Mutations in cardiac T-Box Factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy

The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.

Nurse-determined assessment of cardiac output. Comparing a non-invasive cardiac output device and pulmonary artery catheter: a prospective observational study.

Background The accurate measurement of Cardiac output (CO) is vital in guiding the treatment of critically ill patients. Invasive or minimally invasive measurement of CO is not without inherent risks to the patient. Skilled Intensive Care Unit (ICU) nursing staff are in an ideal position to assess changes in CO following therapeutic measures. The USCOM (Ultrasonic Cardiac Output Monitor) device is a non-invasive CO monitor whose clinical utility and ease of use requires testing. Objectives To compare cardiac output measurement using a non-invasive ultrasonic device (USCOM) operated by a non-echocardiograhically trained ICU Registered Nurse (RN), with the conventional pulmonary artery catheter (PAC) using both thermodilution and Fick methods. Design Prospective observational study. Setting and participants Between April 2006 and March 2007, we evaluated 30 spontaneously breathing patients requiring PAC for assessment of heart failure and/or pulmonary hypertension at a tertiary level cardiothoracic hospital. Methods SCOM CO was compared with thermodilution measurements via PAC and CO estimated using a modified Fick equation. This catheter was inserted by a medical officer, and all USCOM measurements by a senior ICU nurse. Mean values, bias and precision, and mean percentage difference between measures were determined to compare methods. The Intra-Class Correlation statistic was also used to assess agreement. The USCOM time to measure was recorded to assess the learning curve for USCOM use performed by an ICU RN and a line of best fit demonstrated to describe the operator learning curve. Results In 24 of 30 (80%) patients studied, CO measures were obtained. In 6 of 30 (20%) patients, an adequate USCOM signal was not achieved. The mean difference (±standard deviation) between USCOM and PAC, USCOM and Fick, and Fick and PAC CO were small, −0.34 ± 0.52 L/min, −0.33 ± 0.90 L/min and −0.25 ± 0.63 L/min respectively across a range of outputs from 2.6 L/min to 7.2 L/min. The percent limits of agreement (LOA) for all measures were −34.6% to 17.8% for USCOM and PAC, −49.8% to 34.1% for USCOM and Fick and −36.4% to 23.7% for PAC and Fick. Signal acquisition time reduced on average by 0.6 min per measure to less than 10 min at the end of the study. Conclusions In 80% of our cohort, USCOM, PAC and Fick measures of CO all showed clinically acceptable agreement and the learning curve for operation of the non-invasive USCOM device by an ICU RN was found to be satisfactorily short. Further work is required in patients receiving positive pressure ventilation.

Levels of cardiac knowledge and cardiopulmonary resuscitation training among older people in Queensland

Objectives: The current study was conducted to determine levels of cardiac knowledge and cardiopulmonary resuscitation (CPR) training in older people in Queensland, Australia.---------- Methods: A telephone survey of 4490 Queensland adults examined respondents’ knowledge of coronary heart disease (CHD) risk factors, knowledge of heart attack symptoms, knowledge of the local emergency telephone number, as well as respondents’ rates and recency of training in CPR.---------- Results: Older participants, aged 60 years and over, were approximately one and a half times more likely than the 30–39 year-old reference group to have limited knowledge of heart disease risk factors (OR = 1.53), and low knowledge of heart attack symptoms (OR = 1.60). Knowledge of the local emergency telephone number also decreased with age. Older participants had significantly lower rates of training in CPR, with almost three quarters (71.7%) reporting that they had never been trained. Older people who had completed CPR training were significantly less likely to have done so recently.---------- Conclusions: Cardiac knowledge levels and CPR training rates in older Queensland persons were lower than those found in the younger population.

Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker.

BACKGROUND: Although we know much about the molecular makeup of the sinus node (SN) in small mammals, little is known about it in humans. The aims of the present study were to investigate the expression of ion channels in the human SN and to use the data to predict electrical activity. METHODS AND RESULTS: Quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence were used to analyze 6 human tissue samples. Messenger RNA (mRNA) for 120 ion channels (and some related proteins) was measured in the SN, a novel paranodal area, and the right atrium (RA). The results showed, for example, that in the SN compared with the RA, there was a lower expression of Na(v)1.5, K(v)4.3, K(v)1.5, ERG, K(ir)2.1, K(ir)6.2, RyR2, SERCA2a, Cx40, and Cx43 mRNAs but a higher expression of Ca(v)1.3, Ca(v)3.1, HCN1, and HCN4 mRNAs. The expression pattern of many ion channels in the paranodal area was intermediate between that of the SN and RA; however, compared with the SN and RA, the paranodal area showed greater expression of K(v)4.2, K(ir)6.1, TASK1, SK2, and MiRP2. Expression of ion channel proteins was in agreement with expression of the corresponding mRNAs. The levels of mRNA in the SN, as a percentage of those in the RA, were used to estimate conductances of key ionic currents as a percentage of those in a mathematical model of human atrial action potential. The resulting SN model successfully produced pacemaking. CONCLUSIONS: Ion channels show a complex and heterogeneous pattern of expression in the SN, paranodal area, and RA in humans, and the expression pattern is appropriate to explain pacemaking.

Cardiac state diagnosis using higher order spectra of heart rate variability

Heart rate variability (HRV) refers to the regulation of the sinoatrial node, the natural pacemaker of the heart, by the sympathetic and parasympathetic branches of the autonomic nervous system. Heart rate variability analysis is an important tool to observe the heart's ability to respond to normal regulatory impulses that affect its rhythm. A computer-based intelligent system for analysis of cardiac states is very useful in diagnostics and disease management. Like many bio-signals, HRV signals are nonlinear in nature. Higher order spectral analysis (HOS) is known to be a good tool for the analysis of nonlinear systems and provides good noise immunity. In this work, we studied the HOS of the HRV signals of normal heartbeat and seven classes of arrhythmia. We present some general characteristics for each of these classes of HRV signals in the bispectrum and bicoherence plots. We also extracted features from the HOS and performed an analysis of variance (ANOVA) test. The results are very promising for cardiac arrhythmia classification with a number of features yielding a p-value < 0.02 in the ANOVA test.

Runx2 overexpression in bone marrow stromal cells accelerates bone formation in critically-sized femoral defects

The repair of large non-unions in long bones remains a significant clinical problem due to high failure rates and limited tissue availability for auto- and allografts. Many cell-based strategies for healing bone defects deliver bone marrow stromal cells to the defect site to take advantage of the inherent osteogenic capacity of this cell type. However, many factors, including donor age and ex vivo expansion of the cells, cause bone marrow stromal cells to lose their differentiation ability. To overcome these limitations, we have genetically engineered bone marrow stromal cells to constitutively overexpress the osteoblast specific transcription factor Runx2. In the present study, we examined Runx2-modified bone marrow stromal cells, delivered via poly(caprolactone) scaffolds loaded with type I collagen meshes, in critically-sized segmental defects in rats compared to unmodified cells, cell-free scaffolds and empty defects. Runx2 expression in bone marrow stromal cells accelerated healing of critically-sized defects compared to unmodified bone marrow stromal cells and defects receiving cell-free treatments. These findings provide an accelerated method for healing large bone defects which may reduce recovery time and the need for external fixation of critically-sized defects.

Application of autologous periosteal cells for the regeneration of class III furcation defects in Beagle dogs

The aim of this study was to evaluate the healing of class III furcation defects following transplantation of autogenous periosteal cells combined with b-tricalcium phosphate (b-TCP). Periosteal cells obtained from Beagle dogs’ periosteum explant cultures, were inoculated onto the surface of b-TCP. Class III furcation defects were created in the mandibular premolars. Three experimental groups were used to test the defects’ healing: group A, b-TCP seeded with periosteal cells were transplanted into the defects; group B, b-TCP alone was used for defect filling; and group C, the defect was without filling materials. Twelve weeks post surgery, the tissue samples were collected for histology, immunohistology and X-ray examination. It was found that both the length of newly formed periodontal ligament and the area of newly formed alveolar bone in group A, were significantly increased compared with both group B and C. Furthermore, both the proportion of newly formed periodontal ligament and newly formed alveolar bone in group A were much higher than those of group B and C. The quantity of cementum and its percentage in the defects (group A) were also significantly higher than those of group C. These results indicate that autogenous periosteal cells combined with b-TCP application can improve periodontal tissue regeneration in class III furcation defects.

Vision-based classification of solder joint defects

Inspection of solder joints has been a critical process in the electronic manufacturing industry to reduce manufacturing cost, improve yield, and ensure product quality and reliability. The solder joint inspection problem is more challenging than many other visual inspections because of the variability in the appearance of solder joints. Although many research works and various techniques have been developed to classify defect in solder joints, these methods have complex systems of illumination for image acquisition and complicated classification algorithms. An important stage of the analysis is to select the right method for the classification. Better inspection technologies are needed to fill the gap between available inspection capabilities and industry systems. This dissertation aims to provide a solution that can overcome some of the limitations of current inspection techniques. This research proposes two inspection steps for automatic solder joint classification system. The “front-end” inspection system includes illumination normalisation, localization and segmentation. The illumination normalisation approach can effectively and efficiently eliminate the effect of uneven illumination while keeping the properties of the processed image. The “back-end” inspection involves the classification of solder joints by using Log Gabor filter and classifier fusion. Five different levels of solder quality with respect to the amount of solder paste have been defined. Log Gabor filter has been demonstrated to achieve high recognition rates and is resistant to misalignment. Further testing demonstrates the advantage of Log Gabor filter over both Discrete Wavelet Transform and Discrete Cosine Transform. Classifier score fusion is analysed for improving recognition rate. Experimental results demonstrate that the proposed system improves performance and robustness in terms of classification rates. This proposed system does not need any special illumination system, and the images are acquired by an ordinary digital camera. In fact, the choice of suitable features allows one to overcome the problem given by the use of non complex illumination systems. The new system proposed in this research can be incorporated in the development of an automated non-contact, non-destructive and low cost solder joint quality inspection system.