Autologous microsurgical breast reconstruction and coronary artery bypass grafting: an anatomical study and clinical implications

OBJECTIVE: To identify possible avenues of sparing the internal mammary artery (IMA) for coronary artery bypass grafting (CABG) in women undergoing autologous breast reconstruction with deep inferior epigastric artery perforator (DIEP) flaps. BACKGROUND: Optimal autologous reconstruction of the breast and coronary artery bypass grafting (CABG) are often mutually exclusive as they both require utilisation of the IMA as the preferred arterial conduit. Given the prevalence of both breast cancer and coronary artery disease, this is an important issue for women's health as women with DIEP flap reconstructions and women at increased risk of developing coronary artery disease are potentially restricted from receiving this reconstructive option should the other condition arise. METHODS: The largest clinical and cadaveric anatomical study (n=315) to date was performed, investigating four solutions to this predicament by correlating the precise requirements of breast reconstruction and CABG against the anatomical features of the in situ IMAs. This information was supplemented by a thorough literature review. RESULTS: Minimum lengths of the left and right IMA needed for grafting to the left-anterior descending artery are 160.08 and 177.80 mm, respectively. Based on anatomical findings, the suitable options for anastomosis to each intercostals space are offered. In addition, 87-91% of patients have IMA perforator vessels to which DIEP flaps can be anastomosed in the first- and second-intercostal spaces. CONCLUSION: We outline five methods of preserving the IMA for future CABG: (1) lowering the level of DIEP flaps to the fourth- and fifth-intercostals spaces, (2) using the DIEP pedicle as an intermediary for CABG, (3) using IMA perforators to spare the IMA proper, (4) using and end-to-side anastomosis between the DIEP pedicle and IMA and (5) anastomosis of DIEP flaps using retrograde flow from the distal IMA. With careful patient selection, we hypothesize using the IMA for autologous breast reconstruction need not be an absolute contraindication for future CABG

Comparative genomics of the major parasitic worms

Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we report a broad comparative study of 81 genomes of parasitic and non-parasitic worms. We have identified gene family births and hundreds of expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We reveal extensive lineage-specific differences in core metabolism and protein families historically targeted for drug development. From an in silico screen, we have identified and prioritized new potential drug targets and compounds for testing. This comparative genomics resource provides a much-needed boost for the research community to understand and combat parasitic worms

Expression of Stretch-Activated Two-Pore Potassium Channels in Human Myometrium in Pregnancy and Labor

Background: We tested the hypothesis that the stretch-activated, four-transmembrane domain, two pore potassium channels (K2P), TREK-1 and TRAAK are gestationally-regulated in human myometrium and contribute to uterine relaxation during pregnancy until labor. Methodology: We determined the gene and protein expression of K2P channels in non-pregnant, pregnant term and preterm laboring myometrium. We employed both molecular biological and functional studies of K2P channels in myometrial samples taken from women undergoing cesarean delivery of a fetus. Principal Findings: TREK-1, but not TREK-2, channels are expressed in human myometrium and significantly up-regulated during pregnancy. Down-regulation of TREK-1 message was seen by Q-PCR in laboring tissues consistent with a role for TREK-1 in maintaining uterine quiescence prior to labor. The TRAAK channel was unregulated in the same women. Blockade of stretch-activated channels with a channel non-specific tarantula toxin (GsMTx-4) or the more specific TREK-1 antagonist L-methionine ethyl ester altered contractile frequency in a dose-dependent manner in pregnant myometrium. Arachidonic acid treatment lowered contractile tension an effect blocked by fluphenazine. Functional studies are consistent with a role for TREK-1 in uterine quiescence. Conclusions: We provide evidence supporting a role for TREK-1 in contributing to uterine quiescence during gestation an

HCV co-infection in HIV positive population in British Columbia, Canada

<p>Abstract</p> <p>Background</p> <p>As HIV and hepatitis C (HCV) share some modes of transmission co-infection is not uncommon. This study used a population-based sample of HIV and HCV tested individuals to determine the prevalence of HIV/HCV co-infection, the sequence of virus diagnoses, and demographic and associated risk factors.</p> <p>Methods</p> <p>Positive cases of HIV were linked to the combined laboratory database (of negative and positive HCV antibody results) and HCV reported cases in British Columbia (BC).</p> <p>Results</p> <p>Of 4,598 HIV cases with personal identifiers, 3,219 (70%) were linked to the combined HCV database, 1,700 (53%) of these were anti-HCV positive. HCV was diagnosed first in 52% of co-infected cases (median time to HIV identification 3 1/2 years). HIV and HCV was diagnosed within a two week window in 26% of cases. Among individuals who were diagnosed with HIV infection at baseline, subsequent diagnoses of HCV infection was independently associated with: i) intravenous drug use (IDU) in males and females, Hazard Ratio (HR) = 6.64 (95% CI: 4.86-9.07) and 9.76 (95% CI: 5.76-16.54) respectively; ii) reported Aboriginal ethnicity in females HR = 2.09 (95% CI: 1.34-3.27) and iii) males not identified as men-who-have-sex-with-men (MSM), HR = 2.99 (95% CI: 2.09-4.27).</p> <p>Identification of HCV first compared to HIV first was independently associated with IDU in males and females OR = 2.83 (95% CI: 1.84-4.37) and 2.25 (95% CI: 1.15-4.39) respectively, but not Aboriginal ethnicity or MSM. HIV was identified first in 22%, with median time to HCV identification of 15 months;</p> <p>Conclusion</p> <p>The ability to link BC public health and laboratory HIV and HCV information provided a unique opportunity to explore demographic and risk factors associated with HIV/HCV co-infection. Over half of persons with HIV infection who were tested for HCV were anti-HCV positive; half of these had HCV diagnosed first with HIV identification a median 3.5 years later. This highlights the importance of public health follow-up and harm reduction measures for people identified with HCV to prevent subsequent HIV infection.</p

Proximal correlates of metabolic phenotypes during ‘at-risk' and ‘case' stages of the metabolic disease continuum

Extent: 11p.OBJECTIVE: To examine the social and behavioural correlates of metabolic phenotypes during ‘at-risk’ and ‘case’ stages of the metabolic disease continuum. DESIGN: Cross-sectional study of a random population sample. PARTICIPANTS: A total of 718 community-dwelling adults (57% female), aged 18--92 years from a regional South Australian city. MEASUREMENTS: Total body fat and lean mass and abdominal fat mass were assessed by dual energy x-ray absorptiometry. Fasting venous blood was collected in the morning for assessment of glycated haemoglobin, plasma glucose, serum triglycerides, cholesterol lipoproteins and insulin. Seated blood pressure (BP) was measured. Physical activity and smoking, alcohol and diet (96-item food frequency), sleep duration and frequency of sleep disordered breathing (SDB) symptoms, and family history of cardiometabolic disease, education, lifetime occupation and household income were assessed by questionnaire. Current medications were determined by clinical inventory. RESULTS: 36.5% were pharmacologically managed for a metabolic risk factor or had known diabetes (‘cases’), otherwise were classified as the ‘at-risk’ population. In both ‘at-risk’ and ‘cases’, four major metabolic phenotypes were identified using principal components analysis that explained over 77% of the metabolic variance between people: fat mass/insulinemia (FMI); BP; lipidaemia/lean mass (LLM) and glycaemia (GLY). The BP phenotype was uncorrelated with other phenotypes in ‘cases’, whereas all phenotypes were inter-correlated in the ‘at-risk’. Over and above other socioeconomic and behavioural factors, medications were the dominant correlates of all phenotypes in ‘cases’ and SDB symptom frequency was most strongly associated with FMI, LLM and GLY phenotypes in the ‘at-risk’. CONCLUSION: Previous research has shown FMI, LLM and GLY phenotypes to be most strongly predictive of diabetes development. Reducing SDB symptom frequency and optimising the duration of sleep may be important concomitant interventions to standard diabetes risk reduction interventions. Prospective studies are required to examine this hypothesis.MT Haren, G Misan, JF Grant, JD Buckley, PRC Howe, AW Taylor, J Newbury and RA McDermot

Proximal correlates of metabolic phenotypes during ‘at-risk' and ‘case' stages of the metabolic disease continuum

Extent: 11p.OBJECTIVE: To examine the social and behavioural correlates of metabolic phenotypes during ‘at-risk’ and ‘case’ stages of the metabolic disease continuum. DESIGN: Cross-sectional study of a random population sample. PARTICIPANTS: A total of 718 community-dwelling adults (57% female), aged 18--92 years from a regional South Australian city. MEASUREMENTS: Total body fat and lean mass and abdominal fat mass were assessed by dual energy x-ray absorptiometry. Fasting venous blood was collected in the morning for assessment of glycated haemoglobin, plasma glucose, serum triglycerides, cholesterol lipoproteins and insulin. Seated blood pressure (BP) was measured. Physical activity and smoking, alcohol and diet (96-item food frequency), sleep duration and frequency of sleep disordered breathing (SDB) symptoms, and family history of cardiometabolic disease, education, lifetime occupation and household income were assessed by questionnaire. Current medications were determined by clinical inventory. RESULTS: 36.5% were pharmacologically managed for a metabolic risk factor or had known diabetes (‘cases’), otherwise were classified as the ‘at-risk’ population. In both ‘at-risk’ and ‘cases’, four major metabolic phenotypes were identified using principal components analysis that explained over 77% of the metabolic variance between people: fat mass/insulinemia (FMI); BP; lipidaemia/lean mass (LLM) and glycaemia (GLY). The BP phenotype was uncorrelated with other phenotypes in ‘cases’, whereas all phenotypes were inter-correlated in the ‘at-risk’. Over and above other socioeconomic and behavioural factors, medications were the dominant correlates of all phenotypes in ‘cases’ and SDB symptom frequency was most strongly associated with FMI, LLM and GLY phenotypes in the ‘at-risk’. CONCLUSION: Previous research has shown FMI, LLM and GLY phenotypes to be most strongly predictive of diabetes development. Reducing SDB symptom frequency and optimising the duration of sleep may be important concomitant interventions to standard diabetes risk reduction interventions. Prospective studies are required to examine this hypothesis.MT Haren, G Misan, JF Grant, JD Buckley, PRC Howe, AW Taylor, J Newbury and RA McDermot

A reference human induced pluripotent stem cell line for large-scale collaborative studies

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field

Clinical chronobiology: a timely consideration in critical care medicine

A fundamental aspect of human physiology is its cyclical nature over a 24-h period, a feature conserved across most life on Earth. Organisms compartmentalise processes with respect to time in order to promote survival, in a manner that mirrors the rotation of the planet and accompanying diurnal cycles of light and darkness. The influence of circadian rhythms can no longer be overlooked in clinical settings; this review provides intensivists with an up-to-date understanding of the burgeoning field of chronobiology, and suggests ways to incorporate these concepts into daily practice to improve patient outcomes. We outline the function of molecular clocks in remote tissues, which adjust cellular and global physiological function according to the time of day, and the potential clinical advantages to keeping in time with them. We highlight the consequences of "chronopathology", when this harmony is lost, and the risk factors for this condition in critically ill patients. We introduce the concept of "chronofitness" as a new target in the treatment of critical illness: preserving the internal synchronisation of clocks in different tissues, as well as external synchronisation with the environment. We describe methods for monitoring circadian rhythms in a clinical setting, and how this technology may be used for identifying optimal time windows for interventions, or to alert the physician to a critical deterioration of circadian rhythmicity. We suggest a chronobiological approach to critical illness, involving multicomponent strategies to promote chronofitness (chronobundles), and further investment in the development of personalised, time-based treatment for critically ill patients

Cyclic Nucleotide Phosphodiesterases and Compartmentation in Normal and Diseased Heart

International audienceCyclic nucleotide phosphodiesterases (PDEs) degrade the second messengers cAMP and cGMP, thereby regulating multiple aspects of cardiac function. This highly diverse class of enzymes encoded by 21 genes encompasses 11 families which are not only responsible for the termination of cyclic nucleotide signalling, but are also involved in the generation of dynamic microdomains of cAMP and cGMP controlling specific cell functions in response to various neurohormonal stimuli. In myocardium, the PDE3 and PDE4 families are predominant to degrade cAMP and thereby regulate cardiac excitation-contraction coupling. PDE3 inhibitors are positive inotropes and vasodilators in human, but their use is limited to acute heart failure and intermittent claudication. PDE5 is particularly important to degrade cGMP in vascular smooth muscle, and PDE5 inhibitors are used to treat erectile dysfunction and pulmonary hypertension. However, these drugs do not seem efficient in heart failure with preserved ejection fraction. There is experimental evidence that these PDEs as well as other PDE families including PDE1, PDE2 and PDE9 may play important roles in cardiac diseases such as hypertrophy and heart failure. After a brief presentation of the cyclic nucleotide pathways in cardiac cells and the major characteristics of the PDE superfamily, this chapter will present their role in cyclic nucleotide compartmentation and the current use of PDE inhibitors in cardiac diseases together with the recent research progresses that could lead to a better exploitation of the therapeutic potential of these enzymes in the future