Purpose: To use multimodal imaging for identification of risk factors for choroidal nevus transformation into melanoma. Methods: Retrospective chart review of 3806 consecutive choroidal nevi with imaging and 2355 choroidal nevi with additional follow up to identify factors predictive of transformation of choroidal nevus into melanoma. Results: The median patient age was 62.5 years and Caucasian race in 3167 (95%). The choroidal nevus demonstrated median basal diameter of 4.0 mm and thickness of 1.4 mm. Imaging included optical coherence tomography (OCT) showing subretinal fluid (SRF) in 312 (9%), ultrasonography (US) with acoustic hollowness in 309 (9%), and hyper-autofluorescence (AF) in 100 (3%). Of those 2355 choroidal nevi with follow up, Kaplan-Meier estimates of nevus transformation into melanoma at 1, 5, and 10 years were 1.2%, 5.8%, and 13.9%, respectively. Multivariate analysis, using multimodal imaging for detection of factors predictive of nevus transformation into melanoma, included thickness >2 mm on US (hazard ratio (HR) 3.80, p < 0.0001), SRF on OCT as cap over nevus (HR 3.00, p < 0.0001) or SRF ≤3 mm from nevus margin (HR 3.56, p = 0.0003), symptomatic vision loss ≤20/50 on Snellen visual acuity (VA) (HR 2.28, p = 0.005), orange pigment (lipofuscin) hyperautofluorescence on AF (HR 3.07, p = 0.0004), acoustic hollowness on US (HR 2.10, p = 0.0020), and tumor diameter >5 mm on photography (HR 1.84, p = 0.0275). These factors can be recalled by the mnemonic “To Find Small Ocular Melanoma Doing IMaging” (TFSOM-DIM) representing Thickness >2 mm (US), Fluid subretinal (OCT), Symptoms vision loss (VA), Orange pigment (AF), Melanoma hollow (US), and DIaMeter >5mm (photography). The mean 5-year estimates of nevus growth into melanoma were 1% (HR 0.8) for those with 0 risk factor, 11% (HR 3.09) with 1 factor, 22% (HR 10.6) with 2 factors, 34% (HR 15.1) with 3 factors, 51% (HR 15.2) with 4 factors, 55% (HR 26.4) with 5 risk factors, and not-estimable with all 6 risk factors. Conclusion: In this analysis, multimodal imaging was capable of detecting risk factors for nevus transformation into melanoma, including thickness >2 mm (US), fluid subretinal (OCT), symptoms vision loss (Snellen acuity), orange pigment (AF), melanoma hollowness (US), and diameter >5 mm (photography). Increasing number of risk factors imparts greater risk for nevus transformation into melanoma, including thickness >2 mm (US), fluid subretinal (OCT), symptoms vision loss (Snellen acuity), orange pigment (AF), melanoma hollowness (US), and diameter >5 mm (photography). Increasing number of risk factors imparts greater risk for transformation.

Drug eluting stents are associated with late stent thrombosis (LST), delayed healing and prolonged exposure of stent struts to blood flow. Using macroscale disturbed and undisturbed fluid flow waveforms, we numerically and experimentally determined the effects of microscale model strut geometries upon the generation of prothrombotic conditions that are mediated by flow perturbations. Rectangular cross-sectional stent strut geometries of varying heights and corresponding streamlined versions were studied in the presence of disturbed and undisturbed bulk fluid flow. Numerical simulations and particle flow visualization experiments demonstrated that the interaction of bulk fluid flow and stent struts regulated the generation, size and dynamics of the peristrut flow recirculation zones. In the absence of endothelial cells, deposition of thrombin-generated fibrin occurred primarily in the recirculation zones. When endothelium was present, peristrut expression of anticoagulant thrombomodulin (TM) was dependent on strut height and geometry. Thinner and streamlined strut geometries reduced peristrut flow recirculation zones decreasing prothrombotic fibrin deposition and increasing endothelial anticoagulant TM expression. The studies define physical and functional consequences of macro-and microscale variables that relate to thrombogenicity associated with the most current stent designs, and particularly to LST.

Patch clamp and RNA-polymerase chain reaction methods were used to determine the expression of voltage-dependent potassium channel currents and mRNAs in human airway smooth muscle cells, and tension measurements were used to examine the functional role of specific potassium channel gene products in human bronchial smooth muscle. RNA from airway smooth muscle tissue revealed the presence of Kv1.2 (11 kilobases (kb)) and Kv1.5 (3.5 and 4.4 kb) transcripts, as well as Kv1.1 mRNA (9.5 kb), which has not previously been reported in smooth muscle; transcripts from other gene families were not detected. RNA-polymerase chain reaction from cultured human myocytes confirmed that the identified transcripts were expressed by smooth muscle cells. The available voltage-dependent potassium current in human airway myocytes was insensitive to charybdotoxin (200 nM) but blocked by 4-aminopyridine. Dendrotoxin (1-300 nM; inhibits Kv1.1 and Kv1.2 channels), charybdotoxin (10 nM to 1 microM; inhibits KCa and Kv1.2 channels), and glybenclamide (0.1-100 microM; inhibits KATP channels) had no effect on resting tone. Conversely, 4-aminopyridine increased resting tension with an EC50 (1.8 mM) equivalent to that observed for current inhibition (1.9 mM). Human airway myocytes express mRNA from several members of the Kv1 gene family; the channel that underlies the predominate voltage-dependent current and the regulation of basal tone appears to be Kv1.5.

Overexpression of cytokine receptor-like factor 2 (CRLF2) due to chromosomal rearrangement has been observed in acute lymphoblastic leukemia (ALL) and reported to contribute to oncogenesis and unfavorable outcome in ALL. We studied B-ALL and T-ALL patients without CRLF2 rearrangement and observed that CRLF2 is significantly increased in a subset of these patients. Our study shows that high CRLF2expression correlates with high-risk ALL markers, as well as poor survival. We found that the IKZF1-encoded protein, Ikaros, directly binds to the CRLF2 promoter and regulates CRLF2 expression in leukemia cells. CK2 inhibitor, which can increase Ikaros activity, significantly increases Ikaros binding in ALL cells and suppresses CRLF2 expression in an Ikaros-dependent manner. CRLF2 expression is significantly higher in patients with IKZF1 deletion as compared to patients without IKZF1 deletion. Treatment with CK2 inhibitor also results in an increase in IKZF1 binding to the CRLF2 promoter and suppression of CRLF2 expression in primary ALL cells. We further observed that CK2 inhibitor induces increased H3K9me3 histone modifications in the CRLF2 promoter in ALL cell lines and primary cells. Taken together, our results demonstrate that high expression of CRLF2 correlates with high-risk ALL and short survival in patients without CRLF2 rearrangement. Our results are the first to demonstrate that the IKZF1-encoded Ikaros protein directly suppresses CRLF2 expression through enrichment of H3K9me3 in its promoter region. Our data also suggest that high CRLF2 expression works with the IKZF1 deletion to drive oncogenesis of ALL and has significance in an integrated prognostic model for adult high-risk ALL.

We report the electrophysiological and functional properties of Ca(2+)-activated Cl- currents [ICl(Ca)] in rat pulmonary artery smooth muscle and the activation of these currents by the metabolic inhibitor cyanide. Caffeine and norepinephrine (NE) evoked both Ca(2+)-activated K+ currents [IK(Ca)] and ICl(Ca) currents in voltage-clamped myocytes (-50 mV). Niflumic acid (10 microM) reduced the caffeine-induced ICl(Ca) by approximately 64% and reversibly reduced NE-induced tension. Exposure of myocytes to cyanide (2-10 mM) induced a slowly developing inward current (-50 mV) in physiological and K(+)-free solutions, which was identified as ICl(Ca) on the basis of ion selectivity and Ca2+ dependence. Cyanide elevated cytosolic Ca2+ concentration, and this elevation was markedly inhibited by preexposure to caffeine and slightly inhibited by nisoldipine. During exposure to caffeine, the Ca(2+)-activated K+ current was also augmented. Cyanide markedly prolonged ICl(Ca) activated by caffeine, increasing the half-decay time from 3.5 (control) to 29 s (cyanide); the half-decay time of the caffeine-induced IK(Ca) was not significantly affected by cyanide. The results indicate that metabolic inhibition increases [Ca2+]i and activates a prolonged, depolarizing Cl- current in pulmonary artery myocytes.

Purpose: To analyze risk of nevus transformation into melanoma per millimeter increment. Methods: Retrospective analysis of 3,806 choroidal nevi for transformation into melanoma per incremental millimeter thickness (flat [≤1.0 mm], thin [1.1–2.0 mm], thicker [2.1–3.0 mm], and thickest [>3.0 mm]) Results: The median nevus thickness was 1.4 mm, and nevi were categorized (flat, thin, thicker, and thickest) in 1,140 (30%), 2052 (54%), 555 (15%), and 59 (<1%), respectively. There were differences in tumor diameter (2.5, 4.8, 7.5, and 9.3 mm; P < 0.01), optical coherence tomography detection of overlying subretinal fluid (<1, 4, 15, and 11%; P < 0.01), overlying retinal edema (<1, 3, 14, and 25%; P < 0.01), overlying drusen (23, 49, 64, and 64%; P < 0.01), overlying retinal pigment epithelial detachment (1, 4, 4, and 9%; P < 0.01), and overlying lipofuscin hyperautofluoresence (<1, 3, 6, and 7%; P < 0.01). Choroidal nevus transformation into melanoma (n = 90/2,355 cases, 3.8%) was found by Kaplan–Meier 7-year estimates (2.2, 6.1, 31.7, and 34.5%; P < 0.0001) and by hazard ratio (HR) compared with nevus ≤1.0 mm (not available, 4.7 [P = 0.01], 35.7 [P < 0.0001], and 52.0 [P < 0.0001]). For all thicknesses, those with growth displayed increase in mean basal diameter of 2.4 mm and thickness of 1.1 mm, optical coherence tomography increase in subretinal fluid (65%), autofluorescence increase in lipofuscin (40%), and ultrasonography increase in hollowness (30%). Multivariable risk factors, recalled by the mnemonic “To Find Small Ocular Melanoma Doing IMaging” (TFSOM-DIM) representing Thickness >2 mm (ultrasonography), Fluid subretinal (optical coherence tomography), Symptom vision loss (Va), Orange pigment (autofluorescence), Melanoma hollow (ultrasonography), and DIaMeter >5 mm, revealed factors per incremental thickness category (compared with flat) including thin (Fluid overlying, HR 6.1; DIaMeter >5 mm, HR 3.3), thicker (Fluid subretinal ≤3 mm from nevus, HR 5.7; Melanoma acoustic hollowness, HR 2.7), and thickest (Orange pigment, HR 9.1). Conclusion: Each incremental increase in choroidal nevus thickness demonstrated risk of growth into melanoma with HR (compared with flat) 4.7 for thin, 35.7 for thicker, and 52.0 for thickest. The increase from ≤2.0 mm to >2.0 mm thickness conferred the greatest rise for transformation.

AimTo characterise combinations of multimodal imaging risk factors and predictive value for choroidal nevus transformation into melanoma.MethodsThis is a retrospective review of multimodal imaging features for 3806 choroidal nevi from 1 January 2007 through 1 January 2017. Kaplan-Meier estimates and Cox regression analyses were used to calculate 5-year percentages of growth to melanoma and HR.ResultsUsing multimodal imaging, six risk factors predictive of choroidal nevus transformation into melanoma were identified, namely tumour thickness >2 mm, subretinal fluid, symptoms of visual acuity loss to 20/50 or worse, orange pigment, hollow acoustic density and tumour largest basal diameter >5 mm. Kaplan-Meier 5-year estimated tumour growth was found in 1% of nevi with no risk factors, 11% (range 9%–37%) with one factor, 22% (12%–68%) with two factors, 34% (21%–100%) with three factors, 51% (0%–100%) with four factors and 55% (0%–100%) with five factors. HR for growth was 0.1 with no factor, 2.1–7.8 with one factor, 1.8–12.1 with two factors, 4.0–24.4 with three factors, 4.6–170.0 with four factors and 12.0–595.0 with five factors. The highest HR with each combination of two, three, four or five risk factors always included symptoms of visual acuity loss and orange pigment.ConclusionSix risk factors for choroidal nevus transformation into melanoma by multimodal imaging have been identified. Risk for transformation into melanoma is 1% when no factors are present, and approaches 100% with specific combinations of three or more risk factors. Understanding how combinations of factors influence risk of transformation into melanoma can guide counselling and treatment decisions.

Background Modular revision femoral components allow the surgeon to make more precise intraoperative adjustments in anteversion and sizing, which may afford lower dislocation rates and improved osseointegration, but may not offer distinct advantages when compared with less expensive monoblock revision stems. Questions/purposes We compared modular and monoblock femoral components for revision of Paprosky Type I to IIIA femoral defects to determine (1) survivorship of the stems; and (2) complications denoted as intraoperative fracture, dislocation, or failure of osseointegration. Methods Between 2004 and 2010, participating surgeons at three centers revised 416 total hip arthroplasties (THAs) with Paprosky Type I to IIIA femoral defects. Of those with minimum 2-year followup (343 THAs, mean followup 51 ± 13 months), 150 (44%) were treated with modular stems and 193 (56%) were treated with monoblock, cylindrical, fully porous-coated stems. During this time, modular stems were generally chosen when there was remodeling of the proximal femur into retroversion and/or larger canal diameters (usually [ 18 mm). A total of 27 patients died (6%) with stems intact before 2 years, 46 THAs (13%) were lost to followup before 2 years for reasons other than death, and there was no differential loss to followup between the study groups. The modular stems included 101 with a cylindrical distal geometry (67%) and 49 with a tapered geometry (33%). Mean age (64 versus 68 years), percentage of women (53% versus 47%), and body mass index (31 versus 30 kg/m 2 ) were not different between the two cohorts, whereas there was trend toward a slightly greater case complexity in the modular group (55% versus 65% Type 3a femoral defects, p = 0.06). KaplanMeier survivorship was calculated for the endpoint of Each author certifies that he or she, or a member of his or her immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. Conclusions Although rerevisions were less common in patients treated with modular stems, aseptic complications such as intraoperative fractures were more common in that group, and the sample was too small to evaluate corrosionrelated or fatigue concerns associated with modularity. We cannot therefore conclude from this that one design is superior to the other. Larger studies and pooled analyses will need to be performed to answer this question, but we believe modularity should be avoided in more straightforward cases if possible. Level of Evidence Level III, therapeutic study.