Human Herpesvirus-8-Transformed Endothelial Cells Have Functionally Activated Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor

Kaposi's sarcoma is a vascular tumor commonly associated with human immunodeficiency virus (HIV)-1 and human herpesvirus (HHV-8) also known as Kaposi's sarcoma-associated herpesvirus. The principal features of this tumor are abnormal proliferation of vascular structures lined with spindle-shaped endothelial cells. HHV-8 may transform a subpopulation of endothelial cells in vitro via viral and cellular gene expression. We hypothesized that among the cellular genes, vascular endothelial growth factors (VEGFs) and their cognate receptors may be involved in viral-mediated transformation. We have shown that HHV-8-transformed endothelial cells (EC-HHV-8) express higher levels of VEGF, VEGF-C, VEGF-D, and PlGF in addition to VEGF receptors-1, -2, and -3. Furthermore, antibodies to VEGF receptor-2 inhibited cell proliferation and viability. Similarly, inhibition of VEGF gene expression with antisense oligonucleotides inhibited EC-HHV-8 cell proliferation/viability. The growth and viability of primary endothelial cells and a fibroblast cell line however were unaffected by either the VEGF receptor-2 antibody or the VEGF antisense oligodeoxynucleotides. VEGF and VEGF receptors are thus induced in EC-HHV-8 and participate in the transformation. Inhibitors of VEGF may thus modulate the disease process during development and progression.     

Is nail dynamization beneficial after twelve weeks – An analysis of 37 cases

Purpose

Although nail dynamization in femoral and tibial fractures is an effective method of promoting healing, its role beyond twelve weeks is still not clear. It is usually done two to three months following interlocking nailing. This study was done to evaluate the efficacy of late dynamization (after 12 weeks) and factors affecting union.

Safety of therapeutic beta-blockade in patients with coexisting bronchospastic airway disease and coronary artery disease

Atherosclerotic coronary artery disease and bronchospastic airway disease frequently coexist in older patients. There are substantial data suggesting reduced mortality with the use of beta-adrenergic blocking drugs in patients with symptomatic coronary artery disease, especially patients who have postmyocardial infarction and/or severe coronary artery disease associated with left ventricular dysfunction. Conversely, the use of beta-adrenergic blocking drugs (even selective beta(1)-adrenergic blocking drugs) has the potential of exacerbating bronchospasm. This prospective registry evaluates the safety of use of selective beta(1)-adrenergic blocking drugs in patients with symptomatic coronary artery disease and bronchospastic airway disease. A total of 835 consecutive patients with symptomatic coronary artery disease were prospectively evaluated for coexisting coronary and bronchospastic airway disease. Of these, 30 patients (mean age: 61 +/- 14 years) met the qualifying inclusion criteria. All these study patients except 1 (29/30 [96%]) reached therapeutic beta-blockade (resting heart rate <70 beats per minute). The 1 patient who discontinued use of beta-adrenergic blocking drugs as a result of lifestyle-limiting bronchospasm had no serious adverse outcome. No hospitalizations were required because of worsening bronchospasm. Ten percent of patients reported increased requirement of inhaled beta(2)-agonist use. The patients were followed for 15 +/- 9 months. One patient died of stroke at 22 weeks of follow-up. In conclusion, use of selective beta(1)-adrenergic blocking drugs at a therapeutic dose is safe (as long as careful clinical follow-up is available) and should be considered in all patients with coexisting symptomatic coronary artery disease and bronchospastic airway disease.     

A Contemporary Population-Based Profile of Infective Endocarditis Using the Expanded Rochester Epidemiology Project

ObjectiveTo develop a contemporary profile of infective endocarditis (IE) among a population in 6 counties of Olmsted, Dodge, Mower, Steele, Waseca, and Freeborn in southern Minnesota between 2014 and 2018.Patients and MethodsAll possible and definite cases of IE (≥18 years) among residents of 6 counties in southern Minnesota, including Olmsted County, diagnosed between January 1, 2014, and December 31, 2018, were included in this retrospective, population-based investigation, using the Expanded Rochester Epidemiology Project (E-REP).ResultsOverall, 137 patients with IE developed incident IE in the 6-county region, corresponding to an age- and sex-adjusted incidence rate of 11.9 per 100,000 person-years. Men had a significantly higher incidence of IE (17.9 vs 6.8 per 100,000 person-years), and rates increased exponentially with age in both sexes. The median age of incident cases was 68.2 years, and 67.9% were male patients. The percentage of patients with histories of injection-drug use was low, at 6.7%. Bicuspid aortic valve was the most common (9.6%) native valve predisposing condition. Staphylococcus aureus was identified as the predominant pathogen in the overall group (34.8%), with viridans-group streptococci accounting for only 19.3% cases. Central nervous system and musculoskeletal complications were common. The 30-day readmission rate was 27.9%, and the 6-month mortality rate was 31.8%.ConclusionTo our knowledge, this is the first time that the population-based E-REP has been used to determine an age- and sex-adjusted IE incidence. Older male patients predominated, and S aureus was the most common pathogen. Based on these findings, it is not surprising that IE complications were frequently seen.     

Propensity Score Analysis of Conditioning Intensity in Peripheral Blood Haploidentical Hematopoietic Cell Transplantation

T cell replete HLA-haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide was originally described using a reduced-intensity conditioning (RIC) regimen. Given that myeloablative conditioning (MAC) is more effective at preventing disease relapse, we compared outcomes of patients receiving MAC and RIC regimens. We evaluated overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), and graft-versus-host disease (GVHD) of 148 patients that underwent haplo-HCT with either MAC (n?=?61) or RIC (n?=?87). Propensity score adjustment (PSA) was used to balance baseline characteristics between groups and more effectively compare outcomes based on conditioning intensity. After the PSA analysis, relapse was significantly decreased with MAC (hazard ratio [HR], .47; 95% confidence interval [CI], .31 to .70), but was associated with higher NRM (HR, 1.74; 95% CI, 1.13 to 2.67). OS and DFS were not significantly different between groups (HRs for MAC versus RIC were .87 [95% CI, .64 to 1.18] and .90 [95% CI, .68 to 1.18] for OS and DFS, respectively). Rates of acute and chronic GVHD were not significantly different between groups. This analysis suggests that both MAC and RIC regimens are effective in haplo-HCT and that MAC regimens may result in less relapse in selected patients. These results need to be verified in a larger registry study.     

Pretreatment with β‐adrenergic receptor agonists facilitates induction of LTP and sharp wave ripple complexes in rodent hippocampus

Norepinephrine, is involved in the enhancement of learning and memory formation by regulating synaptic mechanisms through its ability to activate pre‐ and post‐synaptic adrenergic receptors. Here we show that β‐agonists of norepinephrine facilitate the induction of both associational LTP and sharp wave ripples (SPW‐Rs) in acute slices of rat hippocampus in area CA3. Surprisingly, this facilitating effect persists when slices are only pretreated with β‐receptor agonists followed by wash out and application of the unspecific β‐adrenoreceptor (βAR) antagonist propranolol. During application of βAR agonists repeated stimulation resulted in facilitated induction of SPW‐Rs. Since SPW‐Rs are thought to be involved in memory replay we studied the effects of βAR‐agonists on spontaneous SPW‐Rs in murine hippocampus and found that amplitude and incidence of SPW‐Rs increased. These effects involve cyclic‐AMP and the activation of protein kinase A and suggest a supportive role in memory consolidation. © 2016 Wiley Periodicals, Inc.     

Pooled analysis of two clinical trials comparing the clinical outcomes of topical ciprofloxacin/dexamethasone otic suspension and polymyxin B/neomycin/hydrocortisone otic suspension for the treatment of acute otitis externa in adults and children

OBJECTIVE: This study aimed to compare the clinical outcome of patients receiving topical ciprofloxacin 0.3%/dexamethasone 0.1% (CD) otic suspension with that of those receiving polymyxin B/neomycin/ hydrocortisone (PNH) otic suspension for the treatment of acute otitis externa (AOE). METHODS: Data from 2 institutional review board-approved, multicenter, observer-masked, parallel-group, randomized, noninferiority clinical trials conducted at 76 institutions across the United States between April 1998 and July 1999 were pooled together for this analysis. Patients > or =1 year of age diagnosed with AOE were considered for inclusion in the studies. Patients with AOE >4 weeks' duration, a perforated tympanic membrane, chronic suppurative otitis media, or use of either antibiotics or steroids within the previous 7 days were excluded from the studies. Patients were randomly assigned to receive CD or PNH for 7 days. CD was administered as 3 drops in children and 4 drops in patients > or =12 years of age BID. PNH was administered as 3 drops in children and 4 drops in patients > or =12 years of age TID. The clinical investigators were blinded to treatment assignment. Due to the different dosing regimens, patients were not blinded, but they also were not directly informed of their treatment assignments. Otic inflammation, tenderness, edema, and discharge were clinically assessed on days 3, 8, and 18 of the studies. Otic inflammation and edema were evaluated using a 4-point scale (none = 0; mild = 1; moderate = 2; and severe = 3). Otic tenderness and discharge were rated on a binomial scale (absent = 0 and present = 1). The clinical assessments were aggregated into a 9-point composite clinical scale (range, 0-8) to compare baseline severity between groups. For the final outcomes assessment in this study, the aggregated clinical scores were dichotomized into cured (0) versus noncured (>0) and analyzed using a Kaplan-Meier survival technique. A log-rank test was used to compare the cure curves between treatment groups. Kaplan-Meier summary statistics provide the mean and median times to cure, and the mean times to cure for the 25th and 75th patient quartiles. Tolerability was assessed by monitoring patients for adverse events at each visit. RESULTS: Data from 1072 patients (1242 ears) were included in the analysis (CD, 537 patients; PNH, 535 patients). Baseline AOE severity and demographic characteristics were similar between the 2 treatment groups. The mean patient age was 21.7 and 22.0 years in the CD and PNH groups, respectively. Both groups were similar with respect to sex, with 50.7% and 53.5% females in the CD and PNH groups, respectively. The racial composition was predominately white (88.6% vs 84.9% in the CD and PNH groups, respectively). The log-rank test revealed a significant difference in the AOE cure curves between the CD and PNH groups (P = 0.038). The proportions cured in the AOE at-risk groups at the day-3, -8, and -18 assessments in the CD and PNH treatment groups were 0.14 and 0.10, 0.75 and 0.72, and 0.98 and 0.97, respectively. The Kaplan-Meier summary statistics indicated that the mean time to cure was 0.6 day less with CD compared with PNH (9.7 vs 10.3 days). Treatment-related adverse event rates were similar between the 2 groups and occurred in 3.8% of the patients. The most common adverse events included otic pruritus (2.1%), otic congestion (0.6%), otic debris (0.5%), otic pain (0.3%), superimposed ear infection (0.3%), and erythema (0.1%). CONCLUSION: These data from 2 previous studies suggest that time to cure was significantly less with CD compared with PNH in patients with AOE.     

Mortality and morbidity following a major bleed in a registry population with acute ST elevation myocardial infarction

Major bleeding has been associated with an increased risk of ischemic events and death in patients with acute coronary syndromes. We examined the relationship between bleeding and outcome in 1,389 consecutive patients with ST-elevation myocardial infarction (STEMI) presenting to a tertiary center between May 1, 2003 and July 10, 2007. We recorded bleeding, length of stay and death during the first 30 days after hospitalization. Major bleeding occurred in 10.9% (152/1389, 95% confidence interval [CI] 9.3–12.6%). In hospital mortality was significantly higher in patients with major bleeding compared to those without major bleeding (19.7 vs. 8.2%, odds ratio [OR] 2.8, 95% CI 1.8–4.3) and was evident in the subgroups of patients with a low TIMI STEMI risk score (7.9 vs. 1.8%, OR 4.6, 95% CI 1.2–17.0) and medium risk score (11.7 vs. 6.3%, OR 2.0, 95% CI 0.6–6.2) but not those with a high TIMI STEMI risk score (28.8 vs. 26.1%, OR 1.2, 95% CI 0.7–2.0) (P for interaction = 0.024). Our data indicate that serious bleeding is common in patients with STEMI treated with thrombolysis or PCI and is a powerful predictor of death, particularly in patients with a low TIMI risk score. Therapies that maintain efficacy while reducing bleeding and that reduce the risk of death in patients who develop bleeding are needed.