Abstract Objective The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA). Methods Wild-type 8-week-old C56BL/6 male mice (n = 120) were equally ...divided into three groups: (1) BAPN group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 μL of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 μL of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5 minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative days 7, 14, 21, 28, and 100, aortic samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement. Results Compared with the elastase group, the BAPN+elastase group had a higher AAA formation rate (93% vs 65%; P < .01) with more advanced AAAs (25 of 42 vs 1 of 40 for stage II and III; P < .001). Aneurysms from the BAPN+elastase group demonstrated persistent long-term growth (221.5% ± 36.6%, 285.8% ± 78.6%, and 801% ± 160% on days 21, 28, and 100, respectively; P < .001), with considerable thrombus formation (54%) and rupture (31%) at the advanced stages of AAA development. Cytokine levels (pro-matrix metalloproteinase 9, interleukin-1β, interleukin-6, chemokine C-C motif ligand 5, triggering receptor expressed on myeloid cells 1, monocyte chemotactic protein 1, and tissue inhibitor of metalloproteinase 1) in the BAPN+elastase group were higher than in the elastase group on day 7. After day 7, cytokine levels returned to baseline, with the exception of elevated matrix metalloproteinase 2 activity. By histology, CD3-positive T cells in the BAPN+elastase group were elevated on days 28 and 100. Conclusions A combination of oral BAPN administration and periaortic elastase application induced a chronic, advanced-stage AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should use this model, especially for examining tissue remodeling during the late stages of aneurysm development.
Abstract Background Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not ...well-documented. Objectives The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk. Methods This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Results Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval CI: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB. Conclusions The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.
Summary Background Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of ...published and unpublished data whether any relation exists between statin use and development of diabetes. Methods We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I2 statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis. Findings We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio OR 1·09; 95% CI 1·02–1·17), with little heterogeneity ( I2 =11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150–852) patients with statins for 4 years resulted in one extra case of diabetes. Interpretation Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. Funding None.
Summary Appendiceal serrated polyps often morphologically resemble their colorectal counterparts and most pathologists employ colorectal diagnostic terminology when evaluating appendiceal serrated ...lesions. We analyzed 132 appendiceal lesions for mutations in the RAS/RAF/MAPK pathway in an attempt to (1) determine the frequency of these mutations in appendiceal serrated lesions and (2) correlate the histopathologic features with molecular alterations. The study group of appendiceal serrated lesions (n = 46) was divided into a non-dysplastic group (28/46, subclassified as 7 hyperplastic polyps and 21 sessile serrated adenoma/polyps (SSA/P) using colorectal diagnostic terminology) and dysplastic group (18/46, subclassified as 9 SSA/Ps with cytological dysplasia, 7 traditional serrated adenomas, and 2 adenomas with prominent serrations). Appendiceal non-serrated dysplastic lesions (n = 86) comprised the control group. Of the 123 lesions analyzed, KRAS mutations were identified in 64 (52%) appendiceal lesions. No significant difference in the presence of KRAS mutations were identified between serrated non-dysplastic lesions (13/25, 52%), serrated dysplastic lesions (7/14, 50%) and the control group of non-serrated dysplastic lesions (44/84, 52%) ( P = 1.0). Importantly, KRAS mutations were identified in lesions that were histologically identical to colorectal hyperplastic polyps (2/6, 33%), SSA/Ps (11/19, 58%), and SSA/Ps with cytological dysplasia (4/7, 57%). Of the 126 lesions tested, BRAF V600E mutations were identified in only 5 (4%) appendiceal lesions. Our results indicate that serrated lesions of the appendix often harbor KRAS mutations rather than BRAF mutations and suggest that the serrated pathway in the appendix is likely different than in the colon and rectum.
Background Literature guiding the management of early-onset scoliosis consists primarily of studies with a low level of evidence. Evaluation of clinical equipoise (i.e., when there is no known ...superiority among treatment modalities) allows for prioritization of research efforts. The objective of this study was to evaluate areas of clinical uncertainty among pediatric spine surgeons regarding the treatment of early-onset scoliosis. Methods Fourteen experienced pediatric spine surgeons participated in semistructured interviews to identify clinical variables that influence decision making in the treatment of early-onset scoliosis. A series of case scenarios of 315 patients with idiopathic and neuromuscular early-onset scoliosis was then developed to be representative of those encountered in clinical practice. Using an online survey, eleven surgeons selected their choice of eight treatment options for each case scenario. Associations between case characteristics and treatment choices were assessed with chi-square and logistic regression analysis. Participants then reviewed the areas of treatment uncertainty identified in the survey, nominated additional research questions of interest, and ranked their interest to further explore the identified research questions. Results Collective equipoise was identified in numerous scenarios in the survey spanning a range of ages and magnitudes of scoliosis, and additional questions were identified during the nominal group technique. Areas that had the greatest clinical uncertainty included the management of patients who have finished treatment with a growing-rod, timing of rod-lengthening intervals, and indications for spine-based and rib-based proximal instrumentation anchors. The use of rib anchors compared with spine-based anchors was ranked highly for consideration in future clinical trials. Conclusions Variability in decision making with regard to the optimum treatment of certain subsets of patients with early-onset scoliosis reflects gaps in the available evidence. Structured consensus methods identified priorities for higher levels of research in this area of scoliosis. Higher-level studies, including randomized trials, should focus on answering the questions highlighted in this report.
Abstract Background We evaluated an “open lung” ventilation (OV) strategy using low tidal volumes, low respiratory rate, low FiO2 , and high continuous positive airway pressure in patients undergoing ...major lung resections. Materials and methods In this phase I pilot study, twelve consecutive patients were anesthetized using conventional ventilator settings (CV) and then OV strategy during which oxygenation and lung compliance were noted. Subsequently, a lung resection was performed. Data were collected during both modes of ventilation in each patient, with each patient acting as his own control. The postoperative course was monitored for complications. Results Twelve patients underwent open thoracotomies for seven lobectomies and five segmentectomies. The OV strategy provided consistent one-lung anesthesia and improved static compliance (40 ± 7 versus 25 ± 4 mL/cm H2O, P = 0.002) with airway pressures similar to CV. Postresection oxygenation (SpO2 /FiO2 ) was better during OV (433 ± 11 versus 386 ± 15, P = 0.008). All postoperative chest x-rays were free of atelectasis or infiltrates. No patient required supplemental oxygen at any time postoperatively or on discharge. The mean hospital stay was 4 ± 1 d. There were no complications or mortality. Conclusions The OV strategy, previously shown to have benefits during mechanical ventilation of patients with respiratory failure, proved safe and effective in lung resection patients. Because postoperative pulmonary complications may be directly attributable to the anesthetic management, adopting an OV strategy that optimizes lung mechanics and gas exchange may help reduce postoperative problems and improve overall surgical results. A randomized trial is planned to ascertain whether this technique will reduce postoperative pulmonary complications.
To compare baseline characteristics, treatment frequency, visual acuity (VA), and morphologic outcomes of eyes with >50% of the lesion composed of blood (B50 group) versus all other eyes (Other ...group) enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).
Prospective cohort study within a multicenter randomized clinical trial.
CATT patients with neovascular age-related macular degeneration (AMD).
Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to 3 different dosing regimens over a 2-year period. Reading center graders evaluated baseline and follow-up morphology in color fundus photographs, fluorescein angiography (FA), and optical coherence tomography (OCT). Masked examiners tested VA.
Morphologic features and VA at 1 and 2 years.
The B50 group consisted of 84 of 1185 (7.1%) patients enrolled in CATT. Baseline lesion characteristics differed between groups. In the B50 group, choroidal neovascularization size was smaller (0.73 vs 1.83 disc areas DA; P < 0.001), total lesion size was greater (4.55 vs 2.31 DA; P <0.001), total retinal thickness was greater (524 vs 455 μm; P = 0.02), and mean VA was worse (56.0 vs 60.9 letters; P = 0.002). Increases in mean VA were similar in the B50 and Other groups at 1 year (+9.3 vs +7.2 letters; P = 0.22) and at 2 years (9.0 vs 6.1 letters; P = 0.17). Eyes treated PRN received a similar number of injections in the 2 groups (12.2 vs 13.4; P = 0.27). Mean lesion size in the B50 group decreased by 1.2 DA at both 1 and 2 years (primarily owing to resolution of hemorrhage) and increased in the Other group by 0.33 DA at 1 year and 0.91 DA at 2 years (P < 0.001). Leakage on FA and fluid on OCT were similar between groups at 1 and 2 years.
In CATT, the B50 group had a visual prognosis similar to the Other group. Lesion size decreased markedly through 2 years. Eyes like those enrolled in CATT with neovascular AMD lesions composed of >50% blood can be managed similarly to those with less or no blood.
We compared pulmonary gas exchange during synchronized intermittent mandatory ventilation (SIMV), pressure support ventilation (PSV), and airway pressure release ventilation (APRV). Nine subjects ...aged 56 to 75 yr were studied from 4 to 19 h after cardiac operations. When subjects were ready to be weaned from mechanical ventilation their ventilation-perfusion distribution was estimated using the multiple inert gas elimination technique during SIMV. The subjects then received PSV and APRV during alternating periods on a randomized basis, and the gas-exchange measurements were repeated. Vasoactive infusions and inspired oxygen fraction were held constant throughout the investigation. The results indicated that the major characteristics of the main mode of the VA/Q distributions (mean, standard deviation, and skew) were similar during all three modes. Dead space was lower during APRV (30.1 +/- 1.7% SEM) than during SIMV (36.2 +/- 1.5%) and PSV (37.1 +/- 2.7%) (p less than 0.05). Right-to-left shunt was significantly greater during APRV (19.9 +/- 2.3%) than during SIMV (15.4 +/- 1.7%) (p less than 0.05). Peak airway pressure (Paw) was higher during SIMV (32.8 +/- 1.3 cm H2O) than both PSV (19.4 +/- 2.1 cm H2O) and APRV (14.3 +/- 1.0 cm H2O) (p less than 0.05). Minute ventilation was lower during APRV (7.5 +/- 0.07 L/min) than during SIMV (9.4 +/- 0.6 L/min) and PSV (9.0 +/- 0.5 L/min) (p less than 0.05). Hemodynamic variables were similar during all three modes. We conclude that all three modes provide acceptable oxygenation and ventilatory support.
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