Imaging human macular pigments with visible light optical coherence tomography and superluminescent diodes.

We demonstrate superluminescent diodes (SLDs) for visible light optical coherence tomography (OCT) of the human retina. SLDs are less costly than supercontinuum sources and have lower intrinsic excess noise, enabling imaging closer to the shot noise limit. While single SLDs are not broadband, they provide power concentrated at specific wavelengths relevant to retinal function. As a new, to the best of our knowledge, application, we image human macular pigments (MPs), which are thought to both aid vision and protect against advanced age-related macular degeneration. Using the unique depth-resolved capabilities of OCT, we localize MPs in depth to Henle's fibers beneath the foveal pit in the living human retina. Our approach reduces the cost of visible light OCT to nearly that of near-infrared (NIR) OCT while also providing information about clinically relevant MPs which cannot be measured in the NIR.

Perioperative and 1-year transcarotid revascularization outcomes in symptomatic patients.

OBJECTIVE: Previously published results of carotid revascularization with both transfemoral stenting and endarterectomy have demonstrated inferior perioperative stroke and death outcomes in neurologically symptomatic patients compared with those without symptoms. This study was completed to establish the real-world, symptom-based perioperative and follow-up outcomes for transcarotid artery revascularization (TCAR). METHODS: An institutional retrospective review of all TCARs performed outside of clinical trial regulations from 2016 to 2019 was completed. Eligible patients were classified as symptomatic or not based on a history of a unilateral neurologic deficit attributable to an extracranial carotid artery lesion within the previous 180 days. Univariate analysis consisting of Fisher's exact and Student t-tests, as appropriate, were performed between cohorts. Kaplan-Meier analysis was completed to estimate the stroke-free survival at 1 year postoperatively. RESULTS: Within the investigational period, 167 patients (85 symptomatic) qualified for study inclusion. Baseline demographics were roughly equivalent, although symptomatic patients were more likely to be female (28.0% vs 9.4%; P < .01). Procedures in symptomatic patients were associated with higher estimated blood loss (41 mL vs 58 mL; P = .04) and operative time (67 minutes vs 75 minutes; P = .06). We did not find an increased incidence of macroscopic debris in the filter of symptomatic patients after stent deployment. For symptomatic patients, we observed a perioperative (30-day) ipsilateral stroke risk of 1.2% (vs 2.4% in asymptomatic patients; P > .99), a myocardial infarction risk of 0% (vs 0%; P > .99), and a mortality risk of 4.9% (vs 0%; P = .06). Most deaths occurred after procedure-related discharge; as such, in-hospital (from index TCAR) mortality in symptomatic patients was 1.2%. The four perioperative deaths observed in our population were secondary to hemorrhagic stroke, acute on chronic congestive heart failure (n = 2), and unknown causes in the last patient. At 1 year after the procedure, 114 patients (54 symptomatic) had available data. In addition to the perioperative risks, in symptomatic patients we observed a rate of reintervention of 0% (vs 0%; P > .99), ipsilateral stroke of 3.7% (vs 0%; P = .22), >50% in-stent restenosis of 1.9% (vs 0%; P = .47), stent thrombosis of 3.7% (vs 0%; P = .22), and all-cause mortality of 13.0% (vs 10.0%; P = .77). Last, no difference was noted with respect to the 1-year stroke-free survival (P = .17) by Kaplan-Meier estimates. CONCLUSIONS: In this institutional series of patients undergoing TCAR, we found that symptomatic patients have a similar perioperative risk of stroke and myocardial infarction as asymptomatic patients. However, we did observe a strong statistical trend suggesting a higher mortality risk in symptomatic patients. There was no difference between cohorts with respect to 1-year stroke-free survival.

Perioperative and Long-term Results of Zenith Fenestrated Aortic Repair in Women.

BACKGROUND: Inferior perioperative outcomes for women receiving major vascular surgery are well established in the literature in multiple arterial distributions. Therefore, this study was completed to determine the perioperative and durability results associated with women undergoing complex aortic reconstruction using the Zenith Fenestrated platform (ZFEN; Cook Medical, Bloomington, IN). METHODS: A retrospective review of a fenestrated endovascular aortic repair (FEVAR) database capturing all ZFENs performed at our institution between October 2012 and March 2019 was completed. Preoperative, intraoperative, perioperative, and follow-up outcomes were tabulated for females and compared with their male counterparts. RESULTS: Within our study period, 136 total ZFEN procedures were performed; of which, 20 devices (14.7%) were implanted in women. Intraoperatively, we observed a higher rate of estimated blood loss (660.0 mL vs. 311.6 mL, P < 0.01) and resultant need for transfusion (1.4 vs. 0.3 units, P < 0.01) in women despite a similar frequency of brachial (5.0% vs. 7.8%, P > 0.99) and femoral artery cutdowns (55.0% vs. 49.1%, P = 0.81). Operative (295.7 min vs. 215.7 mins, P < 0.01) and fluoroscopy (84.3 vs. 58.7 min, P < 0.01) times were also significantly higher in females than those in their male counterparts. In the perioperative (30-day) period, we observed significantly longer length of stay (5.6 days vs. 3.3 days, P = 0.03) and continued need for transfusion (50% vs. 9.5%, P < 0.01) in women. Statistical trends favoring men were also noted with respect to all-cause mortality, reintervention, visceral stent thrombosis, renal failure, acute kidney injury, and respiratory failure. After a mean follow-up of nearly 2 years, we found no differences in late all-cause or aneurysm-related mortality, major adverse cardiovascular events, or need for reinterventions. CONCLUSIONS: The implantation of ZFEN in females is significantly more difficult than that in their male counterparts and may result in increased perioperative, but not necessarily long-term, complications.

Outcomes associated with a transcarotid artery revascularization-centered protocol in high-risk carotid revascularizations using the ENROUTE neuroprotection system.

OBJECTIVE: This investigation describes the perioperative and early follow-up results associated with transcarotid artery revascularization (TCAR) in patients not participating in the Safety and Efficacy Study for Reverse Flow Used During Carotid Artery Stenting Procedure II (ROADSTER-2) registry using the ENROUTE neuroprotection system (ENPS; Silk Road Medical, Sunnyvale, Calif). METHODS: A retrospective review was performed capturing all TCAR/ENPS procedures in patients deemed to be at high risk for complications after traditional carotid endarterectomy. All patients enrolled in the ROADSTER-2 registry were excluded, leaving only those treated outside trial regulations for analysis. Preoperative demographics, intraoperative variables, and perioperative and follow-up outcomes were abstracted and reported herein. RESULTS: From December 2015 to January 2018, there were 75 carotid arteries treated at our institution. All interventions were performed on carotid arteries that were symptomatic with ≥50% stenosis (46.7%) or asymptomatic with ≥80% stenosis (53.3%) by duplex ultrasound and computed tomography angiography. Technical success in our series was 97.3% (73/75), with treatment failures attributed to one case of common carotid artery dissection and another secondary to stent maldeployment in the external carotid artery. Perioperative (30-day) ipsilateral stroke rate was 2.7% (n = 2), myocardial infarction incidence was 0%, and mortality rate was 2.7% (n = 2). We did not observe any cranial nerve injuries. After a mean follow-up of 8.0 ± 6.7 months, no carotid stents required reintervention. However, we noted one instance of minor (<50%) in-stent stenosis and one asymptomatic stent thrombosis. One additional ipsilateral stroke was observed on follow-up, probably from a cardiac source. CONCLUSIONS: We report that dynamic reverse-flow TCAR using the ENPS continues to be safe, feasible, and efficacious with minimal risks of postoperative stroke, myocardial infarction, and mortality outside of ROADSTER-2 regulations.

Fenestrated endovascular aneurysm repair-induced acute kidney injury does not result in chronic renal dysfunction.

OBJECTIVE: Acute kidney injury (AKI) is a common physiologic complication after fenestrated endovascular aneurysm repair (FEVAR). This investigation was initiated to determine the unknown impact of post-FEVAR AKI on long-term renal function after index hospital discharge. METHODS: A retrospective review was performed of an institutional FEVAR database capturing preoperative, intraoperative, and postoperative variables related to the implantation of consecutive Zenith Fenestrated endografts (ZFEN; Cook Medical, Bloomington, Ind) between October 2012 and April 2018. AKI in this study was bimodally defined as qualification by either Risk, Injury, Failure, Loss of kidney function, and End-stage (RIFLE) criteria or a postoperative serum creatinine (sCr) concentration increase of 0.5 mg/dL from baseline. Glomerular filtration rate (GFR) was calculated using the validated Modification of Diet in Renal Disease (MDRD) study equation. RESULTS: During the study period, 120 FEVARs were performed at our institution. Twenty-four (20%) patients exhibited postoperative AKI by our established definitions. Two in-hospital deaths occurred in the AKI cohort compared with none in the remaining FEVARs (P = .04). Four (16.7%) AKI patients required perioperative (<30-day) renal replacement therapy, three of whom were successfully weaned before discharge. FEVARs uncomplicated by AKI exhibited no differences in sCr concentration from baseline to 1-month, 6-month, 1-year, and 2-year follow-up (mean, 1.8 ± 1.4 years). In contrast, patients exhibiting AKI experienced an sCr concentration increase of 57.1% (P = .01) at 1 month after the procedure. This elevation decreased to 14.3% (P = .35) at 6 months after the procedure and was maintained at baseline values at 1- and 2-year office visits (follow-up, 1.3 ± 1.5 years). A similar pattern of gradual recovery during follow-up was also observed with respect to calculated GFR. CONCLUSIONS: AKI is common after FEVAR but rarely results in permanent renal dysfunction as both sCr concentration and GFR return to baseline by 6 months after the procedure.

Aggressive Surveillance Is Needed to Detect Endoleaks and Junctional Separation between Device Components after Zenith Fenestrated Aortic Reconstruction.

BACKGROUND: Junctional separation and resulting type IIIa endoleak is a well-known problem after EVAR (endovascular aneurysm repair). This complication results in sac pressurization, enlargement, and eventual rupture. In this manuscript, we review the incidence of this late finding in our experience with the Cook Zenith fenestrated endoprosthesis (ZFEN, Bloomington, IN). METHODS: A retrospective review was performed of a prospectively maintained institutional ZFEN fenestrated EVAR database capturing all ZFENs implanted at a large-volume, academic hospital system. Patients who experienced junctional separation between the fenestrated main body and distal bifurcated graft (with or without type IIIa endoleak) at any time after initial endoprosthesis implantation were subject to further evaluation of imaging and medical records to abstract clinical courses. RESULTS: In 110 ZFENs implanted from October 2012 to December 2017 followed for a mean of 1.5 years, we observed a 4.5% and 2.7% incidence of clinically significant junctional separation and type IIIa endoleak, respectively. Junctional separation was directly related to concurrent type Ib endoleak in all 5 patients. Three patients presented with sac enlargement. One patient did not demonstrate any evidence of clinically significant endoleak and had a decreasing sac size during follow-up imaging. The mean time to diagnosis of modular separation in these patients was 40 months. Junctional separation was captured in surveillance in 2 patients and reintervened upon before manifestation of endoleak. However, the remaining 3 patients completed modular separation resulting in rupture and emergent intervention in 2 and an aortic-related mortality in the other. CONCLUSIONS: Junctional separation between the fenestrated main and distal bifurcated body with the potential for type IIIa endoleak is an established complication associated with the ZFEN platform. Therefore, we advocate for maximizing aortic overlap during the index procedure followed by aggressive surveillance and treatment of stent overlap loss captured on imaging.

Osteopontin may be a driver of abdominal aortic aneurysm formation.

OBJECTIVE: Previous in vitro and animal studies have suggested that osteopontin (OPN), an inflammatory extracellular matrix protein, is involved in the formation and growth of abdominal aortic aneurysms (AAAs). However, the mechanism by which this occurs continues to be nebulous. The relationship between OPN and inflammation-suppressing lymphocytes present in the human AAA condition was investigated and presented herein. METHODS: Serum OPN concentrations were measured in healthy, risk factor-matched non-AAA and AAA patients by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to determine the source of OPN secretion using aortic tissue collected from multiorgan donors and AAA patients undergoing open surgical repair. Vascular smooth muscle cells (VSMCs) were exposed to various inflammatory mediators, and OPN expression was evaluated by quantitative reverse transcriptase-polymerase chain reaction and ELISA. The inflammatory nature of OPN and the aortic wall was determined using a TR1 suppressor cell induction assay as a surrogate and characterized by ELISA and fluorescence-activated cell sorting. RESULTS: OPN was found to be elevated in both the plasma and aortic homogenate of AAA patients compared with controls. On immunohistochemistry, OPN localized to the tunica media of the diseased aorta but was minimally expressed in healthy aorta. In vitro, cigarette smoke extract was the most potent stimulator of OPN secretion by VSMCs and increased both messenger RNA and supernatant concentrations. OPN demonstrated an ability to inhibit the induction of interleukin 10-secreting TR1 lymphocytes, a depleted population in the AAA patient, from naive precursors. Last, neutralizing receptor targets of OPN in the setting of AAA homogenate coincubation abrogated the inhibition of TR1 induction. CONCLUSIONS: OPN, secreted by the VSMCs of the tunica media, is elevated in the circulating plasma and aortic wall of patients with AAA. It can inhibit the induction of the TR1 suppressor cell, leading to an overall proinflammatory state contributing to progressive aortic wall breakdown and dilation.

Institutional experience with the Zenith Fenestrated aortic stent graft.

OBJECTIVE: The Zenith Fenestrated (ZFEN; Cook Medical, Bloomington, Ind) aortic stent graft system was approved for commercial use by the Food and Drug Administration in April 2012. We report our single-center experience of 100 consecutive patients treated with the ZFEN platform from October 2012 to March 2017. METHODS: A retrospective review of our prospectively maintained fenestrated endovascular aneurysm repair (FEVAR) database at a tertiary care academic institution located in the Midwest United States was performed for descriptive analysis. All continuous variables are reported as a mean ± standard deviation and compared using two-sided Student t-tests. Categorical variables were compared using two-sided Fisher exact tests. RESULTS: All but one of the procedures were elective in nature. Overall intraoperative characteristics included a mean blood loss (estimated blood loss) of 388 ± 385 mL, fluoroscopy time of 63 ± 30 minutes, radiation dose of 437 ± 272 rad, contrast material volume of 99 ± 36 mL, and operative time of 236 ± 87 minutes. Average number of visceral arteries stented was 2.1 ± 0.5. Technical success was achieved in 98% of the patients. Statistically significant (P < .05) improvement in estimated blood loss (2.1-fold) was observed in the second half of our series. Interestingly, no improvements were made in terms of fluoroscopy time, radiation exposure, contrast material use, or operative time. However, procedural difficulty increased in the last half by number of visceral arteries stented as a surrogate (1.9 vs 2.2; P < .05). Mean length of stay was 3.6 ± 4.3 days. Perioperative mortality at 30 days was 2%. Perioperative morbidity included a 5% incidence of any bowel ischemia, 1% of spinal cord ischemia, 3% of renal failure requiring hemodialysis, 1% of stroke, and 4% of myocardial infarction. Average follow-up was 1.7 ± 1.4 years. Reintervention during the follow-up phase was 20%. Of the 209 visceral arteries stented, we noted 6 instances of stent thrombosis, 6 of kinking or stenosis, and 1 of stent fracture in follow-up. Endoleak, most commonly type II, was present or could not be excluded in 15% of all FEVARs at last available computed tomography angiography. CONCLUSIONS: In our experience, FEVAR with the ZFEN system continues to be safe and effective. There is a significant rate of reintervention observed, and close monitoring is fundamental to maintaining good clinical results.

Adjunctive visceral artery chimney in patients undergoing Zenith Fenestrated aortic repair.

OBJECTIVE: Visceral artery chimneys have been employed as an adjunct to endovascular aneurysm repair (EVAR) to treat short-neck infrarenal and juxtarenal aortic aneurysms for more than two decades. With the widespread introduction of fenestrated endovascular aneurysm repair by the Food and Drug Administration-approved Zenith Fenestrated endograft (ZFEN; Cook Medical, Bloomington, Ind) to the United States in 2012, clinicians gained the ability to apply the chimney technique to these custom devices for difficult anatomy. The purpose of this report was to demonstrate feasibility and to provide evidence on the performance of chimneys for the treatment of complex juxtarenal aneurysms that could not be adequately treated with ZFEN alone. METHODS: A retrospective analysis was performed of a prospectively maintained institutional ZFEN database capturing 110 fenestrated endovascular aneurysm repairs from October 2012 to January 2018 to identify patients undergoing a concomitant visceral artery chimney. All patients with <12 months of follow-up were excluded from further analysis. Demographic, anatomic, intraoperative, perioperative, and follow-up characteristics were tabulated and analyzed. RESULTS: Six patients met criteria and were included in this investigation. They were universally male with a mean age of 76.2 years at the time of ZFEN/chimney. Chimneys were placed in a total of six visceral arteries (n = 1 per patient) consisting of three renal arteries, two celiac arteries, and one accessory renal artery. Mean estimated blood loss and operative time were 283 mL and 298 minutes, respectively. Technical success was achieved in all cases. Two small type IA "gutter" endoleaks were detected early; both spontaneously resolved on follow-up. We observed no instances of chimney migration, stenosis, or thrombosis perioperatively or on follow-up. Two reinterventions were performed in these six patients; these consisted of a repeated renal stent for ostial stenosis at a main body fenestration and a common femoral artery endarterectomy and patch angioplasty for an access-related common femoral artery occlusion. CONCLUSIONS: Use of ZFEN in conjunction with a singular chimney is safe, feasible, and durable in patients with difficult anatomy who do not meet instructions for use as demonstrated in this limited series.

Ethnic minorities with critical limb ischemia derive equal amputation risk reduction from autologous cell therapy compared with whites.

OBJECTIVE: Ethnic minorities (nonwhites) with critical limb ischemia (CLI) have historically performed worse compared with whites with regard to major amputation risk reduction and amputation-free survival (AFS) after peripheral vascular intervention. This post hoc analysis was completed to determine whether this precedent also extended to treatment of CLI without a suitable revascularization option with intramuscular injections of concentrated bone marrow aspirate (cBMA). METHODS: The treatment arm of the randomized, double-blind, multicenter MarrowStim PAD Kit for the Treatment of Critical Limb Ischemia in Subjects with Severe Peripheral Arterial Disease (MOBILE) trial was stratified by ethnicity and evaluated for demographics, comorbidities, and outcomes. The primary and therapeutic end point was 1-year AFS and major amputation, respectively. Noninferiority analysis was performed with the margin set at historically reported hazard ratios. RESULTS: Thirty-seven minority (African American, Hispanic, other) CLI patients (9 placebo, 28 cBMA) with no suitable revascularization option were randomized to cBMA or placebo at a 3:1 ratio during the MOBILE trial. At 1-year follow-up for the treatment group, overall AFS was 80%. Of the 28 minority patients randomized to cBMA intervention, an 89% AFS rate was observed compared with 77% in whites. Specifically, 22 of 24 (92%) African Americans survived amputation free at 1-year follow-up. Noninferiority testing confirmed no difference between whites and the ethnic minority treated with cBMA with respect to major amputation reduction; however, noninferiority could not be confirmed with regard to AFS. No significant differences favoring whites treated with cBMA were noted in the secondary end points of vascular quality of life, limb pain, ankle-brachial index, toe-brachial index, transcutaneous oximetry, and 6-minute walk testing. CONCLUSIONS: This post hoc analysis of the MOBILE trial demonstrates noninferiority of cBMA intervention in minorities with no-option CLI for the therapeutic end point of major amputation prevention. cBMA represents a novel treatment paradigm and should be explored for minorities with poor revascularization options who face impending amputation secondary to progressive CLI.

Metformin does not reduce inflammation in diabetics with abdominal aortic aneurysm or at high risk of abdominal aortic aneurysm formation.

INTRODUCTION: The protective effect of diabetes mellitus on abdominal aortic aneurysm formation and growth has been repeatedly observed in population studies but continues to be poorly understood. However, recent investigations have suggested that metformin, a staple antihyperglycemic medication, may be independently protective against abdominal aortic aneurysm formation and growth. Therefore, we describe the effect of metformin in abdominal aortic aneurysm and at-risk patients on markers of inflammation, the driver of early abdominal aortic aneurysm formation and growth. METHODS: Peripheral blood was collected from patients previously diagnosed with abdominal aortic aneurysm or presenting for their U.S. Preventive Task Force-recommended abdominal aortic aneurysm screening. Plasma and circulating peripheral blood mononuclear cells were isolated using Ficoll density centrifugation. Circulating plasma inflammatory and regulatory cytokines were assessed with enzyme-linked immunosorbent assays. CD4+ cell phenotyping was performed using flow cytometric analysis and expressed as a proportion of total CD4+ cells. To determine the circulating antibody to self-antigen response, a modified enzyme-linked immunosorbent assay was performed against antibodies to collagen type V and elastin fragments. RESULTS: Peripheral blood was isolated from 266 patients without diabetes mellitus ( n=182), with diabetes mellitus not treated with metformin ( n=34), and with diabetes mellitus actively taking metformin ( n=50) from 2015 to 2017. We found no differences in the expression of Tr1, Th17, and Treg CD4+ fractions within diabetics ± metformin. When comparing inflammatory cytokines, we detected no differences in IL-1ß, IL-6, IL-17, IL-23, IFN-γ, and TNF-α. Conversely, no differences were observed pertaining to the expression to regulatory cytokines IL-4, IL-10, IL-13, TSG-6, or TGF-ß. Lastly, no differences in expression of collagen type V and elastin fragment antigen and/or antibodies were detected with metformin use in diabetics. CONCLUSION: Metformin in diabetics at-risk for abdominal aortic aneurysm or diagnosed with abdominal aortic aneurysm does not seem to alter the peripheral inflammatory environment.

Eugenol synthase genes in floral scent variation in Gymnadenia species.

Floral signaling, especially through floral scent, is often highly complex, and little is known about the molecular mechanisms and evolutionary causes of this complexity. In this study, we focused on the evolution of "floral scent genes" and the associated changes in their functions in three closely related orchid species of the genus Gymnadenia. We developed a benchmark repertoire of 2,571 expressed sequence tags (ESTs) in Gymnadenia odoratissima. For the functional characterization and evolutionary analysis, we focused on eugenol synthase, as eugenol is a widespread and important scent compound. We obtained complete coding complementary DNAs (cDNAs) of two copies of putative eugenol synthase genes in each of the three species. The proteins encoded by these cDNAs were characterized by expression and testing for activity in Escherichia coli. While G. odoratissima and Gymnadenia conopsea enzymes were found to catalyze the formation of eugenol only, the Gymnadenia densiflora proteins synthesize eugenol, as well as a smaller amount of isoeugenol. Finally, we showed that the eugenol and isoeugenol producing gene copies of G. densiflora are evolutionarily derived from the ancestral genes of the other species producing only eugenol. The evolutionary switch from production of one to two compounds evolved under relaxed purifying selection. In conclusion, our study shows the molecular bases of eugenol and isoeugenol production and suggests that an evolutionary transition in a single gene can lead to an increased complexity in floral scent emitted by plants.

Cardiometabolic risk factors and fat distribution in children and adolescents.

OBJECTIVES: To determine if cardiometabolic risk factors have differential associations with the proportion of fat distributed in the trunk, leg, and arm, in White and African American children and adolescents. STUDY DESIGN: The sample included 391 White and African American 5- to 18 year-olds. Total and regional (trunk, leg, and arm) fat were measured by dual energy X-ray absorptiometry. Resting blood pressure and fasting triglycerides, high density lipoprotein cholesterol (HDL-C), glucose, insulin, and C-reactive protein were measured in a clinical setting. Insulin resistance was determined with the homeostatic model of insulin resistance. Multivariable linear and logistic regression models were used to examine associations between each cardiometabolic risk factor and proportion of fat (trunk, leg, or arm fat divided by whole body fat), with whole body fat, age, sex, race, sexual maturity status, and self-reported physical activity as covariates. RESULTS: Higher odds of low HDL-C, high triglycerides, insulin resistance, and high C-reactive protein were associated with % trunk fat. Lower odds of low HDL-C, high triglycerides, and insulin resistance were associated with % leg fat. No cardiometabolic risk factor was associated with % arm fat. CONCLUSIONS: Cardiometabolic risk factors in children and adolescents were attenuated when a larger proportion of fat was distributed in the leg. The clinical assessment of children's fat distribution may be useful in determining cardiometabolic risk.

Cardiovascular risk escalation with caloric excess: a prospective demonstration of the mechanics in healthy adults.

CONTEXT: The link between weight gain and cardiovascular risk characterized with circadian blood pressure variability [CBPV] and endothelial function [EF] is unexplored. OBJECTIVE: To prospectively demonstrate weight gain in healthy adults, increases body fat [BF], enlarges waist circumference [WC], expands visceral adipose tissue [VAT], exacerbates systemic inflammation [sIF], worsens insulin resistance [IR] and enhances functional cardiovascular disease [CVD] risk. DESIGN, SETTING AND PARTICIPANTS: Healthy men [n=11] and women [n=3] provided initial and eight-week post-caloric excess anthropometric and fasting laboratory measures. Functional CVD risk assessments: CBPV and resting EF were also obtained with 7-day automatic ambulatory BP monitoring and increased test finger peripheral arterial tone [PAT] relative to control [reported as relative hyperemia index (RHI)], respectively. INTERVENTION: After determining individualized mean energy requirements for weight maintenance over 7-days, each participant received a personalized over feeding prescription (1.4 times; 41% carbohydrate, 44% fat, and 15% protein) for 8-weeks. RESULTS: mean (SEM). Participants increased body weight [BW; +7.4(0.1) kg]*, body mass index [BMI; +2.5(0.2) kg/m²]*, BF [+2.0(0.01)%]*, WC [+8.2(1.0) cm]*, and VAT [+0.2(0.03) L]* and intrahepatic lipid [IHL + 0.0004(0.002) L] :*all p < 0.01. Increased subcutaneous adipose cell size [+0.3(0.01) ρL; p = 0.02] accompanied significant sIF [hs-CRP + 0.4(0.09) mg/dL; p = 0.04; leptin 6.63 ng/ml; p = 0.0008] and IR [fasting plasma glucose; [FPG] +7.0(0.6) mg/dL;p = 0.01, fasting insulin; [FI] +5.7(1.4) uIU/ml; p = 0.001, HOMA-IR +1.6(0.5); p = 0.02]. Abn CBPV {systolic [+5.4(0.8); p = 0.002, diastolic [+1.7(0.1); p = 0.07 and pulse pressure [PP] [+3.5(0.4); p = 0.003 mm Hg} or elevated heart rate [HR] [+4.9(0.5) bpm; p = 0.003] ensued. Resting RHI declined by 0.47(0.004) from initial 2.24(0.09) to 1.77(0.1); p = 0.001, indicating endothelial dysfunction [ED]. CONCLUSIONS: Controlled caloric excess in healthy human adults over only 8-weeks significantly increased BF, VAT, sIF [hs-CRP], IR [FPG, FI, HOMA-IR] and functional CVD risk [measured as abnormal circadian blood pressure variability and impaired resting endothelial function].

Maturity-associated variation in total and depot-specific body fat in children and adolescents.

OBJECTIVES: This study considered the association between sexual maturation and adiposity in children and adolescents, and examined the contribution of sexual maturation to ethnic differences in total and depot-specific body fat. METHODS: The sample included 382 White and African American 5-18-year-olds. Body mass index (BMI), waist circumference (WC) and sexual maturity status (breast/genital and pubic hair stage) were assessed in a clinical setting. Total body fat (TBF) was measured by dual-energy X-ray absorptiometry and abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) were measured by magnetic resonance imaging. Analysis of covariance adjusted for age was used to examine the association between sexual maturity status and adiposity, and linear regression adjusted for age was used to examine the influence of sexual maturation on ethnic differences in adiposity. Analysis of VAT also controlled for TBF. Significance was accepted at P < 0.05. RESULTS: Breast/genital stage was significantly associated with BMI, WC, TBF, and SAT in girls of both ethnic groups and in White boys. Breast stage was associated with VAT. Stage of pubic hair was significantly associated with TBF and VAT in White girls only. In girls, sexual maturation attenuated the ethnic effects on BMI and WC, but the ethnic effect in VAT persisted. In boys, sexual maturation did not attenuate ethnic differences on VAT and did not predict WC or SAT. Sexual maturity status independently explained variance in adiposity in girls only. CONCLUSIONS: Sexual maturity status is an important determinant of pediatric adiposity and attenuates ethnic differences in girls' adiposity.

Osteochondroma as an Unusual Cause of Popliteal Artery Pseudoaneurysm and Occlusion.

Osteochondromas are the most common benign bony tumour, usually occurring in the 2nd/3rd decade of life and generally asymptomatic. However, there have been reports of bony tumours causing arterial vascular injuries via erosion into vessel walls. We present a case of a 16-year-old M with no significant past medical history who presented with acute-on-chronic Right Lower Extremity (RLE) pain and numbness who was found to have a popliteal artery pseudoaneurysm and occlusion. We will discuss our initial work up, management, outcomes and follow up and compared our results with an English language literature search for comparable cases.

Identification of white campion (Silene latifolia) guaiacol O-methyltransferase involved in the biosynthesis of veratrole, a key volatile for pollinator attraction.

BACKGROUND: Silene latifolia and its pollinator, the noctuid moth Hadena bicruris, represent an open nursery pollination system wherein floral volatiles, especially veratrole (1, 2-dimethoxybenzene), lilac aldehydes, and phenylacetaldehyde are of key importance for floral signaling. Despite the important role of floral scent in ensuring reproductive success in S. latifolia, the molecular basis of scent biosynthesis in this species has not yet been investigated. RESULTS: We isolated two full-length cDNAs from S. latifolia that show similarity to rose orcinol O-methyltransferase. Biochemical analysis showed that both S. latifolia guaiacol O-methyltransferase1 (SlGOMT1) &S. latifolia guaiacol O-methyltransferase2 (SlGOMT2) encode proteins that catalyze the methylation of guaiacol to form veratrole. A large Km value difference between SlGOMT1 (~10 µM) and SlGOMT2 (~501 µM) resulted that SlGOMT1 is 31-fold more catalytically efficient than SlGOMT2. qRT-PCR expression analysis showed that the SlGOMT genes are specifically expressed in flowers and male S. latifolia flowers had 3- to 4-folds higher level of GOMT gene transcripts than female flower tissues. Two related cDNAs, S. dioica O-methyltransferase1 (SdOMT1) and S. dioica O-methyltransferase2 (SdOMT2), were also obtained from the sister species Silene dioica, but the proteins they encode did not methylate guaiacol, consistent with the lack of veratrole emission in the flowers of this species. Our evolutionary analysis uncovered that SlGOMT1 and SlGOMT2 genes evolved under positive selection, whereas SdOMT1 and SdOMT2 genes show no evidence for selection. CONCLUSIONS: Altogether, we report the identification and functional characterization of the gene, SlGOMT1 that efficiently catalyzes veratrole formation, whereas another copy of this gene with only one amino acid difference, SlGOMT2 was found to be less efficient for veratrole synthesis in S. latifolia.

Role of glutathione in cancer pathophysiology and therapeutic interventions.

Glutathione (GSH) is an important intracellular antioxidant that instills several vital roles within a cell including maintenance of the redox state, drug detoxification, and cellular protection from damage by free radicals, peroxides and toxins. Molecular alterations in the components of the GSH system in various tumors can lead to increased survival and enhanced tumor drug resistance. Early identification of the importance of intracellular GSH to detoxification reactions has now led to investigating the potential importance that GSH chemistry has on signal transduction, molecular regulation of cellular physiology and regulation of apoptosis pathway. Several therapeutic agents that target this system have been developed and used experimentally and clinically in an attempt to improve cancer chemotherapy. This review highlights different roles played by GSH that finally regulate tumor growth and advances in the use of GSH-based drugs to specifically target this detoxifying system in cancer treatment as a means to increase therapeutic response and decrease chemotherapeutic drug resistance.

The effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease.

Adequate vitamin D levels may promote cardiovascular health by improving endothelial function and down-regulating inflammation. The objective of this pilot trial was to investigate the effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease (CAD). Using a double-blind placebo wait-list control design, 90 subjects with CAD and vitamin D deficiency (< 20 ng/ml) were randomized 1:1 to 50,000 IU of oral ergocalciferol or placebo weekly for 12 weeks. Endothelial function (reactive hyperemia peripheral arterial tonometry, RH-PAT), circulating adhesion molecules, and pro-inflammatory cytokines were measured at baseline and 12 weeks. The median increase in serum 25-vitamin D from baseline was 26 ± 17 ng/ml in the active group and 4 ± 8 ng/ml in the placebo group (between-group difference = 22 ng/ml, p < 0.001). The median within-subject change in RH-PAT score was 0.13 ± 0.73 with active treatment and -0.04 ± 0.63 with placebo (between-group difference = 0.17, p = 0.44). Within-group and between-group differences in intercellular adhesion molecule levels were greater with placebo (between-group difference = 6 ng/ml, p = 0.048). Vascular cell adhesion molecule levels decreased in both groups by a similar magnitude (median difference between groups = 8.5 ng/ml, p = 0.79). There was no difference between groups in magnitude of reduction in interleukin (IL)-12 (-8.6 ng/ml, p = 0.72) and interferon-gamma (0.52 ng/ml, p = 0.88). No significant differences in blood pressure, e-selectin, high-sensitivity c-reactive protein, IL-6 or the chemokine CXCL-10 were found with treatment. In conclusion, repleting vitamin D levels in subjects with CAD failed to demonstrate any benefits on surrogate markers of cardiovascular health. These results question the role of vitamin D supplementation in modifying cardiovascular disease.

Dysglycemia induces abnormal circadian blood pressure variability.

BACKGROUND: Prediabetes (PreDM) in asymptomatic adults is associated with abnormal circadian blood pressure variability (abnormal CBPV). HYPOTHESIS: Systemic inflammation and glycemia influence circadian blood pressure variability. METHODS: Dahl salt-sensitive (S) rats (n = 19) after weaning were fed either an American (AD) or a standard (SD) diet. The AD (high-glycemic-index, high-fat) simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD (low-glycemic-index, low-fat) mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG), adipokines (leptin and adiponectin), and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α)] were measured. Rats were surgically implanted with C40 transmitters and blood pressure (BP-both systolic; SBP and diastolic; DBP) and heart rate (HR) were recorded by telemetry every 5 minutes during both sleep (day) and active (night) periods. Pulse pressure (PP) was calculated (PP = SBP-DBP). RESULTS: [mean(SEM)]: The AD fed group displayed significant increase in body weight (after 90 days; p < 0.01). Fasting glucose, adipokine (leptin and adiponectin) concentrations significantly increased (at 90 and 172 days; all p < 0.05), along with a trend for increased concentrations of systemic pro-inflammatory cytokines (MCP-1 and TNF-α) on day 90. The AD fed group, with significantly higher FG, also exhibited significantly elevated circadian (24-hour) overall mean SBP, DBP, PP and HR (all p < 0.05). CONCLUSION: These data validate our stated hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability. This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal CBPV. Our results provide the fundamental basis for examining the relationship between dysglycemia and perturbation of the underlying mechanisms (adipose tissue dysfunction induced local and systemic inflammation, insulin resistance and alteration of adipose tissue precursors for the renin-aldosterone-angiotensin system) which generate abnormal CBPV.