Search

Contemporary data on the epidemiology of acute myocardial infarction (AMI) in Vietnam are extremely limited.We established population-based registries of residents from 2 provinces in a northern urban (Hai Phong), and a central rural (Thanh Hoa), province of Vietnam hospitalized with a validated first AMI in 2018. We described patient characteristics, in-hospital management and clinical complications, and estimated incidence rates of AMI in these two registries.A total of 785 patients (mean age = 71.2 years, 64.7% men) were admitted to the two hospitals with a validated first AMI. Approximately 64% of the AMI cases were ST-segment-elevation AMI. Patients from Thanh Hoa compared with Hai Phong were more likely to delay seeking acute hospital care. The incidence rates (per 100,000 population) of initial AMI in Thanh Hoa and Hai Phong were 16 and 30, respectively. Most patients were treated with aspirin (Thanh Hoa: 96%; Hai Phong: 90%) and statins (both provinces: 91%) during their hospitalization. A greater proportion of patients in Hai Phong (69%) underwent percutaneous revascularization than those in Thanh Hoa (58%). The most common in-hospital complications were heart failure (both provinces:12%), cardiogenic shock (Thanh Hoa: 10%; Hai phong: 7%); and cardiac arrest (both provinces: 9%). The in-hospital case-fatality rates for patients from Thanh Hoa and Hai Phong were 6.8% and 3.8%, respectively.The incidence and hospital case-fatality rates of AMI were low in two Vietnamese provinces. Extent of pre-hospital delay and in-hospital use of evidence-based therapies were suboptimal, being more prominent in the rural province.

During 2015-2018, seven schools in rural Vietnam experienced diphtheria outbreaks. Multilocus sequence types were the same within schools but differed between schools. Low vaccine coverage and crowded dormitories might have contributed to the outbreaks. Authorities should consider administering routine vaccinations and booster doses for students entering the school system.

Background: Pesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations. Epigenetic modifications, such as DNA methylation, may contribute. Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides. Objectives: We conducted an EWAS of DNA methylation in relation to several pesticide active ingredients. Methods: The Agricultural Lung Health Study is a case–control study of asthma, nested within the Agricultural Health Study. We analyzed blood DNA methylation measured using Illumina’s EPIC array in 1,170 male farmers of European ancestry. For pesticides still on the market at blood collection (2009–2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use. We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users. Results: Using family-wise error rate (p

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

Background Lipopolysaccharide‐responsive and beige‐like anchor (LRBA) deficiency is a rare autosomal recessive common variable immunodeficiency (CVID), affecting 1:25,000–1:50,000 people worldwide. Biallelic mutations in the gene LRBA have been implicated in affected individuals. Methods We report a 16‐year‐old Vietnamese, male patient with recurrent CVID symptoms including chronic diarrhea, interstitial pneumonia, cutaneous granulomatous lesions, hepatosplenomegaly, and finger clubbing. Immunological analyses and whole exome sequencing (WES) were performed to investigate phenotypic and genotypic features. Results Immunological analyses revealed hypogammaglobulinemia and low ratios of CD4+/CD8+ T cells. Two novel compound heterozygous stop‐gain mutation in LRBA were identified: c.1933C > T (p.R645X) and c.949C > T (p.R317X). Sanger sequencing confirmed the segregation of these variants from the intact parents. The abolished LRBA protein expression was shown by immunoblot analysis. Subsequent treatment potentially saves the child from the same immune thrombocytopenia which led to his brother's untimely death; likely caused by the same LRBA mutations. Conclusion This first report of LRBA deficiency in Vietnam expands our knowledge of the diverse phenotypes and genotypes driving CVID. Finally, the utilization of WES shows great promise as an effective diagnostic for CVID in our setting., We describe the clinical, immunological, and genetic analyses of a Vietnamese patient presenting with typical and atypical symptoms of common variable immune deficiency. Whole exome sequencing revealed novel compound stop‐gain mutations of LRBA. Our findings also expand the already broad range of known CVID clinical phenotypes and contribute to the understanding of phenotype–genotype correlation in LRBA deficiency.

Supplemental Digital Content is available in the text., Background and Purpose: Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events. Methods: In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–30) or placebo added to aspirin (300–325 mg on day 1 followed by 75–100 mg daily for days 2–30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature. The primary end point was time to the occurrence of stroke or death within 30 days. Results: Of 11 016 randomized patients, 2351 (21.3%) patients had an ipsilateral atherosclerotic stenosis. After 30 days, a primary end point occurred in 92/1136 (8.1%) patients with ipsilateral stenosis randomized to ticagrelor and in 132/1215 (10.9%) randomized to placebo (hazard ratio 0.73 [95% CI, 0.56–0.96], P=0.023) resulting in a number needed to treat of 34 (95% CI, 19–171). In patients without ipsilateral stenosis, the corresponding event rate was 211/4387 (4.8%) and 230/4278 (5.4%), respectively (hazard ratio, 0.89 [95% CI, 0.74–1.08]; P=0.23, Pinteraction=0.245). Severe bleeding occurred in 4 (0.4%) and 3 (0.2%) patients with ipsilateral atherosclerotic stenosis on ticagrelor and on placebo, respectively (P=NS), and in 24 (0.5%) and 4 (0.1%), respectively, in 8665 patients without ipsilateral stenosis (hazard ratio=5.87 [95% CI, 2.04–16.9], P=0.001). Conclusions: In this exploratory analysis comparing ticagrelor added to aspirin to aspirin alone, we found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction but did identify a higher absolute risk and a greater absolute risk reduction of stroke or death at 30 days in patients with ipsilateral atherosclerosis stenosis than in those without. In this easily identified population, ticagrelor added to aspirin provided a clinically meaningful benefit with a number needed to treat of 34 (95% CI, 19–171). Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429.

BACKGROUND: Hypoxia-inducible factors (HIFs), especially HIF-1α and HIF-2α, are key mediators of the adaptive response to hypoxic stress and play essential roles in maintaining lung homeostasis. Human and animal genetics studies confirm that abnormal HIF correlates with pulmonary vascular pathology and chronic lung diseases, but it remains unclear whether endothelial cell (EC) HIF production is essential for microvascular health. The large airway has an ideal circulatory bed for evaluating histologic changes and physiology in genetically-modified rodents. METHODS: The tracheal microvasculature of mice, with conditionally-deleted or overexpressed HIF-1α or HIF-2α, was evaluated for anatomy, perfusion, and permeability. Angiogenic signaling studies assessed vascular changes attributable to dysregulated HIF expression. An orthotopic tracheal transplantation model further evaluated the contribution of individual HIF isoforms in airway ECs. RESULTS: The genetic deletion of Hif-2α, but not Hif-1α, caused tracheal EC apoptosis, diminished pericyte coverage, reduced vascular perfusion, defective barrier function, overlying epithelial abnormalities and subepithelial fibrotic remodeling. HIF-2α promoted microvascular integrity in airways through endothelial angiopoietin-1/TIE2 signaling and Notch activity. In functional tracheal transplants, HIF-2α deficiency in airway donors accelerated graft microvascular loss, whereas HIF-2α or angiopoietin-1 overexpression prolonged transplant microvascular perfusion. Augmented endothelial HIF-2α in transplant donors promoted airway microvascular integrity and diminished alloimmune inflammation. CONCLUSIONS: Our findings reveal that the constitutive expression of endothelial HIF-2α is required for airway microvascular health.

Background Studies suggest that right ventricular (RV) fibrosis is associated with RV remodeling and long-term outcomes in patients with tetralogy of Fallot (TOF). Pre-operative hypoxia may increase expression of hypoxia inducible factor-1-alpha (HIF1α) and promote transforming growth factor β1 (TGFβ1)-mediated fibrosis. We hypothesized that there would be associations between: (1) RV fibrosis and RV function, (2) HIF1α variants and RV fibrosis, and (3) HIF1α variants and RV function among post-surgical TOF cases. Methods We retrospectively measured post-surgical fibrotic load (indexed volume and fibrotic score) from 237 TOF cases who had existing cardiovascular magnetic resonance imaging using late gadolinium enhancement (LGE), and indicators of RV remodeling (i.e., ejection fraction [RVEF] and end-diastolic volume indexed [RVEDVI]). Genetic data were available in 125 cases. Analyses were conducted using multivariable linear mixed-effects regression with a random intercept and multivariable generalized Poisson regression with a random intercept. Results Indexed fibrotic volume and fibrotic score significantly decreased RVEF by 1.6% (p = 0.04) and 0.9% (p = 0.03), respectively. Indexed fibrotic volume and score were not associated with RVEDVI. After adjusting for multiple comparisons, 6 of the 48 HIF1α polymorphisms (representing two unique signals) were associated with fibrotic score. None of the HIF1α polymorphisms were associated with indexed fibrotic volume, RVEDVI, or RVEF. Conclusion The association of some HIF1α polymorphisms and fibrotic score suggests that HIF1α may modulate the fibrotic response in TOF. Electronic supplementary material The online version of this article (10.1186/s12968-019-0555-2) contains supplementary material, which is available to authorized users.

BACKGROUND:The lifetime risk of stroke has been calculated in a limited number of selected populations. We sought to estimate the lifetime risk of stroke at the regional, country, and global level using data from a comprehensive study of the prevalence of major diseases. METHODS:We used the Global Burden of Disease (GBD) Study 2016 estimates of stroke incidence and the competing risks of death from any cause other than stroke to calculate the cumulative lifetime risks of first stroke, ischemic stroke, or hemorrhagic stroke among adults 25 years of age or older. Estimates of the lifetime risks in the years 1990 and 2016 were compared. Countries were categorized into quintiles of the sociodemographic index (SDI) used in the GBD Study, and the risks were compared across quintiles. Comparisons were made with the use of point estimates and uncertainty intervals representing the 2.5th and 97.5th percentiles around the estimate. RESULTS:The estimated global lifetime risk of stroke from the age of 25 years onward was 24.9% (95% uncertainty interval, 23.5 to 26.2); the risk among men was 24.7% (95% uncertainty interval, 23.3 to 26.0), and the risk among women was 25.1% (95% uncertainty interval, 23.7 to 26.5). The risk of ischemic stroke was 18.3%, and the risk of hemorrhagic stroke was 8.2%. In high-SDI, high-middle-SDI, and low-SDI countries, the estimated lifetime risk of stroke was 23.5%, 31.1% (highest risk), and 13.2% (lowest risk), respectively; the 95% uncertainty intervals did not overlap between these categories. The highest estimated lifetime risks of stroke according to GBD region were in East Asia (38.8%), Central Europe (31.7%), and Eastern Europe (31.6%), and the lowest risk was in eastern sub-Saharan Africa (11.8%). The mean global lifetime risk of stroke increased from 22.8% in 1990 to 24.9% in 2016, a relative increase of 8.9% (95% uncertainty interval, 6.2 to 11.5); the competing risk of death from any cause other than stroke was considered in this calculation. CONCLUSIONS:In 2016, the global lifetime risk of stroke from the age of 25 years onward was approximately 25% among both men and women. There was geographic variation in the lifetime risk of stroke, with the highest risks in East Asia, Central Europe, and Eastern Europe. (Funded by the Bill and Melinda Gates Foundation.).

Background We examined the association between the maternal genotype for celiac disease‐associated variants and risk of neural tube defects (NTDs). Methods We conducted a case–control study, using data from the National Birth Defects Prevention Study. We evaluated 667 cases (women with an offspring with NTD) and 743 controls (women with an offspring without a birth defect). We classified women as having low, intermediate, or high risk of celiac disease based on human leukocyte antigen (HLA) variants. We used logistic regression to assess the relationship between HLA celiac risk group (low, intermediate, high) and risk of NTDs. Fifteen non‐HLA variants (identified from genome‐wide association studies of celiac disease) were individually evaluated and modeled additively. Results There was no association between HLA celiac risk group and NTDs (intermediate vs. low risk: aOR, 1.0; 95% CI, 0.8–1.3; high vs. low risk: aOR, 0.8; 95% CI, 0.5–1.3). Of the fifteen non‐HLA variants, we observed five significant associations after accounting for multiple comparisons. Three negative associations were observed with rs10903122, rs13314993, rs13151961 (aOR range: 0.69–0.81), and two positive associations were observed with rs13003464 and rs11221332 (aOR range: 1.27–1.73). Conclusion If confirmed, our results suggest that the maternal variants related to celiac disease may be involved in the risk of NTDs.

Objective The Ozaki procedure for aortic valve reconstruction was reported in 2014 with low mortality, a highly reproducible rate and a good midterm result. However, the procedure still requires conventional sternotomy to be accomplished. The aim of the study was to start an initial evaluation for the feasibility of the minimally invasive approach in combination with the Ozaki technique. Methods From January 06, 2017, to January 12, 2017, nine patients with severe aortic valve diseases underwent minimally invasive Ozaki procedure through an upper ministernotomy. The pericardium was harvested endoscopically using three trocars in different intercostal spaces. Then, a ministernotomy was performed and the Ozaki procedure was accomplished in a similar manner to the conventional technique. We analyzed the in-hospital mortality and complications of this group. Results The mean age was 47.4 years and 55.6% patients were female. The predominant pathology was chronic rheumatic valve disease (66.7%) and other patients were diagnosed with a bicuspid aortic valve. The mean aortic cross-clamp time was 106.8 minutes, the mean cardiopulmonary bypass time was 153.6 minutes, the mean ventilation time was 8.4 hours, and the mean intensive care unit time was 1.6 days. No mortality was recorded in our series, no conversion to full sternotomy was required, one patient experienced right hemothorax requiring drainage, and one patient required valve replacement. Intraoperative transesophageal echocardiography and predischarge transthoracic echocardiography showed five competent valves and three valves with trivial regurgitation, and no stenosis was detected. Conclusions Ministernotomy combined with Ozaki procedure might be feasible, as well as an alternative to conventional sternotomy. This approach is associated with low mortality and morbidity and may be beneficial in younger populations.

Accurate subtyping of renal cell carcinomas (RCCs) has become clinically important for therapy and prognostication. RCC subtypes are defined by distinct morphologic and immunohistochemical profiles, and in some instances recurrent cytogenetic and molecular properties. However, some tumors exhibit overlapping morphologic and immunophenotypic features, frequent enough to pose diagnostic dilemmas. This report concerns six histologically unusual RCCs that showed tubulopapillary architecture, clear cell phenotype, and non-diagnostic immunohistochemical profiles. Further investigation of these tumors utilized a single nucleotide polymorphism (SNP) microarray platform (OncoScan®, Affymetrix) that employed molecular inversion probe (MIP) technology to investigate genome-wide chromosomal copy number changes and loss of heterozygosity in formalin-fixed paraffin-embedded sections. The six tumors were assayed in parallel with and in comparison to RCC with typical morphologic or immunohistochemical features for a specific subtype (clear cell, clear cell papillary, and microphthalmia transcription factor (MiT) family translocation RCC). Three of the unusual RCCs showed a molecular signature of clear cell RCC and one of papillary RCC. The remaining two showed monosomy of chromosome 8. Those two cases were tested via next-generation sequencing, and no pathogenic variants were detected, including those in the genes VHL, PBRM1, SETD2, KDM5C, or BAP1. The addition of molecular investigations such as reported here as applied to histologically and immunohistochemically unusual RCC may help to define additional subtypes and contribute to the development of targeted therapy for renal cancer.

Aim To examine the relationships of serum markers of inflammation and endothelial function to diabetic retinopathy. Methods We recruited 224 patients with diabetes (85 with Type 1 and 139 with Type 2 diabetes) aged 18–70 years. Serum markers of inflammation (high-sensitivity C-reactive protein) and endothelial function (soluble intercell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, endothelin-1 and total nitrite) were assessed using nephelometry, immunoassays and spectroscopy. Diabetic retinopathy was graded from two-field fundus photographs according to the Airlie House Classification system and was categorized into no diabetic retinopathy, mild non-proliferative diabetic retinopathy, moderate non-proliferative diabetic retinopathy and vision-threatening diabetic retinopathy, the latter comprising severe non-proliferative diabetic retinopathy, proliferative diabetic retinopathy or clinically significant macular oedema. Multinomial logistic regression was used to assess the associations between serum markers and diabetic retinopathy. Results In the study, 64% of patients (144/224) had diabetic retinopathy and 25% (57/244) had vision-threatening diabetic retinopathy. After controlling for age, gender, diabetes duration, HbA1c, systolic blood pressure, total and HDL cholesterol, smoking, the use of insulin or oral hypoglycaemic agents, nephropathy and cardiovascular disease, a positive association was found between increasing high-sensitivity C-reactive protein levels and the presence of vision-threatening diabetic retinopathy (odds ratio 1.26; 95% CI 1.05–1.51, per sd increase in high-sensitivity C-reactive protein). After stratifying by BMI ( ≥ 30 and

Juvenile xanthogranuloma is a benign histiocytic tumor predominantly occurring in children as yellowish papules on the head and trunk. Presentations on the volar surfaces are rare and may cause diagnostic confusion with pyogenic granuloma, eccrine poroma and digital fibrokeratoma. We report two patients with unusual presentations of solitary juvenile xanthogranuloma on the palm or sole. Both had lesions lacking the classic yellowish color and demonstrating a well-defined, peripheral hyperkeratotic rim. Histopathological evaluation revealed prominent orthokeratosis corresponding to the rim. Additional histological features, including dermal histiocytes and Touton giant cells, were consistent with the diagnosis of juvenile xanthogranuloma. Given the unusual locations and colors of the lesions, we conclude that histopathological evaluation is central to diagnosing volar juvenile xanthogranuloma. We additionally suggest that juvenile xanthogranuloma should be included in the differential diagnoses of volar lesions displaying a peripheral hyperkeratotic rim.

Objective Retinal microvascular signs are markers of cardiovascular disease risk. There are limited data, on relationships between retinal microvascular signs and retinal microvascular endothelial function. We sought to determine the relationship of retinal vascular signs with retinal microvascular endothelial function in patients with or at high risk of coronary artery disease. Methods Participants with atherosclerosis risk factors and coronary disease ( n = 258; mean age 57 ± 11 years) were recruited to have static and dynamic retinal vascular assessment. Retinal arteriolar dilatation in response to flicker light (FI–RAD) was measured using the Digital Vessel Analyser and expressed as percentage increase over baseline diameter. Static retinal photographs were acquired utilising a digital fundus camera for measurement of central retinal artery and vein equivalent (CRAE and CRVE), arteriovenous nicking (AVN) and focal arteriolar narrowing (FAN). Results Intra-class correlation coefficient was 0.82 for flicker-light induced retinal arteriolar dilatation. There were modest associations in retinal vascular measurements between eyes. For each 10 μm decrease in retinal arteriolar diameter, the absolute increase in FI–RAD was 0.28% (95% CI 0.11, 0.45; p = 0.002) independent of age, gender and atherosclerosis risk factors. AVN and FAN were associated with attenuated FI–RAD ( β = −0.67%; 95% CI −1.20, −0.15; p = 0.012) and ( β = −0.83%; 95% CI −1.44, −0.23; p = 0.007) respectively after adjustment for age and gender. Conclusion Assessment of retinal microvascular endothelial function is reproducible and correlated with retinal microvascular structure and signs, independent of atherosclerosis risk factors. Assessment of retinal vascular structure and function may provide insights into atherosclerotic disease.

The Pediatric Craniofacial Collaborative Group established the Pediatric Craniofacial Surgery Perioperative Registry to elucidate practices and outcomes in children with craniosynostosis undergoing complex cranial vault reconstruction and inform quality improvement efforts. The aim of this study is to determine perioperative management, outcomes, and complications in children undergoing complex cranial vault reconstruction across North America and to delineate salient features of current practices.Thirty-one institutions contributed data from June 2012 to September 2015. Data extracted included demographics, perioperative management, length of stay, laboratory results, and blood management techniques employed. Complications and outlier events were described. Outcomes analyzed included total blood donor exposures, intraoperative and perioperative transfusion volumes, and length of stay outcomes.One thousand two hundred twenty-three cases were analyzed: 935 children aged less than or equal to 24 months and 288 children aged more than 24 months. Ninety-five percent of children aged less than or equal to 24 months and 79% of children aged more than 24 months received at least one transfusion. There were no deaths. Notable complications included cardiac arrest, postoperative seizures, unplanned postoperative mechanical ventilation, large-volume transfusion, and unplanned second surgeries. Utilization of blood conservation techniques was highly variable.The authors present a comprehensive description of perioperative management, outcomes, and complications from a large group of North American children undergoing complex cranial vault reconstruction. Transfusion remains the rule for the vast majority of patients. The occurrence of numerous significant complications together with large variability in perioperative management and outcomes suggest targets for improvement.

We evaluated young patients with type 1 diabetes (T1DM) who had normal left ventricular (LV) ejection fraction and used speckle tracking echocardiography to assess changes in LV untwisting. We used cardiac magnetic resonance imaging (MRI) to assess the LV filling patterns in these subjects.We recruited 33 T1DM patients and 32 age-matched healthy controls (HC) into the study. Study participants underwent echocardiography, cardiac MRI and metabolic exercise testing.The early peak LV untwisting rate (E) was similar in T1DM and HC (-11.9 ± 4.6 0/cm/s vs -11.3 ± 4.7 0/cm/s, P=0.29) but the late peak LV untwisting rate (A) was significantly increased in T1DM (-6.2 ± 3 0/cm/s vs -4.9 ± 3.9 0/cm/s, P0.05). The time to early peak untwisting rate was not different (50.9 ± 9.6% vs 48.4 ± 7.3%, P=0.12) but the time to late peak untwisting rate was significantly delayed in T1DM patients (80.4 ± 12.5% vs 72.7 ± 14.6%, P0.05). The LV filling patterns demonstrated a significantly increased left atrial (LA) contribution to LV filling in T1DM. On linear regression peak late filling rate (r=0.60, P0.000), trans-mitral A wave (r=0.25, P0.05) and A' (r=0.30, P0.01) were predictors of LA contribution to LV filling.We demonstrate for the first time using speckle tracking that LV untwisting rate E is preserved and untwisting rate A is increased and delayed in young patients with uncomplicated T1DM. The LA contribution to LV filling is increased in these patients and is directly related to increases in other indices of LA function like peak late filling rate, trans-mitral A wave and A'.

Many different components of the retina can be affected by inherited degenerative diseases causing blindness. Currently, 5 different mutant strains of chicken have already been studied as potential models for inherited retinal degeneration; however, the potential for the blind strain of White Leghorns, called Smoky Joe (SJ), as a model remains unknown. Ocular symptoms observed within homozygous SJ birds show the birds have varying levels of blindness at hatch and by 8 wk posthatch are completely blind, but details about the development of the blindness are unclear (Salter et al., 1997). The objective of this study was to characterize the retinal development of blind and sighted SJ chicks during embryogenesis, and to monitor the numbers of the retinal cells with cell-type-specific markers. Blind SJ chicks showed less retinal cells throughout embryogenesis compared with sighted SJ chicks (P < 0.0001). Based on the histological analysis, it was determined that amacrine cells within the inner nuclear layer were the most affected cell type, showing lower numbers in the blind SJ compared with the sighted; amacrine cell development was also delayed in the blind birds, beginning 2 d later than in sighted SJ birds. Photoreceptors were also scarcely detected within the blind SJ and potentially may be an additional target of developmental impairment. Further analysis on posthatch SJ will aid in determining degenerative characteristics of a fully developed retina and its cells.

Hypospadias is one of the most common birth defects in male infants. Maternal hypertension is a suspected risk factor; however, few previous studies have addressed the possibility of reporting bias, and several previous studies have not accounted for hypospadias severity. We analyzed data from the Texas Birth Defects Registry for 10,924 nonsyndromic cases and statewide vital records for deliveries during 1999-2009, using Poisson regression. After adjustment for potential confounders, hypospadias was associated with maternal hypertension (adjusted prevalence ratio: 1.5, 95% confidence interval: 1.4-1.7). Similar associations were observed with gestational and pregestational hypertension, including separate analyses restricted to the subset of cases with severe (second- or third-degree) hypospadias. All of these associations were also similar among the subset of cases with isolated hypospadias (without additional birth defects). To evaluate the potential for bias due to potential hypertension misclassification, we repeated our analyses using logistic regression, comparing the cases to controls with other birth defects. In these analyses, the associations with gestational hypertension were similar, but adjusted associations with pregestational hypertension were no longer observed. Our findings support an association between gestational hypertension and hypospadias in offspring, but also suggest that previously observed associations with pregestational hypertension may have been inflated due to differential misclassification of hypertension (e.g., reporting bias). As gestational hypertension is recognized after hypospadias development, more research is needed to determine if this association reflects an increase in gestational hypertension risk secondary to hypospadias or if both conditions have shared risk factors (e.g., precursors of gestational hypertension). © 2016 Wiley Periodicals, Inc.

Objective: Subarachnoid hemorrhage (SAH) is associated with marked sympathetic activation at the time of ictus. The purpose of this study is to determine whether early central catecholamine levels measured from cerebrospinal fluid (CSF) relate to outcome in patients with SAH. Methods: Observational study of consecutive SAH grade 3–5 patients who underwent ventriculostomy placement, but did not undergo open craniotomy for aneurysm obliteration. CSF samples were obtained during the first 48 h following symptom onset and assayed for catecholamine levels. Statistical analyses were performed to determine whether the levels predicted mortality by day 15 or mortality/disability by day 30. Results: For the 102 patients included, mean age was 58, and 73% were female – 21% experienced day-15 mortality, and 32% experienced mortality/disability by day 30. Early mortality was related to Hunt-Hess (H/H) grade (p < 0.001), neurogenic cardiomyopathy (NC) (p = 0.003), cerebral infarction (p = 0.001), elevated intracranial pressure (ICP) (p = 0.029), epinephrine (EPI) level (p = 0.002) and norepinephrine/3,4-dihydroxyphenylglycol (NE/DHPG) ratio (p = 0.003). Mortality/disability was related to H/H grade (p < 0.001), NC (p = 0.018), infarction (p < 0.001), elevated ICP (p = 0.002), EPI (p = 0.004) and NE/DHPG (p = 0.014). Logistic regression identified age [OR 1.09 (95% CI 1.01–1.17)], H/H grade [9.52 (1.19–77)], infarction [10.87 (1.22–100)], ICP elevation [32.26 (2–500)], EPI [1.06 (1.01–1.10)], and (inversely) DHPG [0.99 (0.99–1.00)] as independent predictors of early mortality. For mortality/disability, H/H grade [OR 21.74 (95% CI 5.62–83)], ICP elevation [18.52 (1.93–166)], and EPI [1.05 (1.02–1.09)] emerged as independent predictors. Proportional-hazards analysis revealed age [HR 1.041 (95% CI 1.003–1.08)], H/H grade [6.9 (1.54–31.25)], NC [4.31 (1.5–12.35)], and EPI [1.032 (1.009–1.054)] independently predicted early mortality. Conclusions: CSF catecholamine levels are elevated in SAH patients who experience early mortality or disability. EPI may potentially serve as useful index of outcome in this population of patients with SAH.

PTEN hamartoma tumor syndrome, of which Cowden syndrome (CS) is the most recognized variant, is characterized by multiple benign and malignant tumors of ectodermal, mesodermal, and endodermal origins, secondary to germline mutation in the phosphatase and tensin homolog (PTEN) gene. Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive malignant fibroblastic/myofibroblastic tumor of the skin, characterized by the t(17:22)(q22:q13) translocation resulting in fusion of the COL1A1 and PDGFB genes. An association between CS and DFSP has not been reported in the literature to date. The authors have encountered a male patient with CS and a history of DFSP that developed adjacent to a sclerotic fibroma on the parietal scalp, both excised at age 7. He presented at age 21 with an enlarging pink nodule at the same site on the parietal scalp. Excision revealed a dermal and subcutaneous storiform spindle cell proliferation with fat entrapment and positive staining for CD34, consistent with DFSP. Fluorescence in situ hybridization confirmed PDGFB gene rearrangement. PTEN expression in the patient's recurrent DFSP was nearly absent when compared with that of sporadic DFSP. To our knowledge, this is the first report of DFSP in a patient with CS. Although the association is likely to be coincidental, the authors revisited the PTEN and the PDGF pathways to speculate any possible interplay of the 2 conditions on a molecular level.

Left ventricular torsion is increased and cardiac energetics are reduced in uncomplicated type 1 diabetes mellitus (T1DM). Our aim was to determine the relationships of these abnormalities to cardiovascular autonomic neuropathy (CAN) in subjects with T1DM. A cross-sectional study was conducted in 20 subjects with T1DM free of known coronary heart disease attending an outpatient clinic. Cardiovascular autonomic neuropathy was assessed using heart rate variability studies and the continuous wavelet transform method. Left ventricular function was determined by speckle tracking echocardiography. Magnetic resonance spectroscopy and stress magnetic resonance imaging were used to measure cardiac energetics and myocardial perfusion reserve index, respectively. Twenty subjects (age, 35 ± 8 years; diabetes duration, 16 ± 9 years; hemoglobin A(1c), 8.0% ± 1.1%) were recruited. Forty percent of the subjects exhibited definite or borderline CAN. Log peak radial strain was significantly increased in subjects with CAN compared with those without (1.56 ± 0.06 vs 1.43 ± 0.14, respectively; P = .011). Data were adjusted for log duration of diabetes, and log left ventricular torsion correlated (r = 0.593, P = .01) with log low-frequency to high-frequency ratio during the Valsalva maneuver. Log isovolumic relaxation time correlated significantly with log Valsalva ratio and log proportion of differences in consecutive RR intervals of normal beats greater than 50 milliseconds during deep breathing. However, CAN did not correlate with cardiac energetics or myocardial perfusion reserve index. Spectral analysis of low-frequency to high-frequency ratio power during the Valsalva maneuver is associated with altered left ventricular torsion in subjects with T1DM. Parasympathetic dysfunction is closely associated with diastolic deficits. Cardiovascular autonomic neuropathy is not however the principal cause of impaired cardiac energetics. The role of CAN in the development of cardiomyopathy warrants further evaluation.

OBJECTIVE To describe and compare the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy. RESEARCH DESIGN AND METHODS This was a cross-sectional study of 224 diabetic patients (85 type 1 and 139 type 2) from a diabetes clinic. Diabetic retinopathy was graded from fundus photographs according to the Airlie House Classification system and categorized into mild, moderate, and vision-threatening diabetic retinopathy (VTDR). Serum traditional lipids (total, LDL, non–HDL, and HDL cholesterol and triglycerides) and apolipoprotein AI (apoAI), apolipoprotein B (apoB), and the apoB-to-apoAI ratio were assessed. RESULTS Diabetic retinopathy was present in 133 (59.4%) individuals. After adjustment for age, sex, diabetes duration, A1C, systolic blood pressure, and diabetes medications, the HDL cholesterol level was inversely associated with diabetic retinopathy (odds ratio 0.39 [95% CI 0.16–0.94], highest versus lowest quartile; Ptrend = 0.017). The ApoAI level was inversely associated with diabetic retinopathy (per SD increase, 0.76 [95% CI 0.59–0.98]), whereas apoB (per SD increase, 1.31 [1.02–1.68]) and the apoB-to-apoAI ratio (per SD increase, 1.48 [1.13–1.95]) were positively associated with diabetic retinopathy. Results were similar for mild to moderate diabetic retinopathy and VTDR. Traditional lipid levels improved the area under the receiver operating curve by 1.8%, whereas apolipoproteins improved the area by 8.2%. CONCLUSIONS ApoAI and apoB and the apoB-to-apoAI ratio were significantly and independently associated with diabetic retinopathy and diabetic retinopathy severity and improved the ability to discriminate diabetic retinopathy by 8%. Serum apolipoprotein levels may therefore be stronger biomarkers of diabetic retinopathy than traditional lipid measures.

Background and Purpose— Retinal vascular caliber changes have been shown to predict stroke, but the underlying mechanism of this association is unknown. We examined the relationship between retinal vascular caliber with brachial flow-mediated dilation (FMD), a measure of systemic endothelial function. Methods— The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of persons 45 to 84 years of age residing in 6 US communities free of clinical cardiovascular disease at baseline. Brachial FMD data were collected at baseline (July 2000 to June 2002), and retinal vascular caliber was measured from digital retinal photographs at the second examination, immediately after the first (August 2002 to January 2004). Data were available for 2851 participants for analysis. Results— The mean brachial FMD was 4.39±2.79%. After adjusting for age and gender, brachial FMD was reduced in persons with wider retinal venular caliber (changes in FMD −0.25, 95% CI, −0.36, − 0.13; P 1C (−0.18; 95% CI −0.30, − 0.06; P =0.004, per SD increase in venular caliber). Brachial FMD was not associated with retinal arteriolar caliber. Conclusions— Persons with wider retinal venules have reduced brachial FMD, independent of other vascular risk factors. This suggests that retinal venular caliber, previously shown to predict stroke, may be a marker of underlying systemic endothelial dysfunction.

Background— Asymptomatic subjects with diabetes mellitus have an impaired cardiac energetics status that may play a significant role in the development of heart failure. In the present study, we assessed the role of microvascular dysfunction in the development of impaired cardiac energetics in subjects with type 1 diabetes mellitus. Methods and Results— Twenty-five asymptomatic subjects with type 1 diabetes mellitus (mean age ±1 SD 33±8 years) and 26 age-, sex-, and body mass index–matched healthy control subjects (32±8 years old) were recruited into the study. The type 1 diabetes mellitus subjects were divided into 2 age-matched groups (newly diagnosed [10 years] diabetes) to assess the impact of microvascular disease. All subjects had an echocardiogram and an exercise ECG performed, followed by magnetic resonance spectroscopy and stress magnetic resonance imaging. Compared with healthy control subjects, the phosphocreatine/γ-ATP ratio was reduced significantly both in subjects with longer-term (2.1±0.5 versus 1.5±0.4, P P P =0.32). The mean myocardial perfusion reserve index in the longer-term type 1 diabetes mellitus subjects was significantly lower than in healthy control subjects (1.7±0.6 versus 2.3±0.4, P =0.005). On univariate analysis, there was no significant correlation of phosphocreatine/γ-ATP ratio with myocardial perfusion reserve index ( r =0.21, P =0.26). Conclusions— We demonstrate that young subjects with uncomplicated type 1 diabetes mellitus have impaired myocardial energetics irrespective of the duration of diabetes and that the impaired cardiac energetics status is independent of coronary microvascular function. We postulate that impairment of cardiac energetics in these subjects primarily results from metabolic dysfunction rather than microvascular impairment.

Using speckle-tracking imaging (STI), the aims of this study were to assess dyssynchrony and quantify the myocardial energy wasted by contractility in delayed segments by determining the longitudinal strain delay index (LSDi) in patients with heart failure with preserved ejection fraction (HFpEF).Thirty-eight patients with HFpEF and 33 matched controls were recruited. All subjects underwent clinical examinations, 12-lead electrocardiography, pulmonary function tests, echocardiography, and metabolic exercise tests. LSDi was determined, the magnitude of which is a measure of the amount of wasted energy. Global and segmental systolic and diastolic dyssynchrony was assessed by STI.LSDi was significantly higher in patients with HFpEF than controls (-14.36 +/- 8.24% vs -10.73 +/- 5.62%, P.05). Patients with HFpEF exhibited left ventricular (LV) systolic and diastolic dyssynchrony, with the LV anterior wall displaying the most delayed motion.Patients with HFpEF exhibited increased myocardial contractile inefficiency. They also exhibited LV systolic and diastolic dyssynchrony, with the LV anterior wall displaying the most delayed motion.

The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010–2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p

Background— This study assessed the chronotropic response to exercise and heart rate (HR) recovery after exercise in a carefully phenotyped group of patients with heart failure with preserved left ventricular ejection fraction (HfpEF) and a control group of similar age and gender distribution. Methods and Results— We studied 41 patients with HfpEF, 41 healthy controls, and 16 hypertensive controls. None were taking HR-limiting medications. All study participants had clinical examination, 12-lead ECG, pulmonary function test, echocardiogram, and metabolic exercise test with HR monitoring throughout exercise. Chronotropic response was measured by the percentage of the HR reserve used during maximal exercise and the peak exercise HR as a percentage of predicted maximal HR. Patients with HfpEF were generally women (70%), overweight, aged 69±8 years. Controls were of similar gender (63%) and age (67±6 years). Patients with HfpEF had significantly reduced peak VO 2 compared with controls (20±4 mL · kg −1 · min −1 versus 31±6 mL · kg −1 · min −1 , P e /V co 2 slope) (33±6 versus 29±4, P P =0.01). Hypertensive controls showed similar chronotropic response to peak exercise and HR recovery after exercise as healthy controls. Conclusions— Patients with HfpEF have impaired chronotropic incompetence during maximal exercise and abnormal HR recovery after exercise.

The role of left atrial (LA) function on exercise remains poorly understood in heart failure with preserved ejection fraction (HfpEF) despite its key role in optimizing left ventricular (LV) diastolic function. We used resting and exercise radionuclide ventriculography to investigate the role of LA function in the pathophysiology of HfpEF.A total of 25 patients with HfpEF and 15 age- and gender-matched controls were recruited. All subjects underwent resting echocardiogram, metabolic exercise testing to peak effort, and radionuclide ventriculography (at rest and exercise [to 35% of heart rate reserve]). At rest LA and LV function were similar in patients and controls. During exercise, HfpEF patients had lower left ventricular ejection fraction (69 +/- 9% vs. 73 +/- 10%, P.05) and lower peak early filling rate (387 +/- 109 end-diastolic count/sec vs. 561 +/- 156 end-diastolic count/sec, P.001). During exercise, the atrial contribution to LV filling was significantly higher in patients than controls (46 +/- 11% vs. 30 +/- 9%, P.001). Atrial contribution to LV filling correlated negatively with peak early filling rate during exercise (r = -0.6, P.001). Peak early filling rate correlated positively with peak oxygen consumption (r = 0.485, P = .004) and negatively with minute/carbon dioxide production (r = -0.423, P = .013).Patients with HfpEF have increased atrial contribution to LV filling as a compensatory response to impaired early LV filling during cycle exercise.

Aims We used speckle tracking echocardiography (STE) to make a comparison between the effects of ageing and of heart failure with normal ejection fraction (HfnEF) on left ventricular (LV) torsion and strain patterns. Methods and results Forty patients with HfnEF, 27 young controls and 26 older controls, were prospectively recruited. All subjects underwent clinical examination, 12-lead electrocardiogram, pulmonary function test, echocardiogram, and metabolic exercise test. LV torsion increases with advancing age (older controls vs. young controls, 2.2+ 0.9 vs. 1.4+ 0.88/cm; P ¼ 0.03). Circumferential strain was enhanced in patients with HfnEF (224.7+ 4.7 vs. 220.0+ 4.9%; P ¼ 0.003). Rotational deformation delay (time difference between peak basal rotation and peak apical rotation), global circumferential strain, E-velocity deceleration time, and LV end-diastolic volume index were independent predictors of LV torsion. LV torsion and body mass index were independent predictors of LV untwist rate. Conclusion Ageing is associated with increased LV torsion secondary to reduced rotational deformation delay and increased peak basal rotation. LV torsion and strain patterns in patients with HfnEF are similar to age-related changes apart from circumferential strain, which is enhanced in patients with HfnEF.

OBJECTIVE There are conflicting data regarding relationships of systemic biomarkers of inflammation, hemostasis, and homocysteine with diabetic retinopathy. We examined these relationships in the Multi-Ethnic Study of Atherosclerosis. RESEARCH DESIGN AND METHODS A total of 921 participants with diabetes were included. Diabetic retinopathy was graded from retinal photographs. We defined two outcomes: any diabetic retinopathy and vision-threatening diabetic retinopathy (severe nonproliferative diabetic retinopathy or worse). Systemic markers analyzed were C-reactive protein, homocysteine, fibrinogen, plasmin-α2-antiplasmin complex (PAP), interleukin-6, d-dimer, factor VIII, serum creatinine, and urinary albumin-to-creatinine (UAC) ratio. RESULTS Prevalence of diabetic retinopathy was 33.2% and vision-threatening diabetic retinopathy 7.1%. After adjusting for established risk factors (diabetes duration, A1C, systolic blood pressure, waist-to-hip ratio, and use of diabetes medications), fibrinogen (odds ratio 1.14 [95% CI 1.01–1.32], P = 0.05) and PAP (1.25 [1.05–1.50], P = 0.01) were associated with any diabetic retinopathy, while PAP (1.54 [1.13–2.11], P = 0.007) and homocysteine (1.57 [1.16–2.11], P = 0.003) were associated with vision-threatening diabetic retinopathy. Only PAP remained significant after additional adjustment for serum creatinine and UAC ratio. Area under receiver-operator characteristic curve (AUROC) for diabetic retinopathy was constructed for established and novel risk factors. Established risk factors accounted for a 39.2% increase of the AUROC, whereas novel markers (fibrinogen, PAP, homocysteine, serum creatinine, and UAC ratio) only accounted for an additional 2.2%. CONCLUSIONS There were few associations of novel markers of inflammation, hemostasis, and homocysteine with diabetic retinopathy after controlling for established risk factors. These data suggest that there is limited clinical use of these biomarkers for prediction of diabetic retinopathy.

Recent population-based studies have shown that retinal vascular caliber may predict the risk of clinical coronary artery disease (CAD) events. Whether this association is related to macro- or microvascular mechanisms remains unknown. We investigated the relationship of retinal vascular caliber with severity and extent of CAD in symptomatic cardiac patients.Overall, 98 patients attending diagnostic coronary angiography were recruited. Coronary angiography was used to assess for the severity and extent of CAD. Digital retinal photography was performed immediately prior to cardiac catheterization, and retinal vascular caliber was measured from these photographs by using a computer program and summarized as central retinal arteriolar (CRAE) and venular (CRVE) equivalents.Retinal arteriolar and venular calibers were not associated with increasing severity of CAD, as assessed by Leaman scores (CRAE/CRVE: P for trend=0.17/0.57), presence of clinically significant CAD (CRAE/CRVE: P=0.35/0.32), or number of diseased vessels (CRAE/CRVE: P for trend=0.18/0.69).Retinal vascular caliber changes are not associated with the severity of obstructive CAD in symptomatic patients. These data suggest that the association of retinal vascular caliber with clinical CAD seen in epidemiological studies may not be applicable to clinical symptomatic patients and may be related to microvascular, rather than macrovascular, mechanisms.

We previously identified Rbf as an activator for biofilm formation on polystyrene surfaces in Staphylococcus aureus strain 8325-4. However, strain 8325-4 contains genetic mutations that may affect biofilm formation. To extend the observation to other strains, we used strain Newman, a weak biofilm producer, and strain UAMS-1, an osteomyelitis clinical strain, in this study. We found that mutations in the chromosomal rbf gene did not affect biofilm formation on polystyrene surfaces in these strains, but transformants of these strains carrying a multiple-copy plasmid containing the rbf gene formed stronger biofilms than the wild-type strains and the mutant strains. Using the flow cell method, we found that the chromosomal mutation in the rbf gene delayed biofilm formation, whereas strains with a plasmid containing the rbf gene accelerated biofilm formation in strains Newman and UAMS-1. These results led us to conclude that rbf is an activator of biofilm formation in different strains of S. aureus , although the degree of activation varies among strains. In a murine model of foreign body infection, the rbf mutations in strain Newman, but not in strain UAMS-1, reduced the bacterial survival rate in catheter lumen. However, UAMS-1 carrying multiple copies of rbf in a plasmid increased the bacterial survival rate. The animal studies therefore suggest that Rbf has a role in S. aureus virulence.

To describe the relationship of retinal vascular calibre with diabetes and diabetic retinopathy in an Asian population.A total of 3280 (78.7% response) subjects, aged 40-80 years, of Malay ethnicity residing in Singapore participated in this population-based, cross-sectional study. Retinal vascular calibre was measured and summarized using a validated computer programme from digital retinal photographs. Diabetic retinopathy signs were graded from photographs using the modified Airlie House classification.Of the 3004 subjects with data for this analysis, 682 (22.7%) had diabetes, of whom 194 (28.4%) had retinopathy. After multivariable adjustment, retinal arteriolar calibre was significantly wider in persons with diabetes (141 vs139 microm, P0.001); venular calibre was not associated with diabetes (P=0.93). Among participants with diabetes, venular calibre increased from 218.7 microm in those without retinopathy to 231.1 microm in those with moderate and 231.4 microm in those with severe retinopathy (Pfor trend=0.001); arteriolar calibre was not associated with diabetic retinopathy.This study shows wider retinal arterioles in diabetes and wider venules in those with diabetic retinopathy in an Asian population. These findings confirm earlier data on white population, supporting the concept that a quantitative assessment of retinal vasculature may provide further insights into early diabetic microvascular damage.

Contains fulltext : 70145timmers.pdf (Publisher’s version ) (Open Access) CONTEXT: Patients with adrenal and extra-adrenal abdominal paraganglioma (PGL) almost invariably have increased plasma and urine concentrations of metanephrines, the O-methylated metabolites of catecholamines. We report four cases of biochemically silent abdominal PGL, in which metanephrines were normal despite extensive disease. OBJECTIVE: Our objective was to identify the mechanism underlying the lack of catecholamine hypersecretion and metabolism to metanephrines in biochemically silent PGL. DESIGN: This is a descriptive study. SETTING: The study was performed at a referral center. PATIENTS: One index case and three additional patients with large abdominal PGL and metastases but with the lack of evidence of catecholamine production, six patients with metastatic catecholamine-producing PGL and a mutation of the succinate dehydrogenase subunit B (SDHB) gene, and 136 random patients with catecholamine-producing PGL were included in the study. MAIN OUTCOME MEASURES: Plasma, urine, and tumor tissue concentrations of catecholamines and metabolites were calculated with electron microscopy and tyrosine hydroxylase immunohistochemistry. RESULTS: All four patients with biochemically silent PGL had an underlying SDHB mutation. In the index case, the tumor tissue concentration of catecholamines (1.8 nmol/g) was less than 0.01% that of the median (20,410 nmol/g) for the 136 patients with catecholamine-producing tumors. Electron microscopy showed the presence of normal secretory granules in all four biochemically silent PGLs. Tyrosine hydroxylase immunoreactivity was negligible in the four biochemically silent PGLs but abundant in catecholamine-producing PGLs. CONCLUSIONS: Patients with SDHB mutations may present with biochemically silent abdominal PGLs due to defective catecholamine synthesis resulting from the absence of tyrosine hydroxylase. Screening for tumors in patients with SDHB mutations should not be limited to biochemical tests of catecholamine excess.

Aim: We used Near Infrared Spectrophotometry (NIRS) during arterial occlusion to measure resting skeletal muscle oxygen consumption in chronic heart failure (CHF) patients and in age-matched healthy volunteers (HVs). Methods: Fifteen CHF patients (ten males) and eleven HVs (six males) had echocardiographic evaluation followed by measurement of the oxygen consumption of the brachioradialis muscle using NIRS. This involved continuous measurement of the oxygenated haemoglobin concentration ([Oxy-Hb]) and deoxy-haemoglobin concentration ([Deoxy-Hb]) with an Oxiplex TS NIRS probe first under basal overnight fasted resting conditions followed by 1 min of forearm arterial occlusion. A linear decline was observed in [Oxy-Hb–Deoxy-Hb] during the arterial occlusion and the oxygen consumption rate was calculated from the initial slope observed. Results: CHF patients were 59±2.8 years old with Left Ventricular Ejection Fraction (LVEF) 31%±2.2 and the HVs were 52±4.8 years old with LVEF 62%±2.5. The resting muscle oxygen consumption rate was significantly reduced in CHF patients versus HVs (0.04±0.01 mlO2/min/100 g versus 0.07±0.01 mlO2/min/100 g) p

Purpose: To assess reliability and reproducibility of different analysis methods for retinal capillary flow, volume, and velocity from scanning laser Doppler flowmetry (SLDF) topography. Material and Methods: SLDF topography analysis using the default retinal flowmeter (HRF) were compared to that using automatic full-field perfusion image analyzer (AFFPIA) and quantified as intraclass correlation coefficients (ICC). Results: The AFFPIA full-field method had the highest reliability, with ICC 0.99 for capillary flow. The reproducibility using the AFFPIA full-field method was high ICC 0.74 for capillary flow. Conclusions: The AFFPIA full-field method is highly reliable and superior to the default HRF software.

Phaeochromocytomas are rare neuroendocrine tumours that produce catecholamines and numerous secretory proteins and peptides, including neuropeptide Y (NPY), a vasoactive peptide with influences on blood pressure. The production of catecholamines and NPY by phaeochromocytomas is highly variable. This study examined influences of hereditary factors and differences in catecholamine production on tumour expression of NPY, as assessed by quantitative PCR, enzyme immunoassay and immunohistochemistry. Phaeochromocytomas included hereditary adrenaline-producing tumours (adrenergic phenotype) in multiple endocrine neoplasia type 2 (MEN 2), predominantly noradrenaline-producing tumours (noradrenergic phenotype) in von Hippel–Lindau (VHL) syndrome, and other adrenergic and noradrenergic tumours where there was no clear hereditary syndrome. NPY levels in phaeochromocytomas from VHL patients were lower (P

BACKGROUND: Age-related hearing loss (ARHL) is a leading cause of disability in the elderly. Low-grade inflammation and microvessel pathology may be responsible for initiating or exacerbating some of the hearing loss associated with aging. A growing body of evidence demonstrates an association of hearing loss with cognitive decline. A shared etiological pathway may include a role of inflammation, alongside vascular determinants. The ASPREE-HEARING study aims to determine whether low-dose aspirin decreases the progression of ARHL, and if so, whether this decrease in progression is also associated with retinal microvascular changes and/or greater preservation of cognitive function. DESIGN AND METHODS: A three year double-blind, randomized controlled trial of oral 100 mg enteric-coated aspirin or matching placebo, enrolling 1262 Australians aged ≥70 years with normal cognitive function and no overt cardiovascular disease. The primary outcome is the change in mean pure tone average hearing threshold (decibels) in the better ear, over a 3-year period. Secondary outcomes consist of changes in retinal microvascular indicators, and changes in cognitive function. Participants are recruited from a larger trial, ASPirin in Reducing Events in the Elderly (ASPREE), which is designed to assess whether daily low dose aspirin will extend disability-free life. DISCUSSION: ASPREE-HEARING will determine whether aspirin slows development or progression of ARHL, and will interrogate the relationship between inflammatory and microvascular mechanisms that may underlie the effects of aspirin on ARHL. This study will improve understanding of the patterns of comorbidity with, and the relationships between, aging and ARHL, alongside modeling the impacts of ARHL.

There are no treatments in clinical practice known to mitigate the neurobiological processes that convert a healthy brain into an epileptic one, a phenomenon known as epileptogenesis. Downregulation of protein phosphatase 2A, a protein that causes the hyperphosphorylation of tau, is implicated in neurodegenerative diseases commonly associated with epilepsy, such as Alzheimer's disease and traumatic brain injury. Here we used the protein phosphatase 2A activator sodium selenate to investigate the role of protein phosphatase 2A in three different rat models of epileptogenesis: amygdala kindling, post-kainic acid status epilepticus, and post-traumatic epilepsy. Protein phosphatase 2A activity was decreased, and tau phosphorylation increased, in epileptogenic brain regions in all three models. Continuous sodium selenate treatment mitigated epileptogenesis and prevented the biochemical abnormalities, effects which persisted after drug withdrawal. Our studies indicate that limbic epileptogenesis is associated with downregulation of protein phosphatase 2A and the hyperphosphorylation of tau, and that targeting this mechanism with sodium selenate is a potential anti-epileptogenic therapy.

Modulation of interactions among neurons can manifest as dramatic changes in the state of population dynamics in cerebral cortex. How such transitions in cortical state impact the information processing performed by cortical circuits is not clear. Here we performed experiments and computational modeling to determine how somatosensory dynamic range depends on cortical state. We used microelectrode arrays to record ongoing and whisker stimulus-evoked population spiking activity in somatosensory cortex of urethane anesthetized rats. We observed a continuum of different cortical states; at one extreme population activity exhibited small scale variability and was weakly correlated, the other extreme had large scale fluctuations and strong correlations. In experiments, shifts along the continuum often occurred naturally, without direct manipulation. In addition, in both the experiment and the model we directly tuned the cortical state by manipulating inhibitory synaptic interactions. Our principal finding was that somatosensory dynamic range was maximized in a specific cortical state, called criticality, near the tipping point midway between the ends of the continuum. The optimal cortical state was uniquely characterized by scale-free ongoing population dynamics and moderate correlations, in line with theoretical predictions about criticality. However, to reproduce our experimental findings, we found that existing theory required modifications which account for activity-dependent depression. In conclusion, our experiments indicate that in vivo sensory dynamic range is maximized near criticality and our model revealed an unanticipated role for activity-dependent depression in this basic principle of cortical function., Author Summary When many simple parts interact, the collective behavior of the whole can be astonishingly complex. A particularly striking example is our capacity for sensory perception, which results from the collective interactions of billions of relatively simple neurons. Another example is found in physical systems which undergo a phase transition–for example, liquid water turning to solid ice. When collective interactions among the water molecules are changed, the system transitions from a disordered state (liquid) to an ordered state (crystalline solid). At the tipping point of a critical phase transition, i.e. at criticality, physical systems exhibit very complex behavior. In this study, we show that phase transitions may occur in the cerebral cortex changing the neural activity from a disordered to an ordered state. Moreover, this neural phase transition may be intimately linked with sensory perception. We experimentally manipulate the interactions among neurons and show that sensory dynamic range is maximized when the cerebral cortex of a rat is closest to criticality.

The HSV type 1 tegument virion phosphoprotein (VP) 11/12 (VP11/12) is a major Ag targeted by CD8+ T cells from HSV-seropositive individuals. However, whether and which VP11/12 epitope–specific CD8+ T cells play a role in the “natural” protection seen in seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we used multiple prediction computer-assisted algorithms to identify 10 potential HLA-A*02:01–restricted CD8+ T cell epitopes from the 718-aa sequence of VP11/12. Three of 10 epitopes exhibited high-to-moderate binding affinity to HLA-A*02:01 molecules. In 10 sequentially studied HLA-A*02:01–positive and HSV-1–seropositive ASYMP individuals, the most frequent, robust, and polyfunctional effector CD8+ T cell responses, as assessed by a combination of tetramer frequency, granzyme B, granzyme K, perforin, CD107a/b cytotoxic degranulation, IFN-γ, and multiplex cytokines assays, were predominantly directed against three epitopes: VP11/1266–74, VP11/12220–228, and VP11/12702–710. Interestingly, ASYMP individuals had a significantly higher proportion of CD45RAlowCCR7lowCD44highCD62LlowCD27lowCD28lowCD8+ effector memory CD8+ T cells (TEMs) specific to the three epitopes, compared with symptomatic individuals (with a history of numerous episodes of recurrent ocular herpetic disease). Moreover, immunization of HLA-A*02:01 transgenic mice with the three ASYMP CD8+ TEM cell epitopes induced robust and polyfunctional epitope-specific CD8+ TEM cells that were associated with a strong protective immunity against ocular herpes infection and disease. Our findings outline phenotypic and functional features of protective HSV-specific CD8+ T cells that should guide the development of an effective T cell–based herpes vaccine.

Herpes simplex virus 1 (HSV-1) glycoprotein B (gB)-specific CD8 + T cells protect mice from herpes infection and disease. However, whether and which HSV-1 gB-specific CD8 + T cells play a key role in the “natural” protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we have dissected the phenotypes and the functions of HSV-1 gB-specific CD8 + T cells from HLA-A*02:01 positive, HSV-1 seropositive ASYMP and symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent ocular herpes disease). We found the following. (i) Healthy ASYMP individuals maintained a significantly higher proportion of differentiated HSV-1 gB-specific effector memory CD8 + T cells (T EM cells) (CD45RA low CCR7 low CD44 high CD62L low ). In contrast, SYMP patients had frequent less-differentiated central memory CD8 + T cells (T CM cells) (CD45RA low CCR7 high CD44 low CD62L high ). (ii) ASYMP individuals had significantly higher proportions of multifunctional effector CD8 + T cells which responded mainly to gB 342–350 and gB 561–569 “ASYMP” epitopes, and simultaneously produced IFN-γ, CD107 a/b , granzyme B, and perforin. In contrast, effector CD8 + T cells from SYMP individuals were mostly monofunctional and were directed mainly against nonoverlapping gB 17–25 and gB 183–191 “SYMP” epitopes. (iii) Immunization of an HLA-A*02:01 transgenic mouse model of ocular herpes with “ASYMP” CD8 + T EM cell epitopes, but not with “SYMP” CD8 + T CM cell epitopes, induced a strong CD8 + T cell-dependent protective immunity against ocular herpes infection and disease. Our findings provide insights into the role of HSV-specific CD8 + T EM cells in protection against herpes and should be considered in the development of an effective vaccine. IMPORTANCE A significantly higher proportion of differentiated and multifunctional HSV-1 gB-specific effector memory CD8 + T cells (T EM cells) (CD45RA low CCR7 low CD44 high CD62L low ) were found in healthy ASYMP individuals who are seropositive for HSV-1 but never had any recurrent herpetic disease, while there were frequent less-differentiated and monofunctional central memory CD8 + T cells (T CM cells) (CD45RA low CCR7 high CD44 low CD62L high ) in SYMP patients. Immunization with “ASYMP” CD8 + T EM cell epitopes, but not with “SYMP” CD8 + T CM cell epitopes, induced a strong protective HSV-specific CD8 + T cell response in HLA-A*02:01 transgenic mice. These findings are important for the development of a safe and effective T cell-based herpes vaccine.

To investigate the association between retinal vascular tortuosity and traditional- and vascular-related risk factors in persons with diabetes.We recruited 224 diabetic patients. Retinal vascular tortuosity was measured from fundus photographs. Association of tortuosity with the following factors was assessed after adjusting for significant co-factors: diabetes duration, HbA1c, systolic blood pressure (SBP), cholesterol and body mass index (BMI), flicker-light induced retinal vasodilatation, and markers of endothelial function and inflammation (skin microvacular responses to acetylcholine iontophoresis, soluble e-selectin, inter-cellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelin-1, total nitrite, C-reactive protein).Adjusting for age and gender, longer diabetes duration was associated with more tortuous retinal arterioles (mean difference in arteriolar tortuosity 5.85 × 10(-5), 95% Confidence Interval 1.44-10.3 × 10(-5); p = 0.016; ≤10 versus10 years duration). Reduced flicker-light induced retinal vasodilatation was associated with tortuous arterioles and venules (mean difference in arteriolar tortuosity 5.62 × 10(-5), 4.50-6.72 × 10(-5); p 0.001 and in venules 5.94 × 10(-5), 3.33-8.55 × 10(-5); p 0.001; comparing highest versus lowest tertile of flicker-light vasodilatation). These associations remained after adjusting for co-factors. Diabetes duration explained about 36% and flicker-light vasodilatation 25% of the variation in retinal arteriolar tortuosity. No associations were found between retinal arteriolar or venular tortuosity and HBA1c, SBP, cholesterol, BMI and serum markers of endothelial function.Increased retinal arteriolar tortuosity was related to longer diabetes duration and reduced flicker-light induced vasodilatory response, suggesting that retinal vascular tortuosity in adults with diabetes may be influenced by multiple diabetes-related physio-pathological changes.

ObjectivesThe purpose of this study was to evaluate the safety and feasibility of endovascular cooling during primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI).BackgroundIn experimental models of AMI, mild systemic hypothermia has been shown to reduce metabolic demand and limit infarct size.MethodsIn a multi-center study, 42 patients with AMI (

PURPOSE: To investigate the impact of ambient room lighting on the magnitude of flicker light-induced retinal vasodilations in healthy individuals. METHODS: Twenty healthy nonsmokers participated in a balanced 2 × 2 crossover study. Retinal vascular imaging was performed with the dynamic vessel analyzer under reduced or normal ambient lighting, then again after 20 minutes under the alternate condition. Baseline calibers of selected arteriole and venule segments were recorded in measurement units. Maximum percentage dilations from baseline during 20 seconds of luminance flicker were calculated from the mean of three measurement cycles. Within-subject differences were assessed by repeated measures analysis of variance with the assumption of no carryover effects and pairwise comparisons from the fitted model. RESULTS: Mean (SD) maximum arteriole dilations during flicker stimulation under reduced and normal ambient lighting were 4.8% (2.3%) and 4.1% (1.9%), respectively (P = 0.019). Maximum arteriole dilations were (mean ± 95% confidence interval) 0.7% ± 0.6% lower under normal ambient lighting compared with reduced lighting. Ambient lighting had no significant effect on maximum venular dilations during flicker stimulation or on the baseline calibers of arterioles or venules. CONCLUSIONS: Retinal arteriole dilation in response to luminance flicker stimulation is reduced under higher ambient lighting conditions. Reduced responses with higher ambient lighting may reflect reduced contrast between the ON and OFF flicker phases. Although it may not always be feasible to conduct studies under reduced lighting conditions, ambient lighting levels should be consistent to ensure that comparisons are valid.