, sex, site, and population stratification. Three loci previously associated with resistance to malaria—HBB (11p15.4), HBA1/HBA2 (16p13.3), and G6PD (Xq28)—were associated (P ≤ 1 × 10−6) with RBC traits in the discovery cohort. The loci replicated in the replication cohort (P ≤ 0.02), and were significant at a genome-wide significance level (P &lt; 5 × 10−8) in the combined cohort. The proportions of variance in RBC traits explained by significant variants at these loci were as follows: rs7120391 (near HBB) 1.3% of MCHC, rs9924561 (near HBA1/A2) 5.5% of MCV, 6.9% of MCH and 2.9% of MCHC, and rs1050828 (in G6PD) 2.4% of RBC count, 2.9% of MCV, and 1.4% of MCH, respectively. We were not able to replicate loci identified by a previous GWAS of RBC traits in a European ancestry cohort of similar sample size, suggesting that the genetic architecture of RBC traits differs by race. In conclusion, genetic variants that confer resistance to malaria are associated with RBC traits in African-Americans.

ObjectiveCD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA.MethodsBlood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor.ResultsJIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28nullCD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28nullCD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone γH2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon‐γ and interleukin‐10.ConclusionThese data provide the first evidence of cell senescence, as represented by CD31+CD28null CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR‐independent manner suggests that they are maladaptive and could be potential targets for immunotherapy.

ABSTRACTVenous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two‐stage genome‐wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community‐based studies. Genotypes for genome‐wide single‐nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study‐design appropriate regression methods. Meta‐analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case‐control studies. In the combined data from these two stages, additional genome‐wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10−6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.