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Background Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited. Methods To investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all other omic features via bipartite Pearson correlations. Results This dataset revealed that the set of metabolome and methylome signatures of birthweight have seven signals in common, including three metabolites [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22). CCL22, a macrophage-derived chemokine has not been previously identified in relation to birthweight. Since the results of the omics integration indicated the central role of cholesterol metabolism, we explored the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n = 1097), finding that higher birthweight was associated with increased high-density lipoprotein cholesterol and that high-density lipoprotein cholesterol was lower in small versus large for gestational age newborns. Conclusions Our data suggests that an integration of different omic-layers in addition to single omics studies is a useful approach to generate new hypotheses regarding biological mechanisms. CCL22 and cholesterol metabolism in cord blood play a mechanistic role in birthweight., Highlights • Using multiple omics, we provide an unprecedented window into the biological processes underlying birthweight. • We identified molecular signals never previously linked to birthweight, e.g. gene expression of JAK3 and chemokine CCL22. • Our data suggested that cholesterol and related metabolic pathways are related to birthweight. • The identified signals may create a molecular basis for the onset of health outcomes associated with birthweight variation.

UK Medical Research Council; Wellcome Trust [102215/2/13/2, WT088806, 084762MA]; UK Biotechnology and Biological Sciences Research Council [BB/I025751/1, BB/I025263/1]; UK Medical Research Council Integrative Epidemiology Unit; University of Bristol [MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5, MC_UU_12013_8]; United States National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK10324]; Swedish Research Council; Swedish Heart-Lung Foundation; Freemason Child House Foundation in Stockholm; MeDALL (Mechanisms of the Development of ALLergy), within the European Union [261357]; Stockholm County Council (ALF); Swedish Foundation for Strategic Research (SSF) [RBc08-0027]; Strategic Research Programme (SFO) in Epidemiology at Karolinska Institutet; Swedish Research Council Formas; Swedish Environment Protection Agency; Center for Integrative Research on Childhood Leukemia and the Environment [P01ES018172]; NIH [P50ES018172, R01ES09137, 5P30CA082103, P01 ES009605, R01 ES021369, R01ES023067, K01ES017801, R01ES022216, P30ES007048, R01ES014447, P01ES009581, R826708-01, RD831861-01, P50ES026086, R01DK068001, R01 DK100340, R01 DK076648, R01ES022934, R01HL111108, R01NR013945, R37 HD034568, UL1 TR001082, P30 DK56350]; EPA [RD83451101, RD83615901, RD 82670901, RD 83451301, 83615801-0]; UCSF Comprehensive Cancer Center Support grant [P30 CA82103]; Swiss Science National Foundation [P2LAP3_158674]; Sutter-Stottner Foundation; Commission of the European Community, specific RTD Programme 'Quality of Life and Management of Living Resources' within the 5th Framework Programme [QLRT-2001-00389, QLK1-CT-2002-30582]; 6th Framework Programme [007036]; European Union's Seventh Framework Programme (FP7), project EarlyNutrition [289346]; European Research Council Advanced grant ERC-AdG [322605 META-GROWTH]; Autism Speaks grant [260377]; Funds for Research in Respiratory Health; French Ministry of Research: IFR program; INSERM Nutrition Research Program; French Ministry of Health: Perinatality Program; French National Institute for Population Health Surveillance (INVS); Paris-Sud University; French National Institute for Health Education (INPES); Nestle; Mutuelle Generale de l'Education Nationale (MGEN); French-speaking association for the study of diabetes and metabolism (Alfediam) [2012/51290-6]; EU; European Research Council [ERC-2012-StG.310898, 268479-BREATHE]; Flemish Scientific Research Council (FWO) [N1516112 / G.0.873.11N.10]; European Community's Seventh Framework Programme FP7 project EXPOsOMICS [308610]; People Program (Marie Curie Actions) of the European Union's Seventh Framework Program FP7 under REA grant [628858]; Bijzonder Onderzoeksfonds (BOF) Hasselt University; Ministry of the Flemish Community (Department of Economics, Science and Innovation); Ministry of the Flemish Community (Department of Environment, Nature and Energy); CEFIC LRI award by the Research Foundation-Flanders (FWO); CEFIC LRI award by the Research Foundation-Flanders (FWO) [12L5216N]; Flemish Institute for Technological Research (VITO) [12L5216N]; Bill AMP; Melinda Gates Foundation Grand Challenges Exploration grant [OPP119403]; Sandler Family Foundation; American Asthma Foundation; National Institutes of Health; National Heart, Lung and Blood Institute [HL117004]; National Institute of Environmental Health Sciences [ES24844]; National Institute on Minority Health and Health Disparities [MD006902, MD009523]; National Institute of General Medical Sciences [GM007546]; Tobacco-Related Disease Research Program [24RT-0025]; Hutchison Whampoa Ltd, Hong Kong; University of Groningen; Well Baby Clinic Foundation Icare; Noordlease; Youth Health Care Drenthe; Biobanking and Biomolecular Research Infrastructure Netherlands [CP2011-19]; Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO); Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; European Union's Horizon research and innovation programme [733206, 633595]; National Institute of Child and Human Development [R01HD068437]; Netherlands Organization for Health Research and Development [VIDI 016.136.361]; Consolidator grant from the European Research Council [ERC-2014-CoG-648916]; Netherlands' Organization for Scientific Research (NWO VICI); European Research Council ERC; Netherlands' Organization for Scientific Research (NWO Spinoza Award); Gravitation program of the Dutch Ministry of Education, Culture, and Science; Netherlands Organization for Scientific Research (NWO) [024.001.003]; Lung Foundation Netherlands [3.2.12.089]; Fonds de Recherche du Quebec en Sante (FRQ-S) [20697]; Canadian Institute of Health Reseach (CIHR) [MOP 115071]; Diabete Quebec grant; Canadian Diabetes Association operating grant [OG-3-08-2622]; American Diabetes Association Pathways Accelerator Early Investigator Award [1-15-ACE-26]; MRC Integrative Epidemiology Unit - Medical Research Council [MC_UU_12013/1-9]; National Institute of Environmental Health Sciences, National Institutes of Health [K99ES025817]; Instituto de Salud Carlos III [Red INMA G03/176, CB06/02/0041]; Spanish Ministry of Health [FIS-PI04/1436, FIS-PI08/1151]; Spanish Ministry of Health (FEDER funds) [FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615]; Generalitat de Catalunya [CIRIT 1999SGR 00241]; Fundacio La Marato de TV3 [090430]; EU Commission [261357-MeDALL]; National Institute of Allergy and Infectious Diseases [N01-AI90052]; National Institutes of Health USA [R01 HL082925, R01 HL132321]; Asthma UK [364]; NIAID/NIH [R01AI091905, R01AI121226]; National Institute of Health [R01AI121226, R01 AI091905, R01HL132321]; NIH/NIEHS [N01-ES75558]; NIH/NINDS [1 UO1 NS 047537-01, 2 UO1 NS 047537-06A1]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES-49019, Z01 ES044005, ES049033, ES049032]; Norwegian Research Council/BIOBANK [221097]; Oslo University Hospital; Unger-Vetlesens foundation; Norwegian American Womens Club; INCA/Plan Cancer-EVA-INSERM, France; International Childhood Cancer Cohort Consortium (I4C); INCA/Plan Cancer-EVA-INSERM (France); IARC Postdoctoral Fellowship; EC FP7 Marie Curie Actions-People-Co-funding of regional, national and international programmes (COFUND); NIEHS [R21ES014947, R01ES016772]; NIDDK [R01DK085173]; National Institute of Environmental Health Science [P30 ES025128]; University of Oulu grant [65354]; Oulu University Hospital [2/97, 8/97]; Ministry of Health and Social Affairs [23/251/97, 160/97, 190/97]; National Institute for Health and Welfare, Helsinki [54121]; Regional Institute of Occupational Health, Oulu, Finland [50621, 54231]; EU [QLG1-CT-2000-01643, E51560]; NorFA grant [731, 20056, 30167]; Academy of Finland; NIH-NIEHS [P01 ES022832]; US EPA [RD83544201]; NIH-NIGMS [P20GM104416]; NCI [R25CA134286]; Netherlands Organization for Scientific Research and Development; Netherlands Asthma Fund; Netherlands Ministry of Spatial Planning, Housing, and the Environment; Netherlands Ministry of Health, Welfare, and Sport; MeDALL; European Union under the Health Cooperation Work Program of the 7th Framework program [261357]; Italian National Centre for Disease Prevention and Control (CCM grant); Italian Ministry of Health (art 12); Italian Ministry of Health (12bis Dl.gs.vo) [502/92]; EraNet; EVO; University of Helsinki Research Funds; Signe and Ane Gyllenberg foundation; Emil Aaltonen Foundation; Finnish Medical Foundation; Jane and Aatos Erkko Foundation; Novo Nordisk Foundation; Paivikki and Sakari Sohlberg Foundation; Sigrid Juselius Foundation; University of Helsinki; University of Western Australia (UWA); Curtin University; Raine Medical Research Foundation; UWA Faculty of Medicine, Dentistry and Health Sciences; Telethon Kids Institute; Women's and Infant's Research Foundation (KEMH); Edith Cowan University; National Health and Medical Research Council [1059711]; National Health and Medical Research Council (NHMRC) fellowship [1053384]; Australian National Health and Medical Research Council; United States National Institute of Health; Greek Ministry of Health (programme of prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece); Greek Ministry of Health ('Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health); European Union (EU) [EU FP6-2003-Food-3-NewGeneris, EU FP7 ENV.2007.1.2.2.2, 211250 ESCAPE, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7 ENV.2008.1.2.1.6, 226285 ENRIECO]; National Institutes of Health [NIH-NIMH R01MH094609, NIH-NIEHS R01ES022223, NIH-NIEHS R01ES025145]; Centers for Disease Control and Prevention [U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, U10DD000498]; Autism Speaks [7659]; Swedish Research Council through the Swedish Initiative for research on Microdata in the Social And Medical Sciences (SIMSAM) [340-2013-5867]; Stockholm County Council (ALF projects); Strategic Research Program in Epidemiology at Karolinska Institutet; Swedish Asthma and Allergy Association's Research Foundation; Stiftelsen Frimurare Barnahuset Stockholm; Norwegian Ministry of Health and Care Services; Ministry of the Flemish Community (Flemish Agency for Care and Health); University of Bristol; Ministry of Education and Research; European Union (EU) (EU FP7-HEALTH-single stage CHICOS); European Union (EU) (EU-FP7-HEALTH) [308333 HELIX]; European Union (EU) (EU FP6. STREP HiWATE); UK Medical Research Council; Wellcome Trust [102215/2/13/2, WT088806, 084762MA]; UK Biotechnology and Biological Sciences Research Council [BB/I025751/1, BB/I025263/1]; UK Medical Research Council Integrative Epidemiology Unit; University of Bristol [MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5, MC_UU_12013_8]; United States National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK10324]; Swedish Research Council; Swedish Heart-Lung Foundation; Freemason Child House Foundation in Stockholm; MeDALL (Mechanisms of the Development of ALLergy), within the European Union [261357]; Stockholm County Council (ALF); Swedish Foundation for Strategic Research (SSF) [RBc08-0027]; Strategic Research Programme (SFO) in Epidemiology at Karolinska Institutet; Swedish Research Council Formas; Swedish Environment Protection Agency; Center for Integrative Research on Childhood Leukemia and the Environment [P01ES018172]; NIH [P50ES018172, R01ES09137, 5P30CA082103, P01 ES009605, R01 ES021369, R01ES023067, K01ES017801, R01ES022216, P30ES007048, R01ES014447, P01ES009581, R826708-01, RD831861-01, P50ES026086, R01DK068001, R01 DK100340, R01 DK076648, R01ES022934, R01HL111108, R01NR013945, R37 HD034568, UL1 TR001082, P30 DK56350]; EPA [RD83451101, RD83615901, RD 82670901, RD 83451301, 83615801-0]; UCSF Comprehensive Cancer Center Support grant [P30 CA82103]; Swiss Science National Foundation [P2LAP3_158674]; Sutter-Stottner Foundation; Commission of the European Community, specific RTD Programme 'Quality of Life and Management of Living Resources' within the 5th Framework Programme [QLRT-2001-00389, QLK1-CT-2002-30582]; 6th Framework Programme [007036]; European Union's Seventh Framework Programme (FP7), project EarlyNutrition [289346]; European Research Council Advanced grant ERC-AdG [322605 META-GROWTH]; Autism Speaks grant [260377]; Funds for Research in Respiratory Health; French Ministry of Research: IFR program; INSERM Nutrition Research Program; French Ministry of Health: Perinatality Program; French National Institute for Population Health Surveillance (INVS); Paris-Sud University; French National Institute for Health Education (INPES); Nestle; Mutuelle Generale de l'Education Nationale (MGEN); French-speaking association for the study of diabetes and metabolism (Alfediam) [2012/51290-6]; EU; European Research Council [ERC-2012-StG.310898, 268479-BREATHE]; Flemish Scientific Research Council (FWO) [N1516112 / G.0.873.11N.10]; European Community's Seventh Framework Programme FP7 project EXPOsOMICS [308610]; People Program (Marie Curie Actions) of the European Union's Seventh Framework Program FP7 under REA grant [628858]; Bijzonder Onderzoeksfonds (BOF) Hasselt University; Ministry of the Flemish Community (Department of Economics, Science and Innovation); Ministry of the Flemish Community (Department of Environment, Nature and Energy); CEFIC LRI award by the Research Foundation-Flanders (FWO); CEFIC LRI award by the Research Foundation-Flanders (FWO) [12L5216N]; Flemish Institute for Technological Research (VITO) [12L5216N]; Bill AMP; Melinda Gates Foundation Grand Challenges Exploration grant [OPP119403]; Sandler Family Foundation; American Asthma Foundation; National Institutes of Health; National Heart, Lung and Blood Institute [HL117004]; National Institute of Environmental Health Sciences [ES24844]; National Institute on Minority Health and Health Disparities [MD006902, MD009523]; National Institute of General Medical Sciences [GM007546]; Tobacco-Related Disease Research Program [24RT-0025]; Hutchison Whampoa Ltd, Hong Kong; University of Groningen; Well Baby Clinic Foundation Icare; Noordlease; Youth Health Care Drenthe; Biobanking and Biomolecular Research Infrastructure Netherlands [CP2011-19]; Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO); Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; European Union's Horizon research and innovation programme [733206, 633595]; National Institute of Child and Human Development [R01HD068437]; Netherlands Organization for Health Research and Development [VIDI 016.136.361]; Consolidator grant from the European Research Council [ERC-2014-CoG-648916]; Netherlands' Organization for Scientific Research (NWO VICI); European Research Council ERC; Netherlands' Organization for Scientific Research (NWO Spinoza Award); Gravitation program of the Dutch Ministry of Education, Culture, and Science; Netherlands Organization for Scientific Research (NWO) [024.001.003]; Lung Foundation Netherlands [3.2.12.089]; Fonds de Recherche du Quebec en Sante (FRQ-S) [20697]; Canadian Institute of Health Reseach (CIHR) [MOP 115071]; Diabete Quebec grant; Canadian Diabetes Association operating grant [OG-3-08-2622]; American Diabetes Association Pathways Accelerator Early Investigator Award [1-15-ACE-26]; MRC Integrative Epidemiology Unit - Medical Research Council [MC_UU_12013/1-9]; National Institute of Environmental Health Sciences, National Institutes of Health [K99ES025817]; Instituto de Salud Carlos III [Red INMA G03/176, CB06/02/0041]; Spanish Ministry of Health [FIS-PI04/1436, FIS-PI08/1151]; Spanish Ministry of Health (FEDER funds) [FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615]; Generalitat de Catalunya [CIRIT 1999SGR 00241]; Fundacio La Marato de TV3 [090430]; EU Commission [261357-MeDALL]; National Institute of Allergy and Infectious Diseases [N01-AI90052]; National Institutes of Health USA [R01 HL082925, R01 HL132321]; Asthma UK [364]; NIAID/NIH [R01AI091905, R01AI121226]; National Institute of Health [R01AI121226, R01 AI091905, R01HL132321]; NIH/NIEHS [N01-ES75558]; NIH/NINDS [1 UO1 NS 047537-01, 2 UO1 NS 047537-06A1]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES-49019, Z01 ES044005, ES049033, ES049032]; Norwegian Research Council/BIOBANK [221097]; Oslo University Hospital; Unger-Vetlesens foundation; Norwegian American Womens Club; INCA/Plan Cancer-EVA-INSERM, France; International Childhood Cancer Cohort Consortium (I4C); INCA/Plan Cancer-EVA-INSERM (France); IARC Postdoctoral Fellowship; EC FP7 Marie Curie Actions-People-Co-funding of regional, national and international programmes (COFUND); NIEHS [R21ES014947, R01ES016772]; NIDDK [R01DK085173]; National Institute of Environmental Health Science [P30 ES025128]; University of Oulu grant [65354]; Oulu University Hospital [2/97, 8/97]; Ministry of Health and Social Affairs [23/251/97, 160/97, 190/97]; National Institute for Health and Welfare, Helsinki [54121]; Regional Institute of Occupational Health, Oulu, Finland [50621, 54231]; EU [QLG1-CT-2000-01643, E51560]; NorFA grant [731, 20056, 30167]; Academy of Finland; NIH-NIEHS [P01 ES022832]; US EPA [RD83544201]; NIH-NIGMS [P20GM104416]; NCI [R25CA134286]; Netherlands Organization for Scientific Research and Development; Netherlands Asthma Fund; Netherlands Ministry of Spatial Planning, Housing, and the Environment; Netherlands Ministry of Health, Welfare, and Sport; MeDALL; European Union under the Health Cooperation Work Program of the 7th Framework program [261357]; Italian National Centre for Disease Prevention and Control (CCM grant); Italian Ministry of Health (art 12); Italian Ministry of Health (12bis Dl.gs.vo) [502/92]; EraNet; EVO; University of Helsinki Research Funds; Signe and Ane Gyllenberg foundation; Emil Aaltonen Foundation; Finnish Medical Foundation; Jane and Aatos Erkko Foundation; Novo Nordisk Foundation; Paivikki and Sakari Sohlberg Foundation; Sigrid Juselius Foundation; University of Helsinki; University of Western Australia (UWA); Curtin University; Raine Medical Research Foundation; UWA Faculty of Medicine, Dentistry and Health Sciences; Telethon Kids Institute; Women's and Infant's Research Foundation (KEMH); Edith Cowan University; National Health and Medical Research Council [1059711]; National Health and Medical Research Council (NHMRC) fellowship [1053384]; Australian National Health and Medical Research Council; United States National Institute of Health; Greek Ministry of Health (programme of prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece); Greek Ministry of Health ('Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health); European Union (EU) [EU FP6-2003-Food-3-NewGeneris, EU FP7 ENV.2007.1.2.2.2, 211250 ESCAPE, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7 ENV.2008.1.2.1.6, 226285 ENRIECO]; National Institutes of Health [NIH-NIMH R01MH094609, NIH-NIEHS R01ES022223, NIH-NIEHS R01ES025145]; Centers for Disease Control and Prevention [U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, U10DD000498]; Autism Speaks [7659]; Swedish Research Council through the Swedish Initiative for research on Microdata in the Social And Medical Sciences (SIMSAM) [340-2013-5867]; Stockholm County Council (ALF projects); Strategic Research Program in Epidemiology at Karolinska Institutet; Swedish Asthma and Allergy Association's Research Foundation; Stiftelsen Frimurare Barnahuset Stockholm; Norwegian Ministry of Health and Care Services; Ministry of the Flemish Community (Flemish Agency for Care and Health); University of Bristol; Ministry of Education and Research; European Union (EU) (EU FP7-HEALTH-single stage CHICOS); European Union (EU) (EU-FP7-HEALTH) [308333 HELIX]; European Union (EU) (EU FP6. STREP HiWATE); [R01ES017646]; [R01ES01900]; [R01ES16443]; [USA / NIHH 2000 G DF682]; [50945]; [R01 HL095606]; [R01 HL1143396]

It is well recognized that depression is independently associated with cardiovascular events. However, uncertainties remain on the pathophysiological pathways underlying the association between depression and coronary heart disease. In addition to the traditional cardiovascular risk factors, autonomic nervous system (ANS), low grade of inflammation, platelet and hypothalamic-pituitary-adrenal axis function and genetic factors may adversely impact the endothelium of the arterial wall. We provide an overview of the pathophysiological mechanisms and indices which seem to have a role in promoting and accelerating atherosclerosis and its complications due to plaque rupture and thrombosis. Given that the relationship between depression and atherosclerosis cannot be fully explained by single mechanisms, which seem at least partially interrelated, the depression-related dysfunctions in the ANS and hypothalamic-pituitary-adrenal axis seem to play a major role, promoting chronic inflammation, endothelial dysfunction and platelet activation and aggregation, which in turn are key steps in the development of atherosclerosis and its complications.

The aim of this study was to analyze the very early (first 24 hours) effect of successful or failed thrombolytic therapy on the autonomic nervous system. Thirty consecutive patients with a first acute myocardial infarction were enrolled in the study, and admitted to the Coronary Care Unit within 6 hours of the onset of symptoms and treated with systemic thrombolytic therapy. All patients underwent 24-hour Holter monitoring in order to analyze ST segment variation. The autonomic nervous system was evaluated by frequency-domain heart rate variability: low frequency/high frequency ratio (LF/HF) was measured at the beginning of Holter monitoring (T1), 15 min after reperfusion or 1 hour from the start of thrombolytic therapy (T2) and after 24 hours (T3). Reperfusion status was assessed by aor = 50% reduction in ST segment elevation within 90 min of thrombolytic therapy, and early CK-MB peak. Early coronary reocclusion was detected by early reduction in ST segment elevation followed by stable ST segment re-elevation. Twenty patients (66%) showed successful thrombolytic therapy (Group 1), 5 patients (17%) had no evidence of successful thrombolytic therapy (Group 2) and 5 patients (17%) showed an early reocclusion (Group 3). LF/HF ratio values at T1 were similar in the three groups (5.66 +/- 1.7 vs 5.65 +/- 1.2 vs 5.51 +/- 0.9, NS). At T2, LF/HF ratio was significantly higher in Group 1 and 3 than Group 2 patients (9.21 +/- 1.7 and 11.1 +/- 1.2 vs 5.58 +/- 1.4, respectively, p0.001). In Group 1 LF/HF ratio was significantly lower at T3 when compared with T1 and T2 (1.9 +/- 1 vs 5.66 +/- 1.7 and 9.21 +/- 1.7, respectively, p0.001). Conversely, in Group 3 LF/HF ratio at T3 was similar to values measured at T1 (5.59 +/- 1.7 vs 5.51 +/- 0.9, respectively, NS) and significantly higher than those detected in Group 1. In Group 2, LF/HF ratio resulted substantially unchanged at T3 (5.49 +/- 1.7, NS). In conclusion, 1) successful thrombolytic therapy induces early beneficial effects on the autonomic nervous system function, as shown by increased heart rate variability values, when compared with failed thrombolytic therapy; 2) however, during the early period following coronary reperfusion, a transient but dramatic increase in sympathetic activity is observed. This could trigger coronary flow instability, thus facilitating reocclusion, by activating different pathogenetic mechanisms (increased vascular tone, platelet activation, thrombogenic factor prevalence); 3) early coronary vessel reocclusion precludes favorable effects of reperfusion on sympatho-vagal balance observed after the first 24 hours.

We analyzed 81 cases of primary breast carcinoma and 7 cases of fibroadenoma for microsatellite instability at eight loci. Twenty-seven cases (33.3%) manifested aberrant microsatellite alleles: 7 (8.6%) at one locus and 20 (24.7%) at two or more loci [tumors with replication error-positive (RER+) phenotype]. No evidence of microsatellite instability was observed in fibroadenomas. We investigated correlations between RER+ phenotype and clinicopathological characteristics of the carcinomas. The RER+ phenotype was statistically associated with large tumor diameter; of 19 RER+ tumors with measured size, 16 were2 cm, compared to 28 of 58 tumors with no evidence of microsatellite instability or with shifts in allele sizes limited to one locus (P/= 0.005, chi2 test). Consistently, there was also a strong statistical association between RER+ phenotype and lymph node metastasis; 14 of 19 RER+ tumors with known lymph node status were N+, compared to 15 of 59 tumors with no evidence of microsatellite instability or with allele shifts limited to one locus (P/= 0.0002, chi2 test). Correlations with age of patients, proliferative activity, histotype (ductal versus lobular), and grade of differentiation were not statistically significant, although the RER+ phenotype was more frequent in lobular and high-grade ductal carcinomas, in carcinomas with high proliferative activity, and in carcinomas from patients/=50 years. Data concerning cancer(s) in first and/or second degree relatives were available for 66 cases, including 33 positive and 33 negative for family history of cancer. No correlations were detected between RER+ phenotype and family history of cancer. In conclusion, our results indicate that in breast cancer, microsatellite instability is associated with clinicopathological parameters that are considered predictors of recurrent disease and aggressive behavior.

Cardiac metastases are uncommon but seem to be increasing in incidence, possibly in relation to prolonged survival of cancer patients. Leiomyosarcoma metastatic to the heart is extremely rare. We report the case of a 57-year-old woman previously treated for uterine leiomyosarcoma who presented with dyspnea, electrocardiographic changes mimicking myocardial infarction, and normal enzymes. A left intraventricular mass, suspected as cardiac metastasis, was revealed by echocardiography. The patient died 1 week later. At autopsy the mass proved to be histologically a metastasis of the uterine tumor.

Background— The prognosis for women with chest pain and angiographically normal coronary arteries is believed to be totally benign. Previous studies, however, did not account for the delay of a decade or so in the development of coronary artery disease that women may experience. Methods and Results— This study assessed long-term follow-up of 42 women with de novo angina, evidence of reversible myocardial perfusion defects on SPECT, and normal coronary angiograms. At recruitment, all women underwent endothelial function testing (intracoronary acetylcholine) during catheterization. Patients were followed up for >10 years. Angiography was repeated at the end of the follow-up in 37 patients. At recruitment, 22 patients developed diffuse vasoconstriction during acetylcholine in the absence of identifiable focal coronary spasm (acetylcholine-positive group). The remaining 20 patients showed vasodilation (acetylcholine-negative group). At the end of follow-up, in the acetylcholine-positive group, 1 patient developed cardiac death, 13 still complained of chest pain, and 8 had remission of symptoms. In the acetylcholine-negative group, all patients showed complete resolution of chest pain beginning 6 to 36 months after baseline assessment. Angiography showed development of coronary artery disease in the 13 symptomatic patients in the acetylcholine-positive group. Conclusions— In women with angiographically normal-appearing coronary arteries, persistence of chest pain over the years often relates to development of coronary artery disease. Endothelial dysfunction in a setting of normal coronary arteries is a sign of future development of atherosclerosis.

AIMS: To investigate gender difference in mortality among patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous angioplasty (PPCI). METHODS: We analyzed data from the prospective registries of two hub PPCI centres over a 10-year period to assess the role of female gender as an independent predictor of both all-cause and cardiac death at 30 days and 1 year. To account for all confounding variables, a propensity score (PS)-adjusted multivariable Cox regression model and a PS-matched comparison between the male and female were used. RESULTS: Among 4370 consecutive STEMI patients treated with PPCI at participating centres, 1188 (27.2%) were women. The survival rate at 30 days and 1 year were significantly lower in women (Log-rank P-value

Background Deep inferior epigastric perforator (DIEP) flap reconstruction is the gold standard reconstructive technique for women undergoing breast cancer surgery. A preoperative computed tomography angiography (CTA)-dedicated protocol and 3D reconstructions are mandatory for correct surgical planning. Purpose To evaluate the diagnostic performance of a new preoperative CTA protocol and a new reconstruction method in the assessment of DIEP technique. Material and Methods A total of 263 women (median age 49 years, age range 26–73 years) underwent preoperative CTA examination before DIEP flap breast reconstruction. A CTA-dedicated protocol followed by 3D-reconstructions were performed. Identification, branching pattern, and caliber at origin were assessed for each perforator. Intraoperative findings were the standard of reference. The sensitivity, positive predictive value, and diagnostic accuracy of the preoperative CTA protocol were calculated. Results In 255/263 (97%) patients, the dominant perforators assessed by CTA resulted adequate for surgical reconstruction. In 260/263 (99%) cases, the imaging localization of the dominant perforators corresponded with those seen intraoperatively (mean errors ≤1 cm). The preoperative CTA imaging sensitivity, positive predictive value, and diagnostic accuracy in determining the localization of perforators were 99% (95% CI 98–100), 100% and 99% (95% CI 98–100), respectively. No statistically significant differences were found between the CTA findings and the surgical findings for the assessment of branching pattern and caliber of the dominant perforators ( P Conclusion The present protocol has demonstrated high accuracy in the CTA imaging assessment of the perforators before DIEP flap reconstruction with high reproducibility between CT and surgical findings.

BackgroundThe prognostic role of hyperglycemia in patients with myocardial infarction and obstructive coronary arteries (MIOCA) is acknowledged, while data on non-obstructive coronary arteries (MINOCA) are still lacking. Recently, we demonstrated that admission stress-hyperglycemia (aHGL) was associated with a larger infarct size and inflammatory response in MIOCA, while no differences were observed in MINOCA. We aim to investigate the impact of aHGL on short and long-term outcomes in MIOCA and MINOCA patients.MethodsMulticenter, population-based, cohort study of the prospective registry, designed to evaluate the prognostic information of patients admitted with acute myocardial infarction to S. Orsola-Malpighi and Maggiore Hospitals of Bologna metropolitan area. Among 2704 patients enrolled from 2016 to 2020, 2431 patients were classified according to the presence of aHGL (defined as admission glucose level ≥ 140 mg/dL) and AMI phenotype (MIOCA/MINOCA): no-aHGL (n = 1321), aHGL (n = 877) in MIOCA and no-aHGL (n = 195), aHGL (n = 38) in MINOCA. Short-term outcomes included in-hospital death and arrhythmias. Long-term outcomes were all-cause and cardiovascular mortality.ResultsaHGL was associated with a higher in-hospital arrhythmic burden in MINOCA and MIOCA, with increased in-hospital mortality only in MIOCA. After adjusting for age, gender, hypertension, Killip class and AMI phenotypes, aHGL predicted higher in-hospital mortality in non-diabetic (HR = 4.2; 95% CI 1.9–9.5, p = 0.001) and diabetic patients (HR = 3.5, 95% CI 1.5–8.2, p = 0.003). During long-term follow-up, aHGL was associated with 2-fold increased mortality in MIOCA and a 4-fold increase in MINOCA (p = 0.032 and p = 0.016). Kaplan Meier 3-year survival of non-hyperglycemic patients was greater than in aHGL patients for both groups. No differences in survival were found between hyperglycemic MIOCA and MINOCA patients. After adjusting for age, gender, hypertension, smoking, LVEF, STEMI/NSTEMI and AMI phenotypes (MIOCA/MINOCA), aHGL predicted higher long-term mortality.ConclusionsaHGL was identified as a strong predictor of adverse short- and long-term outcomes in both MIOCA and MINOCA, regardless of diabetes. aHGL should be considered a high-risk prognostic marker in all AMI patients, independently of the underlying coronary anatomy.Trial registrationdata were part of the ongoing observational study AMIPE: Acute Myocardial Infarction, Prognostic and Therapeutic Evaluation. ClinicalTrials.gov Identifier: NCT03883711.

Background Hyperglycemia has been associated with increased inflammatory indexes and larger infarct sizes in patients with obstructive acute myocardial infarction (obs-AMI). In contrast, no studies have explored these correlations in non-obstructive acute myocardial infarction (MINOCA). We investigated the relationship between hyperglycemia, inflammation and infarct size in a cohort of AMI patients that included MINOCA. Methods Patients with AMI undergoing coronary angiography between 2016 and 2020 were enrolled. The following inflammatory markers were evaluated: C-reactive protein, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and neutrophil-to-platelet ratio (NPR). Myocardial infarct size was measured by peak high sensitivity troponin I (Hs-TnI) levels, left-ventricular-end-diastolic-volume (LVEDV) and left ventricular ejection fraction (LVEF). Results The final study population consisted of 2450 patients with obs-AMI and 239 with MINOCA. Hyperglycemia was more prevalent among obs-AMI cases. In all hyperglycemic patients—obs-AMI and MINOCA—NLR, NPR, and LPR were markedly altered. Hyperglycemic obs-AMI subjects exhibited a higher Hs-TnI (p Conclusions Our data confirm the association of hyperglycemic obs-AMI with elevated inflammatory markers and larger infarct sizes. MINOCA patients exhibited modest myocardial damage, regardless of admission glucose levels.

PurposeFamilial partial lipodystrophy type 2 (FPLD2) patients generally develop a wide variety of severe metabolic complications. However, they are not usually affected by primary cardiomyopathy and conduction system disturbances, although a few cases of FPLD2 and cardiomyopathy have been reported in the literature. These were all due to amino-terminal heterozygous lamin A/C mutations, which are considered as new forms of overlapping syndromes.Methods and ResultsHere we report the identification of a female patient with FPLD2 due to a heterozygous missense variant c.604G>A in the exon 3 of the LMNA gene, leading to amino acid substitution (p.Glu202Lys) in the central alpha-helical rod domain of lamin A/C with a high propensity to form coiled-coil dimers. The patient’s cardiac evaluations that followed the genetic diagnosis revealed cardiac rhythm disturbances which were promptly treated pharmacologically.ConclusionsThis report supports the idea that there are “atypical forms” of FPLD2 with cardiomyopathy, especially when a pathogenic variant affects the lamin A/C head or alpha-helical rod domain. It also highlights how increased understanding of the genotype-phenotype correlation could help clinicians to schedule personalized monitoring of the lipodystrophic patient, in order to prevent uncommon but possible devastating manifestations, including arrhythmias and sudden death.

Background Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. Methods and findings We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers’ median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02–1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02–1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07–2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35–1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52–2.34] instead of OR 2.20 [95% CI 2.02–2.42] when reducing from 5–9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39–3.25] and OR 1.93 [95% CI 1.46–2.57] instead of OR 2.95 [95% CI 2.75–3.15] when reducing from ≥10 to 5–9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16–1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. Conclusions We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy., Elise Philips and co-workers investigate parental smoking and associated birth and child outcomes., Author summary Why was this study done? Maternal smoking during pregnancy is an important risk factor for various birth complications and childhood overweight. It is not clear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy. The associations of paternal smoking with birth and childhood outcomes also remain unknown. What did the researchers do and find? We conducted an individual participant data meta-analysis using data from 229,158 families from 28 pregnancy and birth cohorts from Europe and North America to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. We observed that smoking in the first trimester only did not increase the risk of preterm birth and small size for gestational age but was associated with a higher risk of childhood overweight, as compared to nonsmoking. Reducing the number of cigarettes during pregnancy, without quitting, was still associated with higher risks of these adverse outcomes. Paternal smoking seems to be associated, independently of maternal smoking, with the risks of childhood overweight. What do these findings mean? Population strategies should focus on parental smoking prevention before or at the start of, rather than during, pregnancy. Future studies are needed to assess the specific associations of smoking in the preconception and childhood periods with offspring outcomes.

Background This case represents the first report of malignant primary cardiac tumour in a patient with Lynch Syndrome associated with MSH2 pathogenic variant. Case presentation A 57-year-old woman with previous ovarian cystadenocarcinoma was admitted to the emergency room for hematic pericardial effusion. Multimodal diagnostic imaging revealed two solid pericardial vascularized masses. After pericardiectomy, the final histological diagnosis was poorly differentiated pleomorphic sarcomatoid carcinoma. During follow-up she developed an ampulla of Vater adenocarcinoma. Genetic analysis identified an MSH2 pathogenic variant. Conclusion This case contributes to expand the tumour spectrum of Lynch syndrome, suggesting that MSH2 pathogenic variants cause a more complex multi-tumour cancer syndrome than the classic Lynch Syndrome. In MSH2 variant carriers, symptoms such as dyspnoea and chest discomfort might alert for rare tumours and a focused cardiac evaluation should be considered.

Background: Although guidelines do not recommend computerised tomography (CT), positron emission tomography (PET) or magnetic resonance imaging (MRI) for the staging or follow-up of asymptomatic patients with non-metastatic breast cancer, they are often requested in routine clinical practice. The aim of this study was to determine the staging and follow-up patterns, and relative costs in a large population of breast cancer patients living and treated in a Southern Italian region. Methods: We analysed the clinical computerised information recorded by 567 primary-care physicians assisting about 650 000 inhabitants in the Campania region. Patients with non-metastatic breast cancer were identified and divided into calendar years from 2001 to 2010. The number of diagnostic tests prescribed per 100 patients (N/Pts) and the mean cost per patient was determined 3 months before diagnosis and up to 1 year after diagnosis. Costs are expressed in constant 2011 euros. Results: We identified 4680 newly diagnosed cases of asymptomatic non-metastatic breast cancer. N/Pts increased significantly (P

Objective The origin and mechanisms of focal and macro-re-entrant atrial tachycardia occurring after ablation of paroxysmal or persistent atrial fibrillation are difficult to determine and are often the cause of distress for both patients and electrophysiologists. The purpose of this study was to describe a novel practical approach which would be helpful in planning the treatment of atrial tachycardia in patients who had received prior atrial fibrillation ablation. We used an algorithm which aims to facilitate mapping and ablation strategies, using both conventional electrophysiological tools and a three-dimensional electroanatomic approach. Methods We investigated a series of 40 patients with atrial tachycardia who had undergone a prior ablation procedure for paroxysmal or persistent atrial fibrillation with a step-wise approach. This approach consisted of four steps: the use of a decapolar catheter to assess the coronary sinus and an entrainment map to evaluate the cavotricuspid isthmus (CTI). If the CTI was not involved, we used a 20-pole dual-loop circular mapping catheter, AFocusII DL, to map the left atrium chamber rapidly during the rhythm of interest. We identified the target entrainment at the putative channels and performed catheter ablation at the critical isthmus of these macrocircuits until the restoration of sinus rhythm. Results Seventy-five atrial tachycardias were identified in 40 consecutive patients (1.9 +/- 1.6 per patient). In 48, the mechanism was macro-re-entry, and the remaining 27 were focal. During 18 months of follow-up, the treated arrhythmia recurred in only three patients, whereas in another four patients, a different atrial tachycardia was observed. The remaining 33 patients maintained sinus rhythm. Conclusion The increased acquisition speed by AFocusII DL facilitated the reconstruction of the geometric chamber, and the generation of an isochronal activation map reduced processing time and fluoroscopy time per patient, together with the radiation exposure and patient radiation dose. A novel algorithm combining both conventional electrophysiology and a three-dimensional electroanatomic approach for rapid diagnosis, accurate mapping and ablation of iatrogenic atrial tachycardias showed high reproducibility and a satisfactory overall success rate.

Maternal smoking during pregnancy increases childhood asthma risk, but health effects in children of nonsmoking mothers passively exposed to tobacco smoke during pregnancy are unclear. We examined the association of maternal passive smoking during pregnancy and wheeze in children aged ≤2 years.Individual data of 27 993 mother–child pairs from 15 European birth cohorts were combined in pooled analyses taking into consideration potential confounders.Children with maternal exposure to passive smoking during pregnancy and no other smoking exposure were more likely to develop wheeze up to the age of 2 years (OR 1.11, 95% CI 1.03–1.20) compared with unexposed children. Risk of wheeze was further increased by children's postnatal passive smoke exposure in addition to their mothers' passive exposure during pregnancy (OR 1.29, 95% CI 1.19–1.40) and highest in children with both sources of passive exposure and mothers who smoked actively during pregnancy (OR 1.73, 95% CI 1.59–1.88). Risk of wheeze associated with tobacco smoke exposure was higher in children with an allergic versus nonallergic family history.Maternal passive smoking exposure during pregnancy is an independent risk factor for wheeze in children up to the age of 2 years. Pregnant females should avoid active and passive exposure to tobacco smoke for the benefit of their children's health.

Objective Nonalcoholic fatty liver disease is very frequent in both type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MS), which share clinical and metabolic characteristics. Whether and to which extent these characteristics can predict the degree of liver steatosis are not entirely clear. Patients and methods We determined liver fat (divided into four classes) by standard sonographic images, and clinical and biochemical variables, in 60 consecutive patients with T2DM and with features of the MS. We examined both simple and multiple correlations between the degree of liver steatosis and the variables measured. Results Increased liver fat (defined as >5% of liver mass) was detected in 88% of the participants. Using simple regression analysis, the class of steatosis correlated positively with BMI, waist, number of factors of the MS, sex (female > male), diastolic blood pressure, insulin resistance, metabolic control, inflammation, C-reactive protein, fibrinogen, and leptin, whereas it correlated negatively with high-density lipoprotein-cholesterol. Using multiple regression analysis, only metabolic control, insulin resistance and/or plasma insulin, and waist, remained correlated significantly with the degree of steatosis. Using an ordered probit statistical model, metabolic control, waist, and insulin concentration predicted the steatosis class in 58% of the cases (¡Ü97% with allowance for one class in either excess or deficit). Conclusion In patients with T2DM, the extent of liver steatosis is correlated with variables associated with metabolic control and features of the MS. The combination of metabolic control, visceral obesity, and insulin resistance may reasonably predict the degree of liver steatosis in T2DM. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Background: Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results. Objectives: We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years). Methods: First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age < 37 weeks) and low birth weight (< 2500 g) with childhood asthma outcomes. Results: Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P, Supported by the European Community's Seventh Framework Programme FP7/20072013, project CHICOS. The research leading to these results has received funding from the European Respiratory Society and the European Community's Seventh Framework Programme FP7/2007-2013-Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571.

OBJECTIVE: Glucocorticoid excess is widely recognized as one of the most important causes of bone loss. The mechanism of glucocorticoid-induced osteoporosis is presumably multifactorial, and consists of the loss of organic and non-organic compounds. Efforts have been made to develop simple physical methods for the assessment of bone tissue for the screening of subjects at high risk of osteoporosis, without the use of radioactive sources or ionizing radiation. Quantitative ultrasonometry (QUS) has been suggested as a useful method for monitoring patients undergoing glucocorticoid therapy, which is the most common cause of glucocorticoid excess. QUS appears to detect more structural bone changes than the traditional methods and allows assessment of bone density and elasticity, both characteristics influenced by organic and non-organic bone compounds. However, the use of QUS has not yet been extensively investigated in subjects with endogenous cortisol excess. The aim of this study was to evaluate the usefulness and predictive power of QUS in assessing bone loss in subjects with differing degrees of endogenous cortisol excess due to adrenal mass. DESIGN: Thirty-four patients (20 women and 14 men) aged between 21 and 59 years were evaluated; fifteen (9 women and 6 men; median age, 42 years) were affected by overt Cushing's syndrome (CS) and nineteen (11 women and 8 men; median age, 44 years) by subclinical CS, defined as lacking clinical signs of hormone excess despite the presence of at least two abnormalities in hypothalamic-pituitary-adrenal axis function, as assessed by routine endocrine tests. All women included were eumenorrhoic. METHODS: QUS measurement of amplitude-dependent speed of sound was performed on the 2nd to 5th proximal phalanges of the non-dominant hand using a DBM Sonic 1200R bone profiler (Igea S.r.l, Italy). The results were compared with bone density assessed on lumbar vertebrae (L1-L4) and femoral neck sites by dual-energy X-ray absorptiometry (DEXA). RESULTS: A strongly significant bone loss was detected by finger QUS measurement when the patients were considered either all together or as two subgroups (P

In vitro and in vivo studies demonstrated that nociceptin/orphanin FQ inhibits norepinephrine release, while the effects of norepinephrine on nociceptin/orphanin FQ release remain unknown. Previous studies in healthy and hypertensive subjects showed that prolonged and forced hyperventilation induces different blood pressure (BP) responses depending on changes in plasma catecholamine levels. We investigated whether the effects of hyperventilation on the sympatho-adrenergic system involve nociceptin/orphanin FQ release. Fifty-six healthy subjects (26 females, mean age 63 2 and 30 males, mean age 63 3) underwent the hyperventilation test. A hierarchical cluster analysis based on BP response to hyperventilation identified three groups of subjects: group 1 (n = 20) with a decrease in BP, norepinephrine (1311.1 45.5 fmol/ ml versus 900.0 55.3 fmol/ml, P < 0.01) and nociceptin/orphanin FQ (13.0 0.7 pg/ml versus 7.9 0.8 pg/ ml, P < 0.01), group 2 (n = 18) without any change in BP and norepinephrine (1133.0 31.5 fmol/ml versus 1176.0 44.6 fmol/ml), with a decrease in nociceptin/orphanin FQ (12.5 3.2 pg/ml versus 7.4 0.6 pg/ml, P < 0.01) and group 3 (n = 18) with an increase in BP, norepinephrine (1216.7 50.9 fmol/ml versus 1666.7 44.9 fmol/ml, P < 0.01) and nociceptin/orphanin FQ values (11.5 1.6 pg/ml versus 19.9 1.5 pg/ ml,P < 0.01). Norepinephrine changes in response tohyperventilationingroups 1and3weredirectly (P < 0.01) correlated with those of nociceptin/orphanin FQ. Our results showed that vigorous and prolonged hyperventilation changes plasma nociceptin/orphanin FQ levels due to the direct effects of hypocapnic alkalosis or to different sympatho-adrenergic system responses.

OBJECTIVES: The diagnosis and control of hypertension depend on accurate measurement of blood pressure (BP). The literature on the accuracy of BP recording by health professionals is, however, limited, and no study directly interviewed patients in the hospital setting. This multicenter cross-sectional study aimed at evaluating the compliance to current recommendations on BP measurement by health professionals directly from patients and to investigate potential predictors of higher quality in BP recording. METHODS: A trained nurse interviewed a random sample of adult patients hospitalized for an ordinary admission (except in the emergency room) lasting more than one night, without mental disorder, who had their BP routinely measured by the hospital personnel less than 3 h before. The questionnaire contained 15 items on the main procedures that are common to current guidelines. RESULTS: Fourteen public hospitals from seven regions of Italy participated, and 1334 questionnaires were collected. Nine of the recommended practices were followed in the majority (>70%) of BP recordings, whereas some others were infrequent or rare: in 98.6, 82.2 and 81.1% of the participants, respectively, the arm circumference was never recorded, BP was measured only once, and BP was never recorded in both arms. Overall, 10 or more recommended procedures were followed during 33.4% recordings. At multivariate analysis, physicians were less likely than nurses to provide a more accurate BP measurement. CONCLUSIONS: The operator's compliance to some recommendations in BP measurement is unacceptably low. This survey provides detailed indications for medical directors on the procedures and settings to prioritize in educational programs, which are definitely needed.

no Abstract. Editorial

The occurrence of depression in patients with coronary heart disease (CHD) substantially increases the likelihood of a poorer cardiovascular prognosis. Although antidepressants are generally effective in decreasing depression, their use in patients with CHD is controversial. We carried out a meta-analysis to evaluate the health effects of selective serotonin reuptake inhibitors (SSRIs) versus placebo or no antidepressants in patients with CHD and depression. Observational studies and randomized controlled trials (RCTs) were searched in MEDLINE, EMBASE, PsycINFO, Cochrane Controlled Clinical Trial Register and other trial registries, and references of relevant articles. Primary outcomes were readmission for CHD (including myocardial infarction, unstable angina, and stroke) and all-cause mortality; the secondary outcome was severity of depression symptoms. Seven articles on 6 RCTs involving 2,461 participants were included. One study incorrectly randomized participants, and another was a reanalysis of RCT data. These were considered observational and analyzed separately. When only properly randomized trials were considered (n = 734 patients), patients on SSRIs showed no significant differences in mortality (risk ratio 0.39, 95% confidence interval 0.08 to 2.01) or CHD readmission rates (0.74, 0.44 to 1.23) compared to controls. Conversely, when all studies were included, SSRI use was associated with a significant decrease in CHD readmission (0.63, 0.46 to 0.86) and mortality rates (0.56, 0.35 to 0.88). A significantly greater improvement in depression symptoms was always apparent in patients on SSRIs with all selected indicators. In conclusion, in patients with CHD and depression, SSRI medication decreases depression symptoms and may improve CHD prognosis.

Background Although blood pressure (BP) differences from supine to sitting position have long been recognized, limited data are available on other commonly used body positions. We performed a cross-sectional study to compare BP values obtained in supine, sitting, and Fowler's positions in essential hypertensive subjects. Methods Systolic BP (SBP) and diastolic BP (DBP) were recorded using an automatic oscillometric device. Nine measurements were taken: three measurements, in random order, in supine, Fowler's, and sitting position. Two generalized estimating equations models were used to evaluate potential predictors of SBP and DBP adjusting for heart rate and measurement order. Results The sample consisted of 250 subjects (mean age 66.3 ± 13.4 years; 44.4% males). Measured in supine, Fowler's, and sitting position, mean SBPs were 139.3 ± 14.0; 138.1 ± 13.8; 137.2 ± 13.7 mm Hg, respectively, and mean DBPs 80.1 ± 9.1; 81.9 ± 9.4; 83.0 ± 9.6 mm Hg, respectively. At multivariate analysis, mean SBP significantly decreased if measured in Fowler's and sitting positions, as compared to supine. In contrast, DBP significantly increased. A relevant proportion of subjects showed large differences (≤ or ≥10 mm Hg) in mean SBP across positions: i.e., 30.0% comparing supine vs. sitting SBP. An even higher prevalence of large differences was observed according to the measurement order within the same positions, with no univocal direction (random variation). Conclusions Fowler's position may represent a valid alternative to sitting and supine positions for BP measurement in clinical practice. BP random variability was found to be large regardless of body position, reinforcing the need for operators to closely follow current guidelines that recommend ≥2 recordings at each measurement.

The aim of our study was to evaluate the effects of repeated episodes of angina and induced myocardial ischemia on plasma nociceptin/orphanin FQ (N/OFQ) levels. Patients with unstable angina (23 with new onset severe angina or accelerated angina and 18 with subacute angina at rest) who had had repeated spontaneous episodes of chest pain in the last week before the study underwent myocardial perfusion single-photon emission computed tomography using adenosine infusion. Twenty subjects without clinical symptoms of angina matched for age, sex and cardiac risk factors served as a control group. N/OFQ levels were significantly (P

Objective Patients undergoing radiologic and nuclear medicine examination often receive little, if any, information related to the radiologic dose and consequent potential long-term cancer risk. This "economical with the truth" communication may violate basic patients' rights. We assessed the information perceived by patients on the radiation dose exposure during nuclear medicine examinations. Methods We recruited 109 consecutive patients (66 male; aged 66 ± 10 years) who were referred to the Nuclear Medicine laboratory of Sant'Orsola–Malpighi Hospital (Bologna University, Bologna, Italy) for a cardiac rest-stress technetium-99m sestamibi scan. This scan gives an effective dose of approximately 10 mSv, corresponding to a dose equivalent of 500 chest x-rays (European Commission Medical Imaging Guidelines 2001) and an estimated extra lifetime attributable risk of 1 cancer in 1,000 exposed subjects (Biological Effects of Ionizing Radiation VII Committee 2005). Results Radiation dose exposure was correctly identified by 21% of patients, with the remaining 79% underestimating the exposure by at least 500 times, considered to be zero by 11%, one-half of a chest x-ray by 23%, 1 chest x-ray by 35%, and "don't know" by 10%. The long-term cancer risk was correctly estimated by 27% of patients, with the remaining substantially underestimating the risk, considered to be "zero" by 30%, 1 in 1 million by 19%, 1 in 100,000 by 9%, and "don't know" by 10%. Conclusion Patients undergoing common cardiac stress scintigraphy examinations involving significant radiation exposure have little or no awareness about nuclear medicine dose (and corresponding risk). This ineffective communication poses significant ethical concerns and possible vulnerability to legal suits against practitioners and prescribers, especially in case of inappropriate examinations.

Little is known about changes in myocardial perfusion of myocardial regions supplied by angiographically normal or near-normal coronary arteries after percutaneous coronary intervention (PCI) of the target lesion. The purpose of this study was to assess the effect of PCI on coronary blood flow at rest in sites remote from the PCI. We studied 85 patients who underwent successful elective PCI for stable angina. We used the Thrombolysis In Myocardial Infarction frame count to provide a simple continuous index of coronary flow and myocardial perfusion in the target and nontarget arteries. Coronary artery diameters of nontarget vessels did not significantly differ before and after PCI and at 6 months' follow-up. At baseline, the greater the percent diameter stenosis in the target artery, the slower the flow in the target (r = 0.22, p

The expansion of triplet repeat microsatellite sequences is the molecular correlate of anticipation in a number of rare Mendelian neurodegenerative disorders. This finding prompted us to study these sequences in primary breast cancer in which there is evidence of genetic anticipation. We used a PCR/silver stain method to determine whether triplet-repeat instability (TRI) was present in DNA from malignant breast tumors, and analyzed microsatellite instability (MSI) in triplets SCA1, SCA2, SCA3, SCA6, HD, DRPLA and X25-GAA. We studied 54 consecutive primary breast cancers previously analyzed for dinucleotide instability (DI) at 9 loci. Microsatellite instability (TRI and/or DI) was found in 28/54 (52%) cases, ranging from 0 to 56% in each patient. Dinucleotide instability occurred at > or =2 loci in 19/54 (35%) cases and TRI in 6/54 (11%). Considering single locus instability, we found DI in 26/54 (48%) tumors and TRI in 13/54 (24%). Triplets DRPLA and X25-GAA were most frequently unstable (14% of cases); SCA2 instability was not detected. Interestingly, most tumors with TRI had DI (11/13, 85%). There was a correlation between TRI and DI in the same tumor (42 vs 7% in DI+ and DI- tumors respectively, p=0.0028). Furthermore, TRI appears more frequently associated with lymph node metastases and more advanced clinical stages and more frequent in patients

Background: Vagal fibres are distributed both in the perivascular connective tissue and in the adventitia around the circumference of arteries, and contribute to coronary artery dilation. The aim of the manuscript is to examine whether morphologic changes of the vessel wall due to the atherosclerotic process might be associated with autonomic nervous system dysfunction. Methods and results: We studied 42 patients with single vessel disease referred for percutaneous coronary revascularization. Patients underwent intravascular ultrasound at the site of the ischemia-related artery before intervention. The autonomic nervous system activity was assessed by the analysis of heart rate variability (HRV) in the frequency domain. The high frequencies (HF) are predominantly under the influence of the parasympathetic system, while the low/high frequency (LF/HF) ratio represents an index of sympatho-vagal balance. Plaque plus media cross-sectional area was inversely related to HF components (r = -0.34, p < 0.05), and directly related to LF/HF ratio (r = 0.38, p < 0.05). Patients with expansive remodeling showed lower HF values (0.07 ± 0.06 nu versus 0.14 ± 0.09 nu, p < 0.01) and higher LH/HF ratio (2.1 ± 1.1 versus 1.4 ± 1.1; p < 0.05). LF changes were independent of any morphologic features. On multivariate analyses the remodeling index was the only independent determinant of HF and LF/HF ratio. Conclusions: Outward stretch of the vessel wall behind the plaque, as a consequence of increasing plaque size and expansive arterial remodeling is associated to autonomic dysfunction namely due to impairment of the vagal tone. It is unknown if remodeling is a cause of vagal impairment or if vagal impairment may contribute to arterial remodeling

Aims Cardio-cardiac reflexes may be evoked by both myocardial ischaemia and coronary occlusion itself. The aim of the study was to assess the intrapatient behaviour of autonomic nervous system balance during spontaneous and balloon-induced coronary ischaemia. Methods and results We studied a group of patients admitted to the coronary care unit for acute coronary syndrome without ST-segment elevation who experienced spontaneous episodes of myocardial ischaemia during bed rest and ECG monitoring. The inclusion criterion was 80–90% lumen stenosis, amenable to angioplasty. Balloon coronary occlusion was performed at 4–6 atmospheres for 120 s. Autonomic nervous system activity was assessed by heart rate variability (HRV) analysis in frequency domain. We analysed 14 episodes of spontaneous ischaemia and 14 episodes of balloon coronary occlusion. During spontaneous ischaemia, HRV showed an increase in the low/high frequencies ratio (11.8±5.7), as compared to 5 min before and 5 min after (4.4±2.7 and 3.9±1.8, respectively) (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(p=0.001\) \end{document}). The opposite occurred during balloon coronary occlusion (0.8±0.4 vs. 3.9±2.0 and 5.1±2.1, respectively; \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(p=0.001\) \end{document}). Conclusions Balloon inflation and occlusion evokes baroreceptor vagal predominance in response to a stretch stimulus of the coronary artery. Conversely, spontaneous occlusion during unstable angina is accompanied by naturally occurring sympathetic activation. Sympathetic activation may have a role in the natural history of the disease.

Background— Morbidity of patients with Syndrome X (SX; chest pain and normal coronary angiograms) is high and is associated with continuing episodes of chest pain and hospitalization. Impairment of microvascular endothelial function caused by increased oxidative stress has been suggested to be a mechanism of the disease. Superoxide dismutase (SOD) is the major antioxidant enzyme system of the vascular wall. This study sought to establish whether combination treatment with ACE inhibitors and statins reduces oxidative stress and improves quality of life of patients with cardiac SX. Methods and Results— Forty-five patients with SX were randomly assigned to receive either a combination of ramipril (10 mg/d) and atorvastatin (40 mg/d) or placebo for 6 months. We determined the activity of extracellular SOD and its relation to flow-dependent endothelium-mediated dilation (FMD) and quality of life (exercise capacity and score with Seattle Angina Questionnaire [SAQ]) before and after treatment. After 6 months, patients with SX who received atorvastatin and ramipril had significantly reduced ( P =0.001) SOD levels (188.1±29.6 U/mL). No significant changes were seen on placebo (262.9±48.8 U/mL). Reduction of SOD after therapy was negatively correlated with FMD ( r =0.38; P =0.01) and positively with total cholesterol ( r =−0.56; P Conclusions— Six months of therapy with atorvastatin and ramipril improves endothelial function and quality of life of patients with SX. Reduced SOD activity may reflect low superoxide anion production. Benefits of these drugs may be related to reduction of oxidative stress.

We studied the effect of pravastatin on coronary perfusion after percutaneous, transluminal coronary angioplasty. An exercise test performed within 2 weeks after percutaneous transluminal coronary angioplasty induced reversible perfusion defects in 66% of patients taking pravastatin and 64% of those taking placebo. At follow-up, the exercise test still induced reversible perfusion defects in 3% of patients taking pravastatin and 29% of those taking placebo.

p53 and p185 expression in primary breast cancer with microsatellite instability (MSI) is still largely unexplored. To investigate the relationship between these oncoproteins and the pathways of genomic instability, we examined 52 primary invasive breast cancers stratified by the presence and absence of MSI. We determined the status of eight microsatellite loci using radioactive and silver staining methods, and evaluated the immunohistochemical expression of p53 and p185 in a consecutive series of Italian cancer patients characterized by clinical-pathological and biological parameters. Nineteen cases (36.5%) were MSI-positive in at least two loci. p53 was expressed in 15 cases (28.8%) and p185 in eight (15.4%). MSI-positive tumors were inversely correlated with p53 expression ( p = 0.0007); in addition, the percent of p53-expressing cells decreased as the number of MSI-positive loci increased. MSI-positive tumors were correlated with a larger tumor size ( p = 0.04), lymph-node metastasis ( p = 0.001), and advanced clinical stage ( p = 0.0006). These data demonstrate the existence of two subsets of primary breast cancers: one characterized by MSI, the other by p53 expression. MSI-positive patients had a more advanced and/or aggressive disease.

Background Diagnosis costs for cardiovascular disease waste a large amount of healthcare resources. The aim of the study is to evaluate the clinical and economic outcomes of alternative diagnostic strategies in low risk chest pain patients. Methods We evaluated direct and indirect downstream costs of 6 strategies: coronary angiography (CA) after positive troponin I or T (cTn-I or cTnT) (strategy 1); after positive exercise electrocardiography (ex-ECG) (strategy 2); after positive exercise echocardiography (ex-Echo) (strategy 3); after positive pharmacologic stress echocardiography (PhSE) (strategy 4); after positive myocardial exercise stress single-photon emission computed tomography with technetium Tc 99m sestamibi (ex-SPECT-Tc) (strategy 5) and direct CA (strategy 6). Results The predictive accuracy in correctly identifying the patients was 83,1% for cTn-I, 87% for cTn-T, 85,1% for ex-ECG, 93,4% for ex-Echo, 98,5% for PhSE, 89,4% for ex-SPECT-Tc and 18,7% for CA. The cost per patient correctly identified results $2.051 for cTn-I, $2.086 for cTn-T, $1.890 for ex-ECG, $803 for ex-Echo, $533 for PhSE, $1.521 for ex-SPECT-Tc ($1.634 including cost of extra risk of cancer) and $29.673 for CA ($29.999 including cost of extra risk of cancer). The average relative cost-effectiveness of cardiac imaging compared with the PhSE equal to 1 (as a cost comparator), the relative cost of ex-Echo is 1.5×, of a ex-SPECT-Tc is 3.1×, of a ex-ECG is 3.5×, of cTnI is ×3.8, of cTnT is ×3.9 and of a CA is 56.3×. Conclusion Stress echocardiography based strategies are cost-effective versus alternative imaging strategies and the risk and cost of radiation exposure is void.