Neurophysiological investigations of drug resistant epilepsy patients treated with vagus nerve stimulation to differentiate responders from non-responders.

BACKGROUND AND PURPOSE: In patients treated with vagus nerve stimulation (VNS) for drug resistant epilepsy (DRE), up to a third of patients will eventually not respond to the therapy. As VNS therapy requires surgery for device implantation, prediction of response prior to surgery is desirable. It is hypothesized that neurophysiological investigations related to the mechanisms of action of VNS may help to differentiate VNS responders from non-responders prior to the initiation of therapy. METHODS: In a prospective series of DRE patients, polysomnography, heart rate variability (HRV) and cognitive event related potentials were recorded. Polysomnography and HRV were repeated after 1 year of treatment with VNS. Polysomnography, HRV and cognitive event related potentials were compared between VNS responders (≥50% reduction in seizure frequency) and non-responders. RESULTS: Fifteen out of 30 patients became VNS responders after 1 year of VNS treatment. Prior to treatment with VNS, the amount of deep sleep (NREM 3), the HRV high frequency (HF) power and the P3b amplitude were significantly different in responders compared to non-responders (P = 0.007; P = 0.001; P = 0.03). CONCLUSION: Three neurophysiological parameters, NREM 3, HRV HF and P3b amplitude, were found to be significantly different in DRE patients who became responders to VNS treatment prior to initiation of their treatment with VNS. These non-invasive recordings may be used as characteristics for response in future studies and help avoid unsuccessful implantations. Mechanistically these findings may be related to changes in brain regions involved in the so-called vagal afferent network.

Validation of ergonomic instructions in robot-assisted surgery simulator training.

BACKGROUND/AIM: Training in robot-assisted surgery focusses mainly on technical skills and instrument use. Training in optimal ergonomics during robotic surgery is often lacking, while improved ergonomics can be one of the key advantages of robot-assisted surgery. Therefore, the aim of this study was to assess whether a brief explanation on ergonomics of the console can improve body posture and performance. METHODS: A comparative study was performed with 26 surgical interns and residents using the da Vinci skills simulator (Intuitive Surgical, Sunnyvale, CA). The intervention group received a compact instruction on ergonomic settings and coaching on clutch usage, while the control group received standard instructions for usage of the system. Participants performed two sets of five exercises. Analysis was performed on ergonomic score (RULA) and performance scores provided by the simulator. Mental and physical load scores (NASA-TLX and LED score) were also registered. RESULTS: The intervention group performed better in the clutch-oriented exercises, displaying less unnecessary movement and smaller deviation from the neutral position of the hands. The intervention group also scored significantly better on the RULA ergonomic score in both the exercises. No differences in overall performance scores and subjective scores were detected. CONCLUSION: The benefits of a brief instruction on ergonomics for novices are clear in this study. A single session of coaching and instruction leads to better ergonomic scores. The control group showed often inadequate ergonomic scores. No significant differences were found regarding physical discomfort, mental task load and overall performance scores.

Sudden cardiac arrest due to a single sodium channel mutation producing a mixed phenotype of Brugada and Long QT3 syndromes.

Inherited arrhythmia syndromes are a known, albeit rare, cause of sudden cardiac arrest which may present with characteristic electrocardiogram changes in patients with structurally normal heart. There are a variety of distinct arrhythmogenic syndromes that arise from mutations in voltage gated sodium channels, resulting in either gain or loss of function. We describe a patient with a primary inherited arrhythmia syndrome which presented as sudden cardiac arrest. Further workup revealed that her arrest was due to a combination of Brugada syndrome and Long QT3 syndrome secondary to a deleterious mutation of voltage-gated, sodium channel, type V alpha subunit (SCN5A Thr1709Met).

Quantitative analysis of midface fat compartments mass with ageing and body mass index, anatomical study.

INTRODUCTION: Volume restoration is not a new concept in facial rejuvenation. The deep fat compartments would appear to be more greatly subjected to age-related volumetric deflation. However, this view lacks scientific evidence. The purpose of the present study is to quantify fat mass variability in the superficial and deep compartments of the midface as a function of age and BMI. MATERIALS AND METHODS: A cadaveric anatomical study was performed by dissection of superficial and deep facial fat compartment of 40 body. The studied compartments were identified by methylene blue injection and were weighed. The data obtained were analyzed as a function of subject age (two groups: ≤75 or >75), sex, and BMI (three groups: <20, ≥20≤25, or >25). RESULTS: The mean weight of the deep compartments was significantly lower in the group with subjects aged >75 years (1.48g vs 3.41g, P<0.001) and the deep-to-superficial fat ratio decreased significantly by more than 50% (0.2 vs 0.44, P<0.001). No statistically significant difference as concerns the mean weight of the superficial compartments (7.93g vs 6.73g). The deep-to-superficial fat ratio as a function of BMI was largely significantly lower in subjects with BMIs<20 (0.15, vs 0.31 and 0.34, P<0.001). CONCLUSION: The present anatomical study confirmed that fat atrophy affects in priority the deep midface compartments with ageing and in subjects with a BMI less than 20. Thus to obtain natural-looking results in facial rejuvenation, the volumetric restoration of these deep compartments should be considered a priority.

CONTEXT MATTERS: THE IMPORTANCE OF MARKET CHARACTERISTICS IN THE VOLATILITY OF FEEDSTOCK COSTS FOR BIOGAS PLANTS.

Recently, biogas plant managers in Flanders face increased financial uncertainty. Between 2011 and 2012, 20% of the Flemish biogas plants went bankrupt. Difficulties in obtaining feedstock at stable and affordable prices is one reason why the biogas sector struggles. In literature, contracting is often proposed as a way to decrease the volatility of the feedstock costs. However, these studies generally do not consider the context in which the biogas plant manager needs to buy the feedstock. Yet, this context could be of specific importance when biogas plant managers are in competition with other users of the same biomass type. Silage maize is an example of such a feedstock, as it is both used by dairy farmers and biogas plant managers. Using a combination of qualitative research and agent-based modelling, we investigated the effect of specific characteristics of the silage maize market on the acquisition of local silage maize by biogas plant managers. This paper details the institutional arrangements of the silage maize market in Flanders and the results of a scenario analysis, simulating three different scenarios. As shown by the results, the time of entry into the market, as well as the different institutional arrangements used by the biogas plant managers as opposed to dairy farmers could explain the difficulties in obtaining a stable supply of local silage maize by biogas plants. Our findings can help to develop mitigation strategies addressing these difficulties.

A retrospective study of people with familial hypercholesterolaemia in a Belgian lipid clinic.

BACKGROUND: Familial hypercholesterolaemia (FH) is a genetic disease characterised by hypercholesterolaemia and premature cardiovascular events. Early diagnosis and treatment can reduce the cardiovascular burden. We describe the characteristics of patients with heterozygous FH followed in a tertiary hospital in Belgium. METHODS: We retrospectively studied a population of 321 patients with definite heterozygous FH who visited the UZ Leuven lipid clinic at least once between 1 January 2016 and 31 December 2020. Data are represented as mean ± SD. RESULTS: The age at time of diagnosis of FH was 39 ± 18 years. Patients with atherosclerotic disease (secondary prevention) were older (p < .001), more often male (p < .001), had a higher body mass index (p < .001), prevalence of (pre)diabetes (p < .001) and hypertension (p < .001) and had lower levels of low-density lipoprotein-cholesterol (LDL-C) (p < .001) than individuals without atherosclerotic disease (primary prevention). The average LDL-C in both primary (109 ± 53 mg/dL) and secondary (81 ± 63 mg/dL) prevention did not meet the targets of LDL-C as proposed by the 2019 ESC/EAS guidelines for the management of dyslipidaemias. However, LDL-C levels in the subgroup of patients treated with PCSK9 inhibition therapy, and especially in the triple therapy group (combination of statin, ezetimibe and PCSK9 inhibitor), were markedly lower (p < .001). CONCLUSIONS: In this Belgian population, people with heterozygous FH remain undertreated. Reaching treatment targets in FH seems possible, although this requires combination treatment (with PCSK9-targeted therapy) in most patients. Earlier diagnosis of FH, more extensive lipid-lowering treatment and reimbursement options and a more holistic approach are needed to lower LDL-C and cardiovascular risk in patients with FH.

Current pediatric cancer survivorship practices: a report from the Children's Oncology Group.

PURPOSE: The purpose of this study is to describe current survivor services provided by COG institutions. METHODS: A 190-question online survey was distributed to 209 COG member institutions over a 5-month period in 2017. Descriptive statistics were used to describe survivor services and explore their changes between 2007 and 2017. RESULTS: Representatives from 153 (73%) institutions completed the survey. Of these, 96% of institutions reported that they provide pediatric cancer survivor care either in a specialized late effects program (75%) or a regular pediatric oncology clinic (24%). However, only 29.8% of institutions reported that > 75% of eligible patients were seen in a survivorship clinic. The most prevalent reported barriers to survivor care were lack of dedicated time (58%) and lack of funding for program development (41%). In 2017, 88% of institutions provided a treatment summary compared to 31% in 2007. CONCLUSION: The majority of COG institutions have dedicated care for pediatric and young adult survivors of childhood cancer; however, at most institutions, < 75% of eligible patients access this care. Research into more efficient technology strategies is needed to ensure all survivors the opportunity to receive appropriate follow-up care. IMPLICATIONS FOR CANCER SURVIVORS: This survey provides a snapshot of the status of late effects services within COG institutions and provides information on residual gaps in services. Next steps should focus on the importance of attendance in a survivorship clinic on the physical health and psychosocial outcomes in cancer survivors.

Validation of a modified algorithm for the identification of yeast isolates using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS).

Optimising antifungal treatment requires the fast and species-specific identification of yeast isolates. We evaluated a modified protocol for the rapid identification of clinical yeast isolates using matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) technology. First, we evaluated a simplified extraction procedure using 54 clinical yeast isolates. Second, we validated a new protocol with this simplified extraction procedure and lower identification threshold by analysing 167 isolates with either MALDI-TOF or conventional identification techniques. MALDI-TOF analysis with both the standard and short extraction procedure yielded identical identification results, although the log-scores were lower with the latter. With the modified protocol, 163/167 (97.6%) isolates showed a correct identification as compared to conventional identification techniques. A total of 135 out of the 163 (82.8%) correct identifications showed log-scores above 1.7, which we considered as the minimum log-score for secure species identification. The rapid identification of clinical yeast isolates is crucial in patient management. The MALDI-TOF technique using a short extraction procedure can be an alternative for the labourious standard procedure, although the log-scores will be lower. The identification of clinical yeast isolates with the modified protocol is a practical and accurate alternative for conventional identification techniques. If the isolate shows a log-score below 1.7, the standard extraction procedure should be used.

Effect of obesity on gastrointestinal transit, pressure and pH using a wireless motility capsule.

BACKGROUND: Despite the increasing prevalence and medical burden of obesity, the understanding of gastrointestinal physiology in obesity is scarce, which hampers drug development. AIM: To investigate the effect of obesity and food intake on gastrointestinal transit, pressure and pH. MATERIAL AND METHODS: An exploratory cross-sectional study using a wireless motility capsule (SmartPill©) was performed in 11 participants with obesity and 11 age- and gender-matched participants with normal weight (group) in fasted and fed state (visit). During the first visit, the capsule was ingested after an overnight fast. During a second visit, the capsule was ingested after a nutritional drink to simulate fed state. Linear mixed models were constructed to compare segmental gastrointestinal transit, pressure and pH between groups (obesity or control) and within every group (fasted or fed). RESULTS: Food intake slowed gastric emptying in both groups (both P < 0.0001), though food-induced gastric contractility was higher in participants with obesity compared to controls (P = 0.02). In the small intestine, a higher contractility (P = 0.001), shorter transit (P = 0.04) and lower median pH (P = 0.002) was observed in participants with obesity compared to controls. No differences were observed for colonic measurements. CONCLUSION: Obesity has a profound impact on gastrointestinal physiology, which should be taken into account for drug development.

The additive value of restaging-CT during neoadjuvant chemotherapy for gastric cancer.

INTRODUCTION: Computed tomography (CT) is used for restaging of gastric cancer patients during neoadjuvant chemotherapy (NAC). The treatment strategy could be altered after detection of distant interval metastases, possibly leading to a reduction in unnecessary chemotherapy cycles, its related toxicity, and surgical procedures. The aim of this study was to evaluate the additive value of restaging-CT during NAC in guiding clinical decision making in gastric cancer. MATERIALS AND METHODS: This retrospective, multicenter cohort study identified all patients with surgically resectable gastric adenocarcinoma (cT1-4a-x, N0-3-x, M0-x), who started NAC with curative intent. Restaging-CT was performed after 2 out of 3 cycles of NAC. The primary outcome was treatment alterations made based on restaging-CT by a multidisciplinary tumor board. Confirmation of metastases was obtained by surgery or biopsy. RESULTS: Between 2007 and 2015, CT-restaging was performed in 122 out of 152 included patients and timed after 2 cycles (n = 76) or after 3 cycles (n = 46) of NAC. Restaging-CT revealed a metastasis in 1 out of 122 restaged patients (1%) after which surgical resection was omitted, whereas 4 patients (3%) with distant interval metastases were not identified by restaging-CT and underwent a futile laparotomy. In 5 out of 76 patients (7%) disease progression was detected while undergoing NAC, leading to omission of the 3rd cycle of chemotherapy. CONCLUSION: The additive value of restaging-CT during NAC in gastric cancer is limited in guiding clinical decision making and therefore not recommended. Further studies may identify subgroups that may benefit of alternative diagnostic modalities.

Épilepsie et brûlure : épidémiologie et interactions.

A retrospective study was conducted to assess the interactions between epileptic seizure and burn. The study was conducted on all patients treated at the Saint Luc Saint Joseph Hospital Burn Unit from 2000 to 2015 with a diagnosis of epilepsy. Forty-eight cases associating burns and epilepsy were reviewed. Twenty-eight patients had a burn following an epileptic seizure. The average age was 43, and the burned area was 9%. Injuries resulted from contact with hot surface (32%), scald burn (50% - 32% with cooking water and 17.8% by accidental exposure to hot tap water (shower)). Burns by flames were rare (4 cases/28: 14.3%). The burns were deep, and all required surgical treatment by excision - split thickness skin graft. All the cases of tap water burns occurred before 2010 and the changes to hot tap water temperature legislation. Three patients presented a new epileptic seizure during their hospitalization. Primary prevention of domestic accidents, particularly regulation of hot tap water temperature, appears effective. Educating epileptic patients on the importance of therapeutic compliance and the elimination of risky activities during periods of therapeutic modification should further reduce the incidence of seizure-related burns.

Rosuvastatin restores superoxide dismutase expression and inhibits accumulation of oxidized LDL in the aortic arch of obese dyslipidemic mice.

BACKGROUND AND PURPOSE: Our goal was to elucidate mechanisms of the inhibitory effect of rosuvastatin on the accumulation of plaque oxidized low density lipoproteins (oxLDL) and on plaque volume, without lowering cholesterol, in mice with combined leptin and LDL-receptor deficiency (DKO). EXPERIMENTAL APPROACH: Twelve-week old DKO mice were treated with rosuvastatin (10 mg kg(-1) day(-1), s.c.) or placebo or no treatment for 12 weeks. The effect on blood variables, aortic plaque volume and composition and gene expression in the aorta and in THP-1 cells was assessed. KEY RESULTS: Rosuvastatin lowered free fatty acids (FFA), triglycerides, and increased insulin sensitivity, without affecting cholesterol. Rosuvastatin lowered the plaque volume, inhibited macrophage, lipid and oxLDL accumulation, and decreased the oxLDL-to-LDL ratio of plaques in the aortic arch. It increased superoxide dismutase 1 (SOD1), CD36, LXR-alpha, ABCA-1 and PPAR-gamma RNA expression in aortic extracts. SOD1 was the strongest inverse correlate of oxLDL. In THP-1 macrophages and foam cells, expression of SOD1 was lower than in THP-1 monocytes. Rosuvastatin restored expression of SOD1 in THP-1 macrophages and foam cells. CONCLUSIONS AND IMPLICATIONS: Rosuvastatin restored SOD1 expression in THP-1 macrophages and foam cells in vitro and in the aorta of DKO mice. The latter was associated with less oxLDL accumulation within atherosclerotic plaques and inhibition of plaque progression. This effect was obtained at a dose not affecting cholesterol levels but improving insulin sensitivity. SOD1 is a potentially important mediator of the prevention of oxLDL accumulation within atherosclerotic plaques.

Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study.

BACKGROUND: Because survival rates among childhood cancer patients are increasing, assessing the risk of second and subsequent malignant neoplasms (SMNs) is ever more important. Using the Childhood Cancer Survivor Study cohort, we identified the risk of SMNS: METHODS: A retrospective cohort of 13 581 children diagnosed with common cancers before age 21 years and surviving at least 5 years was constructed with the use of data from patients treated at 25 U.S. and Canadian institutions. SMNs were ascertained through self-administered questionnaires and verified by pathology reports. Information on therapeutic exposures was abstracted from medical records. The risk of SMN was evaluated by standardized incidence ratios (SIRs) and excess absolute risk. Poisson multiple regression models were used to assess the impact of host and therapy factors on the risk of developing SMNS: All statistical tests were two-sided. RESULTS: In 298 individuals, 314 SMNs were identified (SIR = 6.38; 95% confidence interval [CI] = 5.69 to 7.13). The largest observed excess SMNs were bone and breast cancers (SIR = 19.14 [95% CI = 12.72 to 27.67] and SIR = 16.18 [95% CI = 12.35 to 20.83], respectively). A statistically significant excess of SMNs followed all childhood cancers. In multivariate regression models adjusted for therapeutic radiation exposure, SMNs of any type were independently associated with female sex (P<.001), childhood cancer at a younger age (P for trend <.001), childhood Hodgkin's disease or soft-tissue sarcoma (P<.001 and P =.01, respectively), and exposure to alkylating agents (P for trend =.02). Twenty years after the childhood cancer diagnosis, the cumulative estimated SMN incidence was 3.2%. However, only 1.88 excess malignancies occurred per 1000 years of patient follow-up. CONCLUSIONS: Success in treating children with cancer should not be overshadowed by the incidence of SMNS: However, patients and health-care providers must be aware of risk factors for SMNs so that surveillance is focused and early prevention strategies are implemented.

Cost and co-morbidities associated with hypoglycemic inpatients in Belgium.

BACKGROUND AND OBJECTIVES: Little is known about the economic burden of hypoglycemia in Belgium, or its related co-morbidities. This study aimed at estimating the cost and length of stay associated with hypoglycemia-related hospitalizations in diabetic patients in Belgium and the association between hypoglycemia and in-hospital all-cause mortality, incidence of traumatic fractures, depression, and cardiovascular diseases (myocardial infarction or unstable angina), using retrospective data from 2011. METHODS: Patient data were retrieved from the IMS Hospital Disease Database, including longitudinal (per calendar year) information on diagnoses, procedures, and drugs prescribed in ∼20% of all Belgian hospital beds. The eligible population included all adult (<19 year) diabetic (both types) patients, further split between those with/without a history of hypoglycemia-related hospitalizations. Diabetes, hypoglycemia, and co-morbidities of interest were identified based on International Classification of Diseases and Related Health Problems Version 9 (ICD-9) diagnosis codes. All costs were extrapolated to 2014 using progression in hospitalization costs since 2001. RESULTS: A total of 43,410 diabetes-related hospitalizations were retrieved, corresponding to 30,710 distinct patients. The average hospitalization cost was €10,258 when hypoglycemia was documented (n = 2625), vs €7173 in other diabetic hospitalized patients (n = 40,785). When controlling for age and sex, a higher mortality risk (OR = 1.59; p-value <0.001), a higher incidence of traumatic fractures (OR = 1.25; p-value = 0.009), and a higher probability of depression-related hospitalizations (OR = 1.90; p-value <0.001) were observed in hypoglycemic patients. A similar risk of cardiovascular event was observed in both groups, but hypoglycemic patients were more at risk of experiencing multiple events. CONCLUSION: Hospitalizations for hypoglycemia are expensive and associated with an increased risk of depression and traumatic fractures as well as increased in-hospital mortality. Interventions that can help reduce the risk of hypoglycemia, and consequently the burden on hospitals and society, without compromising glycemic control, will help to further improve diabetes management.

Endothelial progenitor cells are differentially impaired in ANCA-associated vasculitis compared to healthy controls.

BACKGROUND: Endothelial progenitor cells (EPC) are of major importance in vascular repair under healthy circumstances. Vascular injury in need of repair occurs frequently in ANCA-associated vasculitis (AAV). A specialized T cell subset enhancing EPC function and differentiation has recently been described. These angiogenic T cells (Tang) may have an important impact on the vascular repair process. Therefore, the aim of our study was to investigate EPC and Tang in AAV. METHODS: Fifty-three patients suffering from AAV and 29 healthy controls (HC) were enrolled in our study. Forty-four patients were in remission, nine patients were in active state of disease. Patients were either untreated or were under monotherapy with low-dose steroids (max. 5 mg/day) at the time of sampling. Circulating EPC and Tang were determined by flow cytometry (FACS). The functional capacity of EPC was assessed by established cell culture methods. RESULTS: Circulating EPC were significantly decreased in AAV as compared to HC. The capacity of EPC to differentiate and proliferate was differentially impaired in patients as compared to HC. The outgrowth of endothelial colony-forming cells (ECFC) was severely decreased in patients whereas colony-forming units-endothelial cell (CFU-EC) outgrowth was unaffected. ECFC and CFU-EC differentiation was strictly T cell-dependent. Patients with a relapsing disease course had an impaired ECFC outgrowth and expansion of Tang as compared to patients with a stable, nonrelapsing disease. CONCLUSIONS: The differentiation process of EPC is impaired in AAV. This may favor insufficient vascular repair promoting a relapsing disease course. Finally, these factors may explain a higher cardiovascular morbidity as has been previously documented in AAV.

Adenovirus-mediated gene transfer of human platelet-activating factor-acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: Atherosclerosis is characterized by an early inflammatory response involving proinflammatory mediators such as platelet-activating factor (PAF)-like phospholipids, which are inactivated by PAF-acetylhydrolase (PAF-AH). The effect of adenovirus-mediated expression of PAF-AH on injury-induced neointima formation and spontaneous atherosclerosis was studied in apolipoprotein E-deficient mice. METHODS AND RESULTS: Intravenous administration of an adenovirus (5 x 10(8) plaque-forming units) directing liver-specific expression of human PAF-AH resulted in a 3.5-fold increase of plasma PAF-AH activity at day 7 (P<0.001); this was associated with a 2.4- and 2.3-fold decrease in malondialdehyde-modified LDL autoantibodies and the lysophosphatidylcholine/phosphatidylcholine ratio, respectively (P<0.001 for both). Non-HDL and HDL cholesterol levels in PAF-AH-treated mice were similar to those of control virus-treated mice. Seven days after virus injection, endothelial denudation of the common left carotid artery was induced with a guidewire. Neointima formation was assessed 18 days later. PAF-AH gene transfer reduced oxidized lipoproteins by 82% (P<0.001), macrophages by 69% (P=0.006), and smooth muscle cells by 84% (P=0.002) in the arterial wall. This resulted in a 77% reduction (P<0.001) of neointimal area. Six weeks after adenovirus-mediated gene transfer, spontaneous atherosclerotic lesions in the aortic root were analyzed. PAF-AH gene transfer reduced atherosclerotic lesions by 42% (P=0.02) in male mice, whereas a nonsignificant 14% reduction was observed in female mice. Basal and PAF-AH activity after gene transfer were higher in male mice than in female mice (P=0.01 and P=0.04, respectively). CONCLUSIONS: Gene transfer of PAF-AH inhibited injury-induced neointima formation and spontaneous atherosclerosis in apolipoprotein E-deficient mice. Our data indicate that PAF-AH, by reducing oxidized lipoprotein accumulation, is a potent protective enzyme against atherosclerosis.

Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study.

PURPOSE: Survivors of childhood and adolescent cancer are at risk for long-term effects of disease and treatment. The Childhood Cancer Survivor Study assessed overall and cause-specific mortality in a retrospective cohort of 20,227 5-year survivors. PATIENTS AND METHODS: Eligible subjects were individuals diagnosed with cancer (from 1970 to 1986) before the age of 21 who had survived 5 years from diagnosis. Underlying cause of death was obtained from death certificates and other sources and coded and categorized as recurrent disease, sequelae of cancer treatment, or non-cancer-related. Age and sex standardized mortality ratios (SMRs) were calculated using United States population mortality data. RESULTS: The cohort, including 208,947 person-years of follow-up, demonstrated a 10.8-fold excess in overall mortality (95% confidence interval, 10.3 to 11.3). Risk of death was statistically significantly higher in females (SMR = 18.2), individuals diagnosed with cancer before the age of 5 years (SMR = 14.0), and those with an initial diagnosis of leukemia (SMR = 15.5) or CNS tumor (SMR = 15.7). Recurrence of the original cancer was the leading cause of death among 5-year survivors, accounting for 67% of deaths. Statistically significant excess mortality rates were seen due to subsequent malignancies (SMR = 19.4), along with cardiac (SMR = 8.2), pulmonary (SMR = 9.2), and other causes (SMR = 3.3). Treatment-related associations were present for subsequent cancer mortality (radiation, alkylating agents, epipodophyllotoxins), cardiac mortality (chest irradiation, bleomycin), and other deaths (radiation, anthracyclines). No excess mortality was observed for external causes (SMR = 0.8). CONCLUSION: While recurrent disease remains a major contributor to late mortality in 5-year survivors of childhood cancer, significant excesses in mortality risk associated with treatment-related complications exist up to 25 years after the initial cancer diagnosis.

Oxidized LDL and HDL: antagonists in atherothrombosis.

Increased LDL oxidation is associated with coronary artery disease. The predictive value of circulating oxidized LDL is additive to the Global Risk Assessment Score for cardiovascular risk prediction based on age, gender, total and HDL cholesterol, diabetes, hypertension, and smoking. Circulating oxidized LDL does not originate from extensive metal ion-induced oxidation in the blood but from mild oxidation in the arterial wall by cell-associated lipoxygenase and/or myeloperoxidase. Oxidized LDL induces atherosclerosis by stimulating monocyte infiltration and smooth muscle cell migration and proliferation. It contributes to atherothrombosis by inducing endothelial cell apoptosis, and thus plaque erosion, by impairing the anticoagulant balance in endothelium, stimulating tissue factor production by smooth muscle cells, and inducing apoptosis in macrophages. HDL cholesterol levels are inversely related to risk of coronary artery disease. HDL prevents atherosclerosis by reverting the stimulatory effect of oxidized LDL on monocyte infiltration. The HDL-associated enzyme paraoxonase inhibits the oxidation of LDL. PAF-acetyl hydrolase, which circulates in association with HDL and is produced in the arterial wall by macrophages, degrades bioactive oxidized phospholipids. Both enzymes actively protect hypercholesterolemic mice against atherosclerosis. Oxidized LDL inhibits these enzymes. Thus, oxidized LDL and HDL are indeed antagonists in the development of cardiovascular disease.

Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease.

Our aim was to determine the usefulness of circulating oxidized low density lipoprotein (LDL) in the identification of patients with coronary artery disease (CAD). A total of 304 subjects were studied: 178 patients with angiographically proven CAD and 126 age-matched subjects without clinical evidence of cardiovascular disease. The Global Risk Assessment Score (GRAS) was calculated on the basis of age, total and high density lipoprotein cholesterol, blood pressure, diabetes mellitus, and smoking. Levels of circulating oxidized LDL were measured in a monoclonal antibody 4E6-based competition ELISA. Compared with control subjects, CAD patients had higher levels of circulating oxidized LDL (P<0.001) and a higher GRAS (P<0.001). The sensitivity for CAD was 76% for circulating oxidized LDL (55% for men and 81% for women) compared with 20% (24% for men and 12% for women) for GRAS, with a specificity of 90%. Logistic regression analysis revealed that the predictive value of oxidized LDL was additive to that of GRAS (P<0.001). Ninety-four percent of the subjects with high (exceeding the 90th percentile of distribution in control subjects) circulating oxidized LDL and high GRAS had CAD (94% of the men and 100% of the women). Thus, circulating oxidized LDL is a sensitive marker of CAD. Addition of oxidized LDL to the established risk factors may improve cardiovascular risk prediction.

Arg123-Tyr166 domain of human ApoA-I is critical for HDL-mediated inhibition of macrophage homing and early atherosclerosis in mice.

Atherosclerosis was studied in apolipoprotein E (apoE) knockout mice expressing human apolipoprotein A-I (apoA-I) or an apoA-I/apolipoprotein A-II (apoA-II) chimera in which the Arg123-Tyr166 central domain of apoA-I was substituted with the Ser12-Ala75 segment of apoA-II. High density lipoprotein (HDL) cholesterol levels were identical in apoA-I and apoA-I/apoA-II mice, but at 4 months, plaques were 2.7-fold larger in the aortic root of the apoA-I/apoA-II mice (P<0.01). The macrophage-to-smooth muscle cell ratio of lesions was 2.1-fold higher in apo-I/apoA-II mice than in apoA-I mice (P<0.01). This was due to a 2.7-fold higher (P<0.001) in vivo macrophage homing in the aortic root of apoA-I/apoA-II mice. Plasma platelet-activating factor acetyl hydrolase activity was lower (P<0.01) in apoA-I/apoA-II mice, resulting in increased oxidative stress, as evidenced by the higher titer of antibodies against oxidized low density lipoprotein (P<0.01). Increased oxidative stress resulted in increased stimulation of ex vivo macrophage adhesion by apoA-I/apoA-II beta-very low density lipoprotein and decreased inhibition of beta-very low density lipoprotein-induced adhesion by HDL from apoA-I/apoA-II mice. The cellular cholesterol efflux capacity of HDL from apoA-I/apoA-II mice was very similar to that of apoA-I mice. Thus, the Arg123-Tyr166 central domain of apoA-I is critical for reducing oxidative stress, macrophage homing, and early atherosclerosis in apoE knockout mice independent of its role in HDL production and cholesterol efflux.