Precise Lineage Tracking Using Molecular Barcodes Demonstrates Fitness Trade-offs for Ivermectin Resistance in Nematodes.

A fundamental tenet of evolutionary genetics is that the direction and strength of selection on individual loci varies with the environment. Barcoded evolutionary lineage tracking is a powerful approach for high-throughput measurement of selection within experimental evolution that to date has largely been restricted to studies within microbial systems, largely because the random integration of barcodes within animals is limited by physical and molecular protection of the germline. Here, we use the recently developed TARDIS barcoding system in (Stevenson et al.

The Geometry of Limb Motor Innervation is Controlled by the Dorsal-Ventral Compartment Boundary in the Chick Limbless Mutant.

Precise control of limb muscles, and ultimately of limb movement, requires accurate motor innervation. Motor innervation of the vertebrate limb is established by sequential selection of trajectories at successive decision points. Motor axons of the lateral motor column (LMC) segregate at the base of the limb into two groups that execute a choice between dorsal and ventral tissue: medial LMC axons innervate the ventral limb, whereas lateral LMC axons innervate the dorsal limb.

Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation.

The mineralocorticoid aldosterone is produced in the adrenal zona glomerulosa (ZG) under the control of the renin-angiotensin II (AngII) system. Primary aldosteronism (PA) results from renin-independent production of aldosterone and is a common cause of hypertension. PA is caused by dysregulated localization of the enzyme aldosterone synthase (Cyp11b2), which is normally restricted to the ZG.

Mortality risk factors in intensive care unit patients with acute kidney injury requiring renal replacement therapy: a retrospective cohort study .

Background: Mortality of critically-ill patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT) in an intensive-care setting continues to remain high. There is still uncertainty as to which factors should guide clinical judgement.

Methods: A cohort of 155 patients admitted to an intensive-care unit and necessitating RRT due to AKI were retrospectively analyzed.

Diagnostic evaluation and treatment strategy in patients with suspected prosthetic heart valve dysfunction: The incremental value of MDCT.

Background: In patients with suspected prosthetic heart valve (PHV) dysfunction, routine evaluation echocardiography and fluoroscopy may provide unsatisfactory results for identifying the cause of dysfunction. This study assessed the value of MDCT as a routine, complementary imaging modality in suspected PHV-dysfunction for diagnosing the cause of PHV dysfunction and proposing a treatment strategy.

Methods: Patients with suspected PHV dysfunction were prospectively recruited.

Finding the optimal dose reduction and iterative reconstruction level for coronary calcium scoring.

Objective: To assess the maximally achievable computed tomography (CT) dose reduction for coronary artery calcium (CAC) scoring with iterative reconstruction (IR) by using phantom-experiments and a systematical within-patient study.

Methods: Our local institutional review-board approved this study and informed consent was obtained from all participants. A phantom and patient study were conducted with 30 patients (23 men, median age 55.

Adult Scimitar Syndrome: A Surgical Approach.

Background: Scimitar syndrome is a rare congenital condition characterised by partial or total anomalous pulmonary venous drainage of the right lung. We present an adult case of Scimitar syndrome that was managed with an intra-atrial baffle repair.

Case Description: The patient was a 52 year-old lady who had symptoms of increasing dyspnoea and fatigue with a long-term history of poor exercise tolerance.

Retinoid signaling in progenitors controls specification and regeneration of the urothelium.

The urothelium is a multilayered epithelium that serves as a barrier between the urinary tract and blood, preventing the exchange of water and toxic substances. It consists of superficial cells specialized for synthesis and transport of uroplakins that assemble into a tough apical plaque, one or more layers of intermediate cells, and keratin 5-expressing basal cells (K5-BCs), which are considered to be progenitors in the urothelium and other specialized epithelia. Fate mapping, however, reveals that intermediate cells rather than K5-BCs are progenitors in the adult regenerating urothelium, that P cells, a transient population, are progenitors in the embryo, and that retinoids are critical in P cells and intermediate cells, respectively, for their specification during development and regeneration.

Relation between mild to moderate chronic kidney disease and coronary artery disease determined with coronary CT angiography.

Background: Both end-stage and milder stages of chronic kidney disease (CKD) are associated with an increased risk of adverse cardiovascular events. Several studies found an association between decreasing renal function and increasing coronary artery calcification, but it remains unclear if this association is independent from traditional cardiovascular risk factors. Therefore, the aim of this study was to investigate whether mild to moderate CKD is independently associated with coronary plaque burden beyond traditional cardiovascular risk factors.

Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype.

Background: Vitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE(-/-) model of atherosclerosis.

High-sensitivity cardiac troponin T: risk stratification tool in patients with symptoms of chest discomfort.

Background: Recent studies have demonstrated the association between increased concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and the incidence of myocardial infarction, heart failure, and mortality. However, most prognostic studies to date focus on the value of hs-cTnT in the elderly or general population. The value of hs-cTnT in symptomatic patients visiting the outpatient department remains unclear.

Combined use of exercise electrocardiography, coronary calcium score and cardiac CT angiography for the prediction of major cardiovascular events in patients presenting with stable chest pain.

Background: The usual diagnostic work-up of chest pain patients includes clinical risk profiling and exercise-ECG, possibly followed by additional tests. Recently cardiac computed tomographic angiography (CCTA) has been employed. We evaluated the prognostic value of the combined use of exercise-ECG and CCTA for the development of cardiovascular endpoints.

Sonic hedgehog signaling during adrenal development.

It has been speculated for a number of years that Sonic hedgehog (Shh) signaling plays an important role in adrenal development. Over the past two years several reports have described the expression and function of Shh pathway genes in the adrenal cortex, using primarily mouse models. The key findings are that Shh signals produced by a population of partially differentiated cortical cells located in the outer cortex/zona glomerulosa are received by non-cortical mesenchymal cells located predominantly in the overlying capsule.

Endogenous biotin as a marker of adrenocortical cells with steroidogenic potential.

Interpretation of adrenal cortex phenotypes is greatly facilitated by simultaneous examination of multiple markers at single cell resolution. However, the availability of multiple appropriate antibodies can be rate limiting, while their cognate antigens are often subject to variable accessibility. Specific markers not subject to these constraints thus have obvious utility.

Localization of Sonic hedgehog secreting and receiving cells in the developing and adult rat adrenal cortex.

Sonic hedgehog signaling was recently demonstrated to play an important role in murine adrenal cortex development. The organization of the rat adrenal differs from that of the mouse, with the zona glomerulosa and zona fasciculata separated by an undifferentiated zone in the rat, but not in the mouse. In the present study we aimed to determine the mRNA expression patterns of Sonic hedgehog and the hedgehog signaling pathway components Patched-1 and Gli1 in the developing and adult rat adrenal.

Twist1 activity thresholds define multiple functions in limb development.

The basic helix-loop-helix transcription factor Twist1 is essential for normal limb development. Twist1(-/-) embryos die at midgestation. However, studies on early limb buds found that Twist1(-/-) mutant limb mesenchyme has an impaired response to FGF signaling from the apical ectodermal ridge, which disrupts the feedback loop between the mesenchyme and AER, and reduces and shifts anteriorly Shh expression in the zone of polarizing activity.

Foxp1 and lhx1 coordinate motor neuron migration with axon trajectory choice by gating Reelin signalling.

Topographic neuronal maps arise as a consequence of axon trajectory choice correlated with the localisation of neuronal soma, but the identity of the pathways coordinating these processes is unknown. We addressed this question in the context of the myotopic map formed by limb muscles innervated by spinal lateral motor column (LMC) motor axons where the Eph receptor signals specifying growth cone trajectory are restricted by Foxp1 and Lhx1 transcription factors. We show that the localisation of LMC neuron cell bodies can be dissociated from axon trajectory choice by either the loss or gain of function of the Reelin signalling pathway.

The extent of coronary atherosclerosis is associated with increasing circulating levels of high sensitive cardiac troponin T.

Objective: This study explored the relationship between coronary atherosclerotic plaque burden and quantifiable circulating levels of troponin measured with a recently introduced high sensitive cardiac troponin T (hs-cTnT) assay.

Methods And Results: Cardiac patients suspected of having coronary artery disease (CAD) but without acute coronary syndrome were studied. Cardiac troponin T levels were assessed using the fifth-generation hs-cTnT assay.

Cardiac troponin T elevations, using highly sensitive assay, in recreational running depend on running distance.

Background: Endurance exercise is frequently associated with cardiac troponin (cTn) concentrations, otherwise corresponding to minor myocardial infarction. However, research on the underlying mechanisms has been limited because of assay restraints in the low concentration range.

Methods And Results: Using the pre-commercial, highly sensitive hs-cTnT assay, cTnT concentrations were measured in samples from recreational runners obtained before and after running 5 km (trained, n = 43/untrained, n = 122), 15 km (n = 38), 21 km (n = 10), and 42 km (n = 85) (all trained).

Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages.

The adrenal cortex is a critical steroidogenic endocrine tissue, generated at least in part from the coelomic epithelium of the urogenital ridge. Neither the intercellular signals that regulate cortical development and maintenance nor the lineage relationships within the adrenal are well defined. We have explored adrenal Shh activity and found that Shh is expressed in relatively undifferentiated steroidogenic cells, which signal to the overlying capsule and subjacent nonsteroidogenic mesenchyme cells that we also find are progenitors of steroidogenic lineages.

Molecular imaging of macrophage cell death for the assessment of plaque vulnerability.

The ability to identify atherosclerotic plaques that are prone to rupture, also called vulnerable plaques, may provide a major step forward in the recognition of patients that have a high risk of developing acute myocardial infarction. Current clinical risk profiling algorithms, such as the Framingham and Procam risk scores, have reasonable predictive value in the assessment of the 10 year risk. These clinical risk profiling scores typically classify patients into low risk (10-year risk, less than 5%), intermediate risk (5% to 20% risk), and high risk (greater than 20%).

Negative Smad expression and regulation in the developing chick limb.

The inhibitory or negative Smads, Smad6 and Smad7, block TGFbeta superfamily signals of both the BMP and TGFbeta classes by antagonizing the intracellular signal transduction machinery. We report the cloning of one Smad6 and two Smad7 (Smad7a and Smad7b) chick homologs and their expression and regulation in the developing limb. Smad6 and Smad7a are expressed in dynamic patterns reflecting the domains of BMP gene expression in the limb.