Breast cancer is one of the most common malignancies of women in the reproductive years. In the Western world there is a trend towards delaying pregnancy to later in life, and in combination with an increased incidence of breast cancer an increased number of women are diagnosed with breast cancer before they have completed their reproductive plans. In addition, breast cancer during pregnancy may affect an increased number of women as the childbearing years are delayed. The survival rate after breast cancer has improved during the last decades, and many young breast cancer survivors will consider a pregnancy subsequent to the completion of adjuvant breast cancer therapy. Traditionally, many women are advised against a pregnancy due to a fear of increased risk of recurrence, especially women with estrogen receptor-positive breast cancer. Due to feasibility issues, evidence from large prospective randomized trials is missing regarding the safety of pregnancy after breast cancer. Today guidelines are based on cohort studies and population-based registry evidence with its limitations. Overall, data suggest that pregnancy after breast cancer therapy is safe, and the current evidence is summarized in this overview.
AIMS: galectin-3 is an emerging biomarker which has been studied in relatively small heart failure (HF) cohorts with predominantly systolic HF. We studied the prognostic value of base-line galectin-3 in a large HF cohort, with preserved and reduced left ventricular ejection fraction (LVEF), and compared this to other biomarkers.
METHODS: we studied 592 HF patients who had been hospitalized for HF and were followed for 18 months. The primary end-point was a composite of all-cause mortality and HF hospitalization.
RESULTS: a doubling of galectin-3 levels was associated with a hazard ratio (HR) of 1.97 (1.62-2.42) for the primary outcome (P < 0.001). After correction for age, gender, BNP, eGFR, and diabetes the HR was 1.38 (1.07-1.78; P = 0.015). Galectin-3 levels were correlated with higher IL-6 and CRP levels (P < 0.002). Changes of galectin-3 levels after 6 months did not add prognostic information to the base-line value (n = 291); however, combining plasma galectin-3 and BNP levels increased prognostic value over either biomarker alone (ROC analysis, P < 0.05). The predictive value of galectin-3 was stronger in patients with preserved LVEF (n = 114) compared to patients with reduced LVEF (P < 0.001).
CONCLUSIONS: galectin-3 is an independent marker for outcome in HF and appears to be particularly useful in HF patients with preserved LVEF.
Background/objective: Type 2 diabetes is a major risk factor for atherosclerotic disease. It is well agreed that the reactivity of diabetic platelets is increased but how platelet reactivity regulates is unknown. In our laboratory, density separated platelets have been investigated extensively and high- and low-density platelets circulate in an activated state. The density distribution of circulating platelets is altered in diabetes type 2 as well. We hypothesize that such platelets modify whole blood (WB) in vitro a-thrombin-evoked (10 mu M/mL) activity in type 2 diabetes. Thus, the study aims to identify features of circulating normal-sized density subpopulations affecting whole blood (WB) platelet reactivity in type 2 diabetes. Patients and methods: Patients with type 2 diabetes (n = 16) were enrolled. Their normal-sized platelets were divided into density subfractions (n = 16) using continuous polyvinylpyrrolidone-coated silica (Percoll (TM)) gradients (density span, 1.090-1.040 kg/L) containing prostaglandin E-1. The proportions (%) of such density-separated platelets expressing lysosomal-associated membrane protein 1 (LAMP-1) were analyzed using a flow cytometer. Further, determinations of WB alpha-thrombin-evoked (10 U/mL) surface LAMP-1 (an assessment of lysosomal release), the fibrinogen (a(IIb)beta(3)) receptor activity, annexin V (binds to exposed membrane phosphatidylserine), and mitochondrial transmembrane potentials (an estimate of organelle integrity) were performed. Surface LAMP-1 expressions of individual normal-sized platelet density subpopulations were stratified into equal-sized groups (n = 2) depending on reactivity, as judged from the alpha-thrombin-induced WB activity markers. Results: With some exceptions, the proportion of normal-sized circulating platelets showing spontaneous LAMP-1 was strongly associated with WB alpha-thrombin-evoked (10 U/mL) surface LAMP-1 and a(IIb)beta(3) receptor activity. LAMP-1-expressing normal-sized platelets also displayed inverse associations with WB alpha-thrombin-induced surface annexin V and mitochondrial damage, which are features of procoagulant platelets. Conclusions: From the current descriptive work only involving type 2 diabetes, it is impossible to judge whether the findings are features of the disease or if they occur in healthy individuals as well. However, the study describes LAMP-1 expressing subpopulations of circulating normal-sized platelets that associate with WB a-thrombin (10 U/mL) responses in vitro. Increased proportions of such platelets induced lysosomal release and a(IIb)beta(3) receptor activity, whereas lower proportions promoted WB agonist-induced procoagulant platelet creation. It is to hypothesize that the new described regulatory mechanism could in the future offer a possibility to influence platelet behavior in type 2 diabetes. KEY MESSAGES circle Lysosomal exocytosis of circulating platelets influences reactivity, as determined by agonistinduced platelet reactions in vitro circle Thus, the low release of lysosomes by normal-sized platelets in vivo increases agonist-evoked procoagulant platelet production. circle Higher lysosomal exocytosis of circulating normal-sized platelets promotes platelet aggregation and secretion.
Background. Few studies have looked into the ability of measurements of apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-1) or apoB/apoA-1 to predict new coronary heart disease (CHD) events in patients with CHD on statin treatment. Aims. In the IDEAL trial, to compare lipoprotein components to predict CHD events and to what degree differences in those parameters could explain the observed outcome. Methods. We compared the ability of treatment with atorvastatin 80 mg/day to that of simvastatin 20-40 mg/day to prevent CHD events in patients with CHD and used Cox regression models to study the relationships between on-treatment levels of lipoprotein components to subsequent major coronary events (MCE). Findings. Variables related to low-density lipoprotein cholesterol (LDL-C) carried more predictive information than those related to high-density lipoprotein cholesterol (HDL-C), but LDL-C was less predictive than both non-HDL-C and apoB. The ratio of apoB to apoA-1 was most strongly related to MCE. However, for estimating differences in relative risk reduction between the treatment groups, apoB and non-HDL-C were the strongest predictors. Interpretation. The on-treatment level of apoB/apoA-1 was the strongest predictor of MCE in the pooled patient population, whereas apoB and non-HDL-C were best able to explain the difference in outcome between treatment groups. Measurements of apoB and apoA-1 should be more widely available for routine clinical assessments. © 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS).
BACKGROUND: Inflammation may play an important role in type 2 diabetes. It has been proposed that dietary strategies can modulate inflammatory activity.
METHODS: We investigated the effects of diet on inflammation in type 2 diabetes by comparing a traditional low-fat diet (LFD) with a low-carbohydrate diet (LCD). Patients with type 2 diabetes were randomized to follow either LFD aiming for 55-60 energy per cent (E%) from carbohydrates (n = 30) or LCD aiming for 20 E% from carbohydrates (n = 29). Plasma was collected at baseline and after 6 months. C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), IL-6, tumour necrosis factor receptor (TNFR) 1 and TNFR2 were determined.
RESULTS: Both LFD and LCD led to similar reductions in body weight, while beneficial effects on glycaemic control were observed in the LCD group only. After 6 months, the levels of IL-1Ra and IL-6 were significantly lower in the LCD group than in the LFD group, 978 (664-1385) versus 1216 (974-1822) pg/mL and 2.15 (1.65-4.27) versus 3.39 (2.25-4.79) pg/mL, both P < 0.05.
CONCLUSIONS: To conclude, advice to follow LCD or LFD had similar effects on weight reduction while effects on inflammation differed. Only LCD was found significantly to improve the subclinical inflammatory state in type 2 diabetes.
Objective: Mechanisms behind sustained inflammation in patients with coronary artery disease (CAD) are not clarified but hypothalamus-pituitary-adrenal (HPA) axis dysfunction may have a role. Here, we investigated whether inflammatory status of peripheral blood mononuclear cells (PBMCs) was associated with altered glucocorticoid sensitivity in CAD patients. Methods: In 55 CAD patients and 30 controls, mRNA levels of GR-alpha, GR-beta, NF-kappa B, I kappa B alpha, MMP-9 and TIMP-1 were measured in PBMCs. Suppressive effects of dexamethasone on GR-alpha, GR-beta, NF-kappa B, I kappa B alpha, MMP-9 and TIMP-1 mRNA levels were assessed in PBMCs ex vivo. Salivary cortisol was repeatedly measured over 3 days. Results: GR-alpha mRNA levels were higher in CAD patients than in controls, 0.50 (0.38-0.59) versus 0.26 (0.18-0.37), pamp;lt;.001, while GR-beta mRNA levels were equally low in both groups. GR-alpha mRNA expression was associated with inflammatory gene expression and, also, with flatter diurnal cortisol rhythm. In both patients and controls, dexamethasone suppressed gene expression of NF-B, IB, MMP-9 and TIMP-1 (p amp;lt; .001). Dexamethasone also reduced GR-alpha mRNA levels (p amp;lt; .001), while LPS increased it (p amp;lt; .001). Conclusions: PBMCs from CAD patients displayed an inflammatory gene expression profile. This was not explained by reduced glucocorticoid sensitivity. Instead, inflammation was associated with increased expression of GR-alpha mRNA, suggesting a hypocortisolemic state.
Background : There have been no human prospective randomized studies of the amount of alcohol that can induce hepatic steatosis. less thanbrgreater than less thanbrgreater thanMethods : Thirty-two healthy women and twelve healthy men (34 +/- 9 years of age) were randomized to consume 150 ml of red wine/day for women (16 g ethanol/day) or double that amount for men (33 g ethanol/day), or to alcohol abstention for 90 days. Participants underwent proton-nuclear magnetic-resonance spectroscopy for measurement of hepatic triglyceride content (HTGC). Blood samples for assessment of cardiovascular risk were drawn before and after the intervention. less thanbrgreater than less thanbrgreater thanResults: After exclusion of three subjects with steatosis at baseline a trend towards increased HTGC was apparent for red wine (before median: 1.1%, range 0.2-3.9%, after median: 1.1%, range 0.5-5.2%, P = 0.059) a difference that was statistically significant compared with abstainers (p = 0.02). However, no subject developed hepatic steatosis. Low-density lipoprotein (LDL)-cholesterol was lowered by red wine (-0.3 mmol/l, SE-0.1, 95% CI-0.6 to -0.04). less thanbrgreater than less thanbrgreater thanConclusions: Moderate consumption of red wine during three months increased HTGC in subjects without steatosis at baseline. However, since not a single participant developed steatosis we suggest that the threshold of alcohol consumption to define nonalcoholic fatty liver disease should not be lower than the amount in our study.
Statins may act rapidly to reverse abnormalities of the arterial wall that may predispose to recurrent ischemic events after acute coronary syndromes. Such abnormalities are endothelial dysfunction, a local inflammatory response, and an exaggerated thrombogenic tendency. In one study almost 20 000 patients with first myocardial infarction were studied with regard to statin treatment (28%) or not. Baseline characteristics were adjusted using multivariate regression analysis including propensity analysis. One year mortality was 3.7/5.0% in statin/not statin groups, respectively, P = 0.001, relative risk 0.75. In another study of more than 20 000 patients, 18% were prescribed statin after an acute coronary syndrome and followed for six months. Propensity analysis was performed in this study as well. Deaths in statin/not statin groups were 1.7/3.5%, P < 0.0001, relative risk 0.48. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL), a double-blind randomized, placebo-controlled intervention study, 3086 patient with acute non-Q-wave coronary syndromes were allocated immediately in hospital to receive atorvastatin 80 mg daily or placebo for four months. No lower limit for plasma LDL cholesterol was used. Primary endpoint was time to first occurrence of death, non-fatal myocardial infarction, cardiac arrest, and worsening angina with objective evidence of ischemia. This was significantly reduced compared to the placebo group by 2.4% (14.8 versus 17.2%, relative risk 0.84, P = 0.048). Atorvastatin also reduced significantly fatal or non-fatal strokes. Possible mechanisms behind these acute beneficial effects are discussed. The studies highlight the importance of treatment with a statin in the early management of acute coronary syndromes and the need to incorporate this therapeutic strategy in national guidelines and treatment recommendations.
BACKGROUND: Telomeres are causally involved in senescence. Senescence is a potential factor in the pathogenesis and progression of heart failure. In heart failure telomeres are shorter, but the prognostic value associated with telomere length has not been defined. METHODS: Telomere length was prospectively determined by quantitative polymerase chain reaction in 890 patients with New York Heart Association (NYHA) functional class II to IV heart failure. After 18 months, we examined the association between telomere length and the predefined primary end-point: time to death or hospitalization for heart failure. RESULTS: Mean age of the patients was 71 years, 39% were women, 51% were in NYHA class II, and 49% were in class III/IV. A total of 344 patients reached the primary end-point (130 deaths and 214 hospitalizations). Patients with shorter telomeres were at an increased risk of reaching the primary end-point (hazard ratio 1.79; 95% confidence interval (CI) 1.21-2.63). In multivariate analysis shorter telomere length remained associated with a higher risk for death or hospitalization (hazard ratio, 1.74; 95% CI 1.07-2.95) after adjustment for age of heart failure onset, gender, hemoglobin, renal function, and N-terminal pro-B-type natriuretic peptide level, a history of stroke, atrial fibrillation, and diabetes. CONCLUSIONS: Shorter length of telomeres predicts the occurrence of death or hospitalization in patients with chronic heart failure.
Introduction: Life after stroke is a comprehensive area that involves engagement in meaningful everyday activities, including work, and can be adversely affected by post-stroke fatigue. This study investigates post-stroke fatigue, its development over time, and its impact on return to work and other everyday life activities. In addition, we investigated whether post-stroke fatigue could predict functioning in everyday life activities one year after stroke.Material and methods: This prospective registry-based study includes 2850 working age (18 - 63 years) patients registered in the Swedish Stroke Register (Riksstroke) during year 2017 and 2018. Post-stroke fatigue and everyday activities were analyzed 3- and 12-months post-stroke.Results: The mean age of the included participants was 54 years and the majority, 65%, were men. Three months post-stroke, 43% self-reported fatigue, at 12-months the proportion increased to 48%. About 90% of the patients were independent in basic ADL at 3-month. Dependence in complex activities one year post-stroke was significantly associated with fatigue. Not experiencing fatigue one year after stroke could predict positive functioning in everyday activities, increasing the chance of returning to work (OR = 3.7) and pre-stroke life and everyday activities (OR = 5.7).Conclusion: Post-stroke fatigue is a common persistent disability that negatively impacts complex activities; therefore, fatigue needs to be acknowledged and addressed long term after discharge.
Urban living in built environments, combined with the use of processed water and food, may not provide the microbial stimulation necessary for a balanced development of immune function. Many chronic inflammatory disorders, including allergic, autoimmune, metabolic, and even some behavioural disorders, are linked to alteration in the human commensal microbiota. Sedentary lifestyle is associated with reduced exposure to a broad spectrum of environmental micro-organisms and surplus energy balance, both risk factors of chronic inflammatory disorders. According to the Biodiversity Hypothesis, an environment with diverse macrobiota and microbiota modifies and enriches the human microbiota, which in turn is crucial in the development and maintenance of appropriate immune function. These issues were discussed in the symposium Chronic Inflammation, Lifestyle and Environment , held in Helsinki, 20 - 22 August 2014, under the sponsorship of the Yrjo Jahnsson Foundation. This paper briefly outlines the recent findings in the context of the environment, lifestyle, and health; discusses the forces that undermine immune tolerance in urban environments; and highlights the possibilities to restore broken immune tolerance among urban dwellers, summarizing the main messages in four statements and calling for actions to combat major public health threats.
The iron hypothesis as an alternative explanation for the gender difference in the incidence and mortality of atherosclerosis has provoked increased debates and public health concerns. In this review we summarize the historical and recent literature on the iron hypothesis and discuss several related clinical issues and their implications. Apart from misconstruction of study populations, lack of a good method to reflect the iron contents of tissues may be the major factor for causing inconsistent results from epidemiological studies. Published data from 11 countries clearly indicate that the mortality from cardiovascular diseases is correlated with liver iron. We propose that redox-active iron in tissue is the atherogenic portion of total iron stores. Recently developed magnetic resonance imaging techniques in combination with Fe chelators may allow future studies to examine this component of body iron in lesions and the whole body. Several clinical situations characterized by increased iron stores have been proposed as 'human models' suitable for further tests of the iron hypothesis. Patients with end-stage renal disease may be the most unique cohort, having significant increases in their iron stores, low-density lipoprotein (LDL) oxidation, and cardiovascular events. Other patient groups may be well suited for specific studies of different atherogenic events. With a better understanding of iron-driven oxidative damage, well controlled and effectively designed studies on these models will finally bring us to the truth of the iron hypothesis.