State diagrams of the heart – a new approach to describing cardiac mechanics

<p>Abstract</p> <p>Background</p> <p>Cardiac time intervals have been described as a measure of cardiac performance, where prolongation, shortening and delay of the different time intervals have been evaluated as markers of cardiac dysfunction. A relatively recently developed method with improved ability to measure cardiac events is Tissue Doppler Imaging (TDI), allowing accurate measurement of myocardial movements.</p> <p>Methods</p> <p>We propose the state diagram of the heart as a new visualization tool for cardiac time intervals, presenting comparative, normalized data of systolic and diastolic performance, providing a more complete overview of cardiac function. This study aimed to test the feasibility of the state diagram method by presenting examples demonstrating its potential use in the clinical setting and by performing a clinical study, which included a comparison of the state diagram method with established echocardiography methods (E/E' ratio, LVEF and WMSI). The population in the clinical study consisted of seven patients with non ST-elevation myocardial infarction (NSTEMI) and seven control subjects, individually matched according to age and gender. The state diagram of the heart was generated from TDI curves from seven positions in the myocardium, visualizing the inter- and intraventricular function of the heart by displaying the cardiac phases.</p> <p>Results</p> <p>The clinical examples demonstrated that the state diagram allows for an intuitive visualization of pathological patterns as ischemia and dyssynchrony. Further, significant differences in percentage duration between the control group and the NSTEMI group were found in eight of the totally twenty phases (10 phases for each ventricle), e.g. in the transition phases (Pre-Ejection and Post-Ejection). These phases were significantly longer (> 2.18%) for the NSTEMI group than for the control group (p < 0.05). No significant differences between the groups were found for the established echocardiography methods.</p> <p>Conclusion</p> <p>The test results clearly indicate that the state diagram has potential to be an efficient tool for visualization of cardiac dysfunction and for detection of NSTEMI.</p

Determinants of lung function and airway hyperresponsiveness in asthmatic children

SummaryBackgroundAsthma patients exhibit an increased rate of loss of lung function. Determinants to such decline are largely unknown and the modifying effect of steroid therapy is disputed. This cross-sectional study aimed to elucidate factors contributing to such decline and the possible modifying effect of steroid treatment.MethodsWe analyzed determinants of lung function and airway hyperresponsiveness (AHR) in a Scandinavian study of 2390 subjects from 550 families. Families were selected for the presence of two or more asthmatic children as part of a genetic study, Scandinavian Asthma Genetic Study (SAGA).ResultsThe primary analysis studied the association between the lung function and delay of inhaled corticosteroids (ICS) after asthma diagnosis among asthmatic children and young adults with a history of regular ICS treatment (N=919). FEV1 percent predicted (FEV1% pred) was 0.25% lower per year of delay from diagnosis until treatment (p=0.039). This association was significantly greater in allergy skin prick test negative children. There was no significant influence of gender, age at asthma onset, or smoking.In the secondary analysis of the whole population of 2390 asthmatics and non-asthmatics, FEV1% pred was inversely related to having asthmatic siblings (−7.9%; p<0.0001), asthma diagnosis (−2.7%; p=0.0007), smoking (−3.5%; p=0.0027), and positive allergy skin prick test (−0.47% per test; p=0.012), while positively related to being of female gender (1.8%; p=0.0029). Risk of AHR was higher by having asthmatic siblings (OR 2.7; p<0.0001), being of female gender (OR 2.0; p<0.0001), and having asthma (OR 2.0; p<0.0001).ConclusionsThese data suggest that lung function is lower in asthmatics with delayed introduction of ICS therapy, smoking, and positive allergy skin prick test. Lung function is lower and AHR higher in female asthmatics and subjects with asthmatic siblings or established asthma

An experimental and numerical investigation on the process efficiency of the focused TIG welding of Inconel 718 thick plates

A combined experimental and numerical approach was adopted to investigate the focused tungsten inert gas (TIG) welding process by producing bead-on-plate welds in Inconel 718 plates. Experimental investigations were carried out by means of thermocouple measurements and optical macrographs of the weld cross-section. Three dimensional finite element (FE) simulations were conducted using the commercial specialized FE software Sysweld in order to predict the thermal field induced by the process in the plates. The work presents an approach to investigate the process efficiency and calibrate the heat source model in order to produce a full thermal characterization the plasmatron welding apparatus

Novel role of PKR in inflammasome activation and HMGB1 release

The inflammasome regulates release of caspase activation-dependent cytokines, including IL-1β, IL-18, and high-mobility group box 1 (HMGB1)1-5. During the course of studying HMGB1 release mechanisms, we discovered an important role of double-stranded RNA dependent protein kinase (PKR) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminum, rotenone, live E. coli, anthrax lethal toxin, DNA transfection, and S. Typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1beta, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with multiple inflammasome components, including NLR family pyrin domain-containing 3 (NLRP3), NLR family pyrin domain-containing 1 (NLRP1), NLR family CARD domain-containing protein 4 (NLRC4), Absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell free system with recombinant NLRP3, ASC and pro-casapse-1 reconstitutes inflammasome activity. These results reveal a critical role of PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation

Genetic and environmental influence on lung function impairment in Swedish twins

<p>Abstract</p> <p>Background</p> <p>The understanding of the influence of smoking and sex on lung function and symptoms is important for understanding diseases such as COPD. The influence of both genes and environment on lung function, smoking behaviour and the presence of respiratory symptoms has previously been demonstrated for each of these separately. Hence, smoking can influence lung function by co-varying not only as an environmental factor, but also by shared genetic pathways. Therefore, the objective was to evaluate heritability for different aspects of lung function, and to investigate how the estimates are affected by adjustments for smoking and respiratory symptoms.</p> <p>Methods</p> <p>The current study is based on a selected sample of adult twins from the Swedish Twin Registry. Pairs were selected based on background data on smoking and respiratory symptoms collected by telephone interview. Lung function was measured as FEV₁, VC and DLco. Pack years were quantified, and quantitative genetic analysis was performed on lung function data adjusting stepwise for sex, pack years and respiratory symptoms.</p> <p>Results</p> <p>Fully adjusted heritability for VC was 59% and did not differ by sex, with smoking and symptoms explaining only a small part of the total variance. Heritabilities for FEV₁and DLco were sex specific. Fully adjusted estimates were10 and 15% in men and 46% and 39% in women, respectively. Adjustment for smoking and respiratory symptoms altered the estimates differently in men and women. For FEV₁and DLco, the variance explained by smoking and symptoms was larger in men. Further, smoking and symptoms explained genetic variance in women, but was primarily associated with shared environmental effects in men.</p> <p>Conclusion</p> <p>Differences between men and women were found in how smoking and symptoms influence the variation in lung function. Pulmonary gas transfer variation related to the menstrual cycle has been shown before, and the findings regarding DLco in the present study indicates gender specific environmental susceptibility not shown before. As a consequence the results suggest that patients with lung diseases such as COPD could benefit from interventions that are sex specific.</p

Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy

Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy

The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML

Obesity and nocturnal gastro-oesophageal reflux are related to onset of asthma and respiratory symptoms

Several studies have identified obesity as a risk factor for asthma in both children and adults. An increased prevalence of asthma in subjects with gastro-oesophageal reflux (GOR) and obstructive sleep apnoea syndrome has also been reported. The aim of this investigation was to study obesity, nocturnal GOR and snoring as independent risk factors for onset of asthma and respiratory symptoms in a Nordic population. In a 5-10 yr follow-up study of the European Community Respiratory Health Survey in Iceland, Norway, Denmark, Sweden and Estonia, a postal questionnaire was sent to previous respondents. A total of 16,191 participants responded to the questionnaire. Reported onset of asthma, wheeze and night-time symptoms as well as nocturnal GOR and habitual snoring increased in prevalence along with the increase in body mass index (BMI). After adjusting for nocturnal GOR, habitual snoring and other confounders, obesity (BMI >30) remained significantly related to the onset of asthma, wheeze and night-time symptoms. Nocturnal GOR was independently related to the onset of asthma and in addition, both nocturnal GOR and habitual snoring were independently related to onset of wheeze and night-time symptoms. This study adds evidence to an independent relationship between obesity, nocturnal gastro-oesophageal reflux and habitual snoring and the onset of asthma and respiratory symptoms in adults

Immunophenotyping of Circulating T Helper Cells Argues for Multiple Functions and Plasticity of T Cells In Vivo in Humans - Possible Role in Asthma

BACKGROUND: The immune process driving eosinophilic and non-eosinophilic asthma is likely driven by different subsets of T helper (Th) cells. Recently, in vitro studies and animal studies suggest that Th cell subsets displays plasticity by changing their transcription factor or by expressing multiple transcription factors. Our aim was to determine whether individuals with asthma and elevated circulating eosinophils express signs of different regulatory immune mechanisms compared with asthmatics with low blood eosinophils and non-asthmatic control subjects. In addition, determine the relationship between eosinophilia and circulating Th cell subsets. METHODOLOGY/PRINCIPAL FINDINGS: Participants were selected from a random epidemiological cohort, the West Sweden Asthma Study. Immunophenotypes of fresh peripheral blood cells obtained from stable asthmatics, with and without elevated eosinophilic inflammation (EOS high and EOS low respectively) and control subjects, were determined by flow cytometry. No differences in the number of Th1 (T-bet), Th2 (GATA-3), Th17 (RORγt) or Treg (FOXP3) cells were observed between the groups when analysing each subset separately. However, in all groups, each of the Th subsets showed expression of additional canonical transcription factors T-bet, GATA-3, RORγt and FOXP3. Furthermore, by in vitro stimulation with anti-CD3/anti-CD28 there was a significant increase of single expressing GATA-3(+) and co-expressing T-bet(+)GATA-3(+) cells in the EOS high asthmatics in comparison with control subjects. In addition, T-bet(-)GATA-3(+)RORγt(+)FOXP3(+) were decreased in comparison to the EOS low asthmatics. Finally, in a group of control subjects we found that the majority of proliferating Th cells (CD4(+)CD25(+)Ki67(+)) expressed three or four transcription factors. CONCLUSIONS: The ability of human Th cells to express several regulatory transcription factors suggests that these cells may display plasticity in vivo

MD-2 is required for disulfide HMGB1-dependent TLR4 signaling

Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2–deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2–HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4–MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness