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Supplementary Tables 1-2 from Distinct B-Cell and T-Cell Lymphoproliferative Disease Prevalence among Dog Breeds Indicates Heritable Risk

Immunophenotypes in lymphoproliferative diseases (LPD) are prognostically significant, yet causative factors for these conditions, and specifically those associated with heritable risk, remain elusive. The full spectrum of LPD seen in humans occurs in dogs, but the incidence and lifetime risk of naturally occurring LPD differs among dog breeds. Taking advantage of the limited genetic heterogeneity that exists within dog breeds, we tested the hypothesis that the prevalence of LPD immunophenotypes would differ among different breeds. The sample population included 1,263 dogs representing 87 breeds. Immunophenotype was determined by the presence of clonal rearrangements of immunoglobulin heavy chain or T-cell receptor γ chain. The probability of observing the number of B-cell or T-cell tumors in a particular breed or breed group was compared with three reference populations. Significance was computed using χ2 test, and logistic regression was used to confirm binomial predictions. The data show that, among 87 breeds tested, 15 showed significant differences from the prevalence of LPD immunophenotypes seen across the dog population as a whole. More significantly, elevated risk for T-cell LPD seems to have arisen ancestrally and is retained in related breed groups, whereas increased risk for B-cell disease may stem from different risk factors, or combinations of risk factors, arising during the process of breed derivation and selection. The data show that domestic dogs provide a unique and valuable resource to define factors that mediate risk as well as genes involved in the initiation of B-cell and T-cell LPD.

PURPOSE: Assess systemic vascular endothelial growth factor-A (VEGF) levels after treatment with intravitreous aflibercept, bevacizumab or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab following a retreatment algorithm. PARTICIPANTS: Participants with available plasma samples (N=436) METHODS: Plasma samples were collected before injections at baseline, 4-week, 52-week and 104-week visits. In a pre-planned secondary analysis, systemic free-VEGF levels from an ELISA immunoassay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free-VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61, −0.31±0.54, −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted CI; P-value) were −0.01 (−0.12, +0.10; P=0.89), −0.31 (−0.44, −0.18; P

Objective To evaluate the association between death due to drug overdose and a history of laminectomy. Design A retrospective matched case-control study of 234 drug overdose decedents from the Jefferson County Coroner/Medical Examiner's Office in Birmingham, Alabama were matched 1:2 on age to a control group consisting of decedents with any manner of death (accident, natural, suicide, homicide, or undetermined). Laminectomy cases were identified by the presence of a linear surgical scar near the spine in an orientation and place typical for a laminectomy. Results Decedents whose cause of death was a drug overdose were 2.43 times (95% confidence interval [CI] 1.37-4.31) more likely to have a laminectomy scar compared to decedents in a control group consisting of all manners of death. This association held for males (odds ratio [OR] 2.34; 95% CI: 1.09-5.04) and whites (OR 2.35; 95% CI 1.06-5.18) after stratification. Conclusion In the absence of an obvious cause for death, the presence of a laminectomy scar suggests the possibility of a fatal overdose and is a factor to consider in favor of performing an autopsy and toxicological analysis for drugs of abuse.

Objectives The goal of this study was to define the mechanism of preserved ejection fraction (EF) despite depressed myocardial strains in hypertension (HTN). Background Concentric left ventricular (LV) remodeling in HTN may have normal or supranormal EF despite depressed myocardial strains. The reason for such discordance is not clear. The aim of this study was to comprehensively evaluate the LV mechanics in a well-defined HTN population to define underlying reasons for such a paradox. Methods Sixty-seven patients with resistant HTN and 45 healthy control subjects were studied by cardiac magnetic resonance imaging and tissue tagging with 3-dimensional analysis. Amplitude and directional vector of longitudinal (Ell), circumferential (Ecc), and principal strain for maximal shortening (E3) were computed at basal, mid, and distal LV levels, respectively. LV torsion, defined as the rotation angle of apex relative to base, and LV twist, which accounts for the effects of differential LV remodeling on torsion for comparison among the 2 groups, were also calculated. Results LV mass index and LV mass/LV end-diastolic volume ratio were significantly higher in the HTN group compared with controls, consistent with concentric LV remodeling. Ell and Ecc were significantly decreased in amplitude with altered directional vector in HTN compared with controls. However, the amplitude of E3 was similar in the 2 groups. Torsion and twist were significantly higher in HTN, which was mainly due to increase in apical rotation. The HTN group demonstrated significantly increased LV wall thickening compared with controls that resulted in greater LVEF in the HTN group compared with controls (70% vs. 65%, p Conclusions In compensated LV remodeling secondary to HTN, there is increased LV wall thickening with preserved E3 and increased torsion compared with normal controls. This, therefore, contributes to supranormal LVEF in HTN despite depressed longitudinal and circumferential strains.

Multiple Sclerosis (MS) annualized relapse rates (ARRs) in trials may be declining due to changes in diagnostic criteria, MS etiology, study criteria, and selection biases. This review examines if there is a trend in the ARR for relapsing—remitting MS patients (RRMS) over time and if so, why. A comprehensive literature search was performed using PubMed, Web of Science®, and the Cochrane Library using electronic searches, screen scraping for abstracts, and hand searching of references for randomized trials conducted between 1960 and 2008. Out of 72 randomized trials, 56 (77.8%) defined relapse. This study uses 32 placebo relapsing—remitting studies out of the 37 (66.1%) with RRMS. The mean ARR for the treatment arms was 0.68 and the one for the placebo groups was 1.002. The year of publication was negatively associated with the ARR ( p = 0.0001). The annual reduction amounts to 0.36 relapses over a 10-year period. Age and duration of symptoms were negatively associated with the ARR. Year of publication was significantly negatively associated with ARR after controlling for covariates. ARRs have fallen with relapse definition, entrance criteria remain important, but time exceeds all these variables and reflects two likely sources, selection of patients for trials by clinicians and rescue of patients truncating the number of multiple relapses. The impact of truncating the number of relapses on the falling rates is important, not only on the ARRs, but also on the impact of informative censoring in drop-outs.

We propose a discrete version of the skew Laplace distribution. In contrast with the discrete normal distribution, here closed form expressions are available for the probability density function, the distribution function, the characteristic function, the mean, and the variance. We show that this distribution on integers shares many properties of the skew Laplace distribution on the real line, including unimodality, infinite divisibility, closure properties with respect to geometric compounding, and a maximum entropy property. We also discuss statistical issues of estimation under this model.

The late-systolic murmur of mitral regurgitation (MR) in degenerative mitral valve disease is widely believed to represent regurgitation of a degree that is not associated with hemodynamic significance. However, the extent of left ventricular (LV) remodeling associated with the late-systolic murmur has not been systematically assessed. Accordingly, we studied 82 patients sent for evaluation of at least moderate isolated MR by echocardiography/Doppler examination. All patients had a physical examination and cardiac magnetic resonance imaging to measure LV volumes by summation of serial short-axis slices. Forty-five patients had a pan-systolic murmur and 37 had a late-systolic murmur on auscultation that was verified by timing of onset of regurgitant turbulence by cine magnetic resonance imaging. Systolic blood pressures (124 +/- 3 versus 124 +/- 3 mm Hg) and LV ejection fraction (61 +/- 1% versus 61 +/- 1%) did not differ significantly between pan-systolic and late-systolic murmur groups. Although LV end-diastolic volume index was greater in the pan-systolic versus late-systolic murmur (108 +/- 4 versus 95 +/- 4 mL/m2, P = 0.007), both groups were significantly greater than normals (68 +/- 2 mL/m2, P0.0001). However, LV end-systolic volume index (42 +/- 2 versus 38 +/- 2 mL/m2) and LV end-systolic dimension (38 +/- 1 versus 37 +/- 1 mm), critical markers of adverse LV remodeling in isolated MR, did not differ significantly between pan-systolic and late-systolic murmur groups. In conclusion, the late systolic isolated MR murmur may be associated with significant adverse LV remodeling, and should not be considered evidence of hemodynamically unimportant MR.

Background: Published data suggest a link between obesity and adverse outcomes in Crohn ’ s disease (CD). We aimed to test the hypothesis that obese CD patients would be more likely than non-obese CD patients to have poor surgical outcome when undergoing surgery for a complication of CD. Methods: We designed a retrospective cohort study to test our hypothesis. The population comprised of adult CD patients who underwent CD related surgery at a tertiary referral center. The exposed and unexposed cohorts were represented by patients who were obese vs. non-obese at the pre-op visit respectively. Outcome was represented by successful vs. unsuccessful surgical outcome as deemed by the treating clinician. Results: Ninety CD patients were eligible for inclusion into this cohort study of which 36 were obese (exposed cohort) and 54 were non-obese (unexposed cohort). Among obese CD patients, 64% had an unsuccessful surgical outcome vs. 41% with unsuccessful surgical outcome among the non-obese. Based on unadjusted bivariate analysis, potential confounders identified included age and type of surgery. Gender distribution, disease duration, ethnicity, tobacco use, steroid use, traditional and biological immune modulator use and clinical disease activity were similar between the two groups. Logistic regression adjusted for age and type of surgery revealed that obese CD patients were approximately 2.5 times more likely to have a poor surgical outcome than patients with CD who were not obese (P = 0.05 OR 2.53 95% CI 0.99 - 6.52). BMI as a continuous variable (adjusted for age and type of surgery) appeared to be associated with poor surgical outcome (P = 0.06 OR 1.07 95% CI 0.99 - 1.15). Conclusions: Obesity may be associated with poor surgical outcome in CD patients. doi: http://dx.doi.org/10.4021/gr553w

Objectives The purpose of the study was to evaluate the effect of long-term β 1 -aderergic receptor (AR) blockade on left ventricular (LV) remodeling and function in patients with chronic, isolated, degenerative mitral regurgitation (MR). Background Isolated MR currently has no proven therapy that attenuates LV remodeling or preserves systolic function. Methods Thirty-eight asymptomatic subjects with moderate to severe, isolated MR were randomized either to placebo or β 1 -AR blockade (Toprol-XL, AstraZeneca, London, United Kingdom) for 2 years. Magnetic resonance imaging with tissue tagging and 3-dimensional analysis was performed at baseline and at 6-month intervals for 2 years. Rate of progression analysis was performed for endpoint variables for primary outcomes: LV end-diastolic volume/body surface area, LV ejection fraction, LV end-diastolic (ED) mass/ED volume ratio, LV ED 3-dimensional radius/wall thickness; LV end-systolic volume/body surface area, LV longitudinal strain rate, and LV early diastolic filling rate. Results Baseline LV magnetic resonance imaging or demographic variables did not differ between the 2 groups. Significant treatment effects were found on LV ejection fraction (p = 0.006) and LV early diastolic filling rate (p = 0.001), which decreased over time in untreated patients on an intention-to-treat analysis and remained significant after sensitivity analysis. There were no significant treatment effects found on LV ED or LV end-systolic volumes, LV ED mass/LV ED volume or LV ED 3-dimensional radius/wall thickness, or LV longitudinal strain rate. Over 2 years, 6 patients treated in the placebo group and 2 patients in the β 1 -AR blockade group required mitral valve surgery (p = 0.23). Conclusions β 1 -AR blockade improves LV function over a 2-year follow-up in isolated MR and provides the impetus for a large-scale clinical trial with clinical outcomes. (Molecular Mechanisms of Volume Overload-Aim 1 [SCCOR in Cardiac Dysfunction and Disease]; NCT01052428 )

We have shown previously that patients with resistant hypertension and hyperaldosteronism have increased brain natriuretic peptide suggestive of increased intravascular volume. In the present study, we tested the hypothesis that hyperaldosteronism contributes to cardiac volume overload. Thirty-seven resistant hypertensive patients with hyperaldosteronism (urinary aldosterone ≥12 μg/24 hours and plasma renin activity ≤1.0 ng/mL per hour) and 71 patients with normal aldosterone status were studied. Both groups had similar blood pressure and left ventricular mass, whereas left and right ventricular end-diastolic volumes measured by cardiac MRI were greater in high versus normal aldosterone subjects ( P

Background: Current guidelines recommend valve repair for chronic organic mitral regurgitation (MR) if LVEF drops below 60% to preserve LV function and maximize outcome. Post-operative drop in LVEF is typical, and widely believed to be due to alteration in loading conditions. Here we address whether cardiomyocyte damage may contribute to postoperative dysfunction. Methods: Three-dimensional magnetic resonance imaging (3D-MRI) with tissue tagging was performed in 23 MR patients, prior to and six months following mitral valve repair. LV biopsy was obtained from all MR patients at time of surgery. Immunohistochemistry was performed to assess for signs of oxidative stress, specifically lipofuscin deposition, and presence and quantity of xanthine oxidase (XO). Plasma XO levels were measured before, and six months post-surgery. Results: MR patients (n=23) demonstrated decreased LVEF (62 ± 1 to 54 ± 2% p=0.0002) and LV end-diastolic volume (116 ± 5 to 79 ± 5 ml/m 2 p Conclusions: Decreased LV strain rates 6 months post MV repair indicate myocyte contractile dysfunction in chronic MR patients despite pre-surgical LVEF >60%. This is supported by marked cardiomyocyte myofibrillar degeneration and oxidative damage at the time of surgery. While raising questions regarding timing of surgery for MR, these findings generate hypothesis concerning XO and oxidative stress-related myocyte damage in the pathophysiology of LV contractile dysfunction in MR.

Background: Hyperaldosteronism is being recognized to be increasingly prevalent particularly in patients with resistant hypertension and is believed in addition to raising blood pressure (BP) to induce cardiac fibrosis and LVH. We hypothesize that spironolactone a mineralocorticoid receptor antagonist, could improve blood pressure control and LVH in this high risk population. Methods: Patients with resistant hypertension (defined as requiring 4 or more antihypertensive agents) were treated with spironolactone 25mg once daily and up titrated to 50mg daily. Clinic BP, 24-hr ambulatory BP, cardiac MRI, plasma renin activity (PRA), brain natriuretic peptide (BNP) were measured before and 6 months after treatment with spironolactone. Results: Eleven subjects with a mean age 54.5_7.2 years and BMI 36.1_6.2 kg/m2 were evaluated. Ten of 11 subjects were receiving optimal doses of a thiazide diuretic as part of their treatment regimen. Clinic BP (134_13/81_7 vs. 120_11/76_7 mm Hg; p _ 0.015, p_ns), ambulatory daytime BP (142_15/83_10 vs. 132_16/76_12 mm Hg; p_ns), nighttime BP (132_16/ 74_14 vs. 121_14/65_11 mm Hg; p_0.05), 24-hr ABPM (139_15/80_11 vs. 129_15/ 73_12 mm Hg; p_ns), BNP (44.1_52.0 vs. 16.1_18.1 pg/ml; p _ 0.02), left ventricular (LV) end diastolic volume (170.0_43.9 vs. 160.9_46.4 ml; p_ns), end diastolic LV mass (178.4_48.6 vs. 148.5_33.4 gm; p _ 0.006), end systolic LV mass (195.2_55.6 vs. 155.5_34.6 gm; p _ 0.003), mean LV mass (186.8_51.9 vs. 151.9_33.8 gm; p _ 0.004), LV posterior wall thickness (10_1.9 vs. 9_1.8 mm; p_ns), interventricular septal thickness (11.3_2.4 vs. 9.6_2.2 mm; p _ 0.008) were lower at the end of six months following spiranolactone treatment compared to baseline. Serum potassium (3.7_0.4 vs. 4.3_0.5 mEq/L; p _ 0.006), serum creatinine (0.99_0.2 vs. 1.2_0.3 mg/dl; p_0.02) and PRA (1.7_2.2 vs. 12.2_16.1 ng/ml/hr; p_0.002) were higher. Conclusion: Our findings demonstrate for the first time in humans that spironolactone improves BP control and reduces LVH in patients with resistant hypertension who are receiving optimal doses of thiazide diuretics. These results suggest that mineralocorticoid receptor blockade specifically benefits patients with resistant hypertension beyond conventional diuretic therapy.

Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME).To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy.Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015.Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME.The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization.Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified.Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy.clinicaltrials.gov Identifier: NCT01489189.

Immunophenotypes in lymphoproliferative diseases (LPD) are prognostically significant, yet causative factors for these conditions, and specifically those associated with heritable risk, remain elusive. The full spectrum of LPD seen in humans occurs in dogs, but the incidence and lifetime risk of naturally occurring LPD differs among dog breeds. Taking advantage of the limited genetic heterogeneity that exists within dog breeds, we tested the hypothesis that the prevalence of LPD immunophenotypes would differ among different breeds. The sample population included 1,263 dogs representing 87 breeds. Immunophenotype was determined by the presence of clonal rearrangements of immunoglobulin heavy chain or T-cell receptor γ chain. The probability of observing the number of B-cell or T-cell tumors in a particular breed or breed group was compared with three reference populations. Significance was computed using χ2 test, and logistic regression was used to confirm binomial predictions. The data show that, among 87 breeds tested, 15 showed significant differences from the prevalence of LPD immunophenotypes seen across the dog population as a whole. More significantly, elevated risk for T-cell LPD seems to have arisen ancestrally and is retained in related breed groups, whereas increased risk for B-cell disease may stem from different risk factors, or combinations of risk factors, arising during the process of breed derivation and selection. The data show that domestic dogs provide a unique and valuable resource to define factors that mediate risk as well as genes involved in the initiation of B-cell and T-cell LPD.