Effect of Global Cardiac Ischemia on Human Ventricular Fibrillation: Insights from a Multi-scale Mechanistic Model of the Human Heart

Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements

A Dedicated Promoter Drives Constitutive Expression of the Cell-Autonomous Immune Resistance GTPase, Irga6 (IIGP1) in Mouse Liver

Background: In general, immune effector molecules are induced by infection. Methodology and Principal Findings: However, strong constitutive expression of the cell-autonomous resistance GTPase, Irga6 (IIGP1), was found in mouse liver, contrasting with previous evidence that expression of this protein is exclusively dependent on induction by IFNc. Constitutive and IFNc-inducible expression of Irga6 in the liver were shown to be dependent on transcription initiated from two independent untranslated 59 exons, which splice alternatively into the long exon encoding the full-length protein sequence. Irga6 is expressed constitutively in freshly isolated hepatocytes and is competent in these cells to accumulate on the parasitophorous vacuole membrane of infecting Toxoplasma gondii tachyzoites. Conclusions and Significance: The role of constitutive hepatocyte expression of Irga6 in resistance to parasites invading from the gut via the hepatic portal system is discussed

Family history of breast cancer and young age at diagnosis of breast cancer increase risk of second primary malignancies in women: a population-based cohort study

Among 152 600 breast cancer patients diagnosed during 1958–2000, there was a 22% increased risk of developing a second primary non-breast malignancy (standardised incidence ratio (SIR)=1.22; 95% confidence interval (CI): 1.19–1.24). The highest risk was seen for connective tissue cancer (SIR=1.78; 95% CI: 1.49–2.10). Increased risks were noted among women diagnosed with breast cancer before age 50. Oesophagus cancer and non-Hodgkin's lymphoma showed six- and four-fold higher risks, respectively, in women with a family history of breast cancer compared to those without in the ⩾10-year follow-up period

Auditory Function in the Tc1 Mouse Model of Down Syndrome Suggests a Limited Region of Human Chromosome 21 Involved in Otitis Media

Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K+ currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca2+ activated K+ current (IK,f), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active

Municipal distribution of breast cancer mortality among women in Spain

<p>Abstract</p> <p>Background</p> <p>Spain has one of the lowest rates of breast cancer in Europe, though estimated incidence has risen substantially in recent decades. Some years ago, the Spanish Cancer Mortality Atlas showed Spain as having a heterogeneous distribution of breast cancer mortality at a provincial level. This paper describes the municipal distribution of breast cancer mortality in Spain and its relationship with socio-economic indicators.</p> <p>Methods</p> <p>Breast cancer mortality was modelled using the Besag-York-Molliè autoregressive spatial model, including socio-economic level, rurality and percentage of population over 64 years of age as surrogates of reproductive and lifestyle risk factors. Municipal relative risks (RRs) were independently estimated for women aged under 50 years and for those aged 50 years and over. Maps were plotted depicting smoothed RR estimates and the distribution of the posterior probability of RR>1.</p> <p>Results</p> <p>In women aged 50 years and over, mortality increased with socio-economic level, and was lower in rural areas and municipalities with higher proportion of old persons. Among women aged under 50 years, rurality was the only statistically significant explanatory variable.</p> <p>For women older than 49 years, the highest relative risks were mainly registered for municipalities located in the Canary Islands, Balearic Islands, the Mediterranean coast of Catalonia and Valencia, plus others around the Ebro River. In premenopausal women, the pattern was similar but tended to be more homogeneous. In mainland Spain, a group of municipalities with high RRs were located in Andalusia, near the left bank of the Guadalquivir River.</p> <p>Conclusion</p> <p>As previously observed in other contexts, mortality rates are positively related with socio-economic status and negatively associated with rurality and the presence of a higher proportion of people over age 64 years. Taken together, these variables represent the influence of lifestyle factors which have determined the increase in breast cancer frequency over recent decades. The results for the younger group of women suggest an attenuation of the socio-economic gradient in breast cancer mortality in Spain. The geographical variation essentially suggests the influence of other environmental variables, yet the descriptive nature of this study does not allow for the main determinants to be established.</p

Autoimmune Disease Classification by Inverse Association with SNP Alleles

With multiple genome-wide association studies (GWAS) performed across autoimmune diseases, there is a great opportunity to study the homogeneity of genetic architectures across autoimmune disease. Previous approaches have been limited in the scope of their analysis and have failed to properly incorporate the direction of allele-specific disease associations for SNPs. In this work, we refine the notion of a genetic variation profile for a given disease to capture strength of association with multiple SNPs in an allele-specific fashion. We apply this method to compare genetic variation profiles of six autoimmune diseases: multiple sclerosis (MS), ankylosing spondylitis (AS), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), Crohn's disease (CD), and type 1 diabetes (T1D), as well as five non-autoimmune diseases. We quantify pair-wise relationships between these diseases and find two broad clusters of autoimmune disease where SNPs that make an individual susceptible to one class of autoimmune disease also protect from diseases in the other autoimmune class. We find that RA and AS form one such class, and MS and ATD another. We identify specific SNPs and genes with opposite risk profiles for these two classes. We furthermore explore individual SNPs that play an important role in defining similarities and differences between disease pairs. We present a novel, systematic, cross-platform approach to identify allele-specific relationships between disease pairs based on genetic variation as well as the individual SNPs which drive the relationships. While recognizing similarities between diseases might lead to identifying novel treatment options, detecting differences between diseases previously thought to be similar may point to key novel disease-specific genes and pathways

Transcriptomic response of the red tide dinoflagellate, Karenia brevis, to nitrogen and phosphorus depletion and addition

<p>Abstract</p> <p>Background</p> <p>The role of coastal nutrient sources in the persistence of <it>Karenia brevis </it>red tides in coastal waters of Florida is a contentious issue that warrants investigation into the regulation of nutrient responses in this dinoflagellate. In other phytoplankton studied, nutrient status is reflected by the expression levels of N- and P-responsive gene transcripts. In dinoflagellates, however, many processes are regulated post-transcriptionally. All nuclear encoded gene transcripts studied to date possess a 5' <it>trans</it>-spliced leader (SL) sequence suggestive, based on the trypanosome model, of post-transcriptional regulation. The current study therefore sought to determine if the transcriptome of <it>K. brevis </it>is responsive to nitrogen and phosphorus and is informative of nutrient status.</p> <p>Results</p> <p>Microarray analysis of N-depleted <it>K. brevis </it>cultures revealed an increase in the expression of transcripts involved in N-assimilation (nitrate and ammonium transporters, glutamine synthetases) relative to nutrient replete cells. In contrast, a transcriptional signal of P-starvation was not apparent despite evidence of P-starvation based on their rapid growth response to P-addition. To study transcriptome responses to nutrient addition, the limiting nutrient was added to depleted cells and changes in global gene expression were assessed over the first 48 hours following nutrient addition. Both N- and P-addition resulted in significant changes in approximately 4% of genes on the microarray, using a significance cutoff of 1.7-fold and p ≤ 10^-4. By far, the earliest responding genes were dominated in both nutrient treatments by pentatricopeptide repeat (PPR) proteins, which increased in expression up to 3-fold by 1 h following nutrient addition. PPR proteins are nuclear encoded proteins involved in chloroplast and mitochondria RNA processing. Correspondingly, other functions enriched in response to both nutrients were photosystem and ribosomal genes.</p> <p>Conclusions</p> <p>Microarray analysis provided transcriptomic evidence for N- but not P-limitation in <it>K. brevis</it>. Transcriptomic responses to the addition of either N or P suggest a concerted program leading to the reactivation of chloroplast functions. Even the earliest responding PPR protein transcripts possess a 5' SL sequence that suggests post-transcriptional control. Given the current state of knowledge of dinoflagellate gene regulation, it is currently unclear how these rapid changes in such transcript levels are achieved.</p

A knowledge-based taxonomy of critical factors for adopting electronic health record systems by physicians: a systematic literature review

<p>Abstract</p> <p>Background</p> <p>The health care sector is an area of social and economic interest in several countries; therefore, there have been lots of efforts in the use of electronic health records. Nevertheless, there is evidence suggesting that these systems have not been adopted as it was expected, and although there are some proposals to support their adoption, the proposed support is not by means of information and communication technology which can provide automatic tools of support. The aim of this study is to identify the critical adoption factors for electronic health records by physicians and to use them as a guide to support their adoption process automatically.</p> <p>Methods</p> <p>This paper presents, based on the PRISMA statement, a systematic literature review in electronic databases with adoption studies of electronic health records published in English. Software applications that manage and process the data in the electronic health record have been considered, i.e.: computerized physician prescription, electronic medical records, and electronic capture of clinical data. Our review was conducted with the purpose of obtaining a taxonomy of the physicians main barriers for adopting electronic health records, that can be addressed by means of information and communication technology; in particular with the information technology roles of the knowledge management processes. Which take us to the question that we want to address in this work: "What are the critical adoption factors of electronic health records that can be supported by information and communication technology?". Reports from eight databases covering electronic health records adoption studies in the medical domain, in particular those focused on physicians, were analyzed.</p> <p>Results</p> <p>The review identifies two main issues: 1) a knowledge-based classification of critical factors for adopting electronic health records by physicians; and 2) the definition of a base for the design of a conceptual framework for supporting the design of knowledge-based systems, to assist the adoption process of electronic health records in an automatic fashion. From our review, six critical adoption factors have been identified: user attitude towards information systems, workflow impact, interoperability, technical support, communication among users, and expert support. The main limitation of the taxonomy is the different impact of the adoption factors of electronic health records reported by some studies depending on the type of practice, setting, or attention level; however, these features are a determinant aspect with regard to the adoption rate for the latter rather than the presence of a specific critical adoption factor.</p> <p>Conclusions</p> <p>The critical adoption factors established here provide a sound theoretical basis for research to understand, support, and facilitate the adoption of electronic health records to physicians in benefit of patients.</p