Acute complete heart block in dogs

A study has been conducted immediately and up to 18 days after the surgical production of complete heart block in dogs. Immediately after surgery cardiac output, coronary flow, and mean arterial pressure were reduced in rough proportion to the degree of bradycardia. In time, these measures began to return toward preoperative levels. Paralleling the diminished left ventricular work was a diminished left ventricular oxygen consumption with little consequent change in myocardial efficiency. Small rises were detected in central venous pressure. At autopsy, the only unequivocal abnormality was myocardial hypertrophy which became measurable between 2 and 18 days after operation

A photoisomerizable muscarinic antagonist. Studies of binding and of conductance relaxations in frog heart

These experiments employ the photoisomerizable compound, 3,3'-bis- [alpha-(trimethylammonium)methyl]azobenzene (Bis-Q), to study the response to muscarinic agents in frog myocardium. In homogenates from the heart, trans-Bis-Q blocks the binding of [3H]-N-methylscopolamine to muscarinic receptors. In voltage-clamped atrial trabeculae, trans- Bis-Q blocks the agonist-induced potassium conductance. The equilibrium dose-response curve for carbachol is shifted to the right, suggesting competitive blockade. Both the biochemical and electrophysiological data yield a dissociation constant of 4-5 microM for trans-Bis-Q; the cis configuration is severalfold less potent as a muscarinic blocker. Voltage-clamped preparations were exposed simultaneously to carbachol and Bis-Q and were subjected to appropriately filtered flashes (less than 1 ms duration) from a xenon flashlamp. Trans leads to cis and cis leads to trans photoisomerizations cause small (less than 20%) increases and decreases, respectively, in the agonist-induced current. The relaxation follows an S-shaped time course, including an initial delay or period of zero slope. The entire waveform is described by [1 - exp(-kt)]n. At 23 degrees C, k is approximately 3 s-1 and n is 2. Neither k nor n is affected when: (a) [Bis-Q] is varied between 5 and 100 microM; (b) [carbachol] is varied between 1 and 50 microM; (c) carbachol is replaced by other agonists (muscarine, acetylcholine, or acetyl-beta-methylcholine); or (d) the voltage is varied between the normal resting potential and a depolarization of 80 mV. However, in the range of 13-30 degrees C, k increases with temperature; the Q10 is between 2 and 2.5. In the same range, n does not change significantly. Like other investigators, we conclude that the activation kinetics of the muscarinic K+ conductance are not determined by ligand-receptor binding, but rather by a subsequent sequence of two (or more) steps with a high activation energy

Chronic heart block in dogs; a method for producing experimental heart failure

A method is described for the production of chronic atrioventricular block in dogs, by incision of the region of the bundle of His through the open right atrium during temporary caval occlusion. Exercise tolerances, chest x-ray films, electrocardiograms, phonocardiograms, cardiac outputs, intracardiac pressures, femoral pressures, and left ventricular coronary flows were obtained preoperatively and from 1 to 10 months postoperatively. The majority of the animals developed clinical, laboratory, and pathological evidence of congestive heart failure. All animals had generalized myocardial hypertrophy

A primary breast cancer with distinct foci of estrogen receptor-alpha positive and negative cells derived from the same clonal origin as revealed by whole exome sequencing

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Background/purpose: Tumor heterogeneity is a now well-recognized phenomenon that can affect the classification, prognosis and treatment of human cancers. Heterogeneity is often described in primary breast cancers based upon histologic subtypes, hormone- and HER2-receptor status, and immunolabeling for various markers, which can be seen within a single tumor as mixed cellular populations, or as separate discrete foci. Experimental design/methods: Here, we present a case report of a patient’s primary breast cancer that had two separate but adjacent histologic components, one that was estrogen receptor (ER) positive, and the other ER negative. Each component was subjected to whole exome sequencing and compared for gene identity to determine clonal origin. Results: Using prior bioinformatic tools, we demonstrated that both the ER positive and negative components shared many variants, including passenger and driver alterations. Copy number variations also supported the two components were derived from a single common clone. Conclusions: These analyses strongly suggest that the two ER components of this patient’s breast cancer were derived from the same clonal origin. Our results have implications for the evolution of breast cancers with mixed histologies, and how they might be best managed for optimal therapy

Cellular Resolution Maps of X Chromosome Inactivation: Implications for Neural Development, Function, and Disease

SummaryFemale eutherian mammals use X chromosome inactivation (XCI) to epigenetically regulate gene expression from ∼4% of the genome. To quantitatively map the topography of XCI for defined cell types at single cell resolution, we have generated female mice that carry X-linked, Cre-activated, and nuclear-localized fluorescent reporters—GFP on one X chromosome and tdTomato on the other. Using these reporters in combination with different Cre drivers, we have defined the topographies of XCI mosaicism for multiple CNS cell types and of retinal vascular dysfunction in a model of Norrie disease. Depending on cell type, fluctuations in the XCI mosaic are observed over a wide range of spatial scales, from neighboring cells to left versus right sides of the body. These data imply a major role for XCI in generating female-specific, genetically directed, stochastic diversity in eutherian mammals on spatial scales that would be predicted to affect CNS function within and between individuals

The effectiveness of public health interventions to reduce the health impact of climate change:a systematic review of systematic reviews

Climate change is likely to be one of the most important threats to public health in the coming years. Yet despite the large number of papers considering the health impact of climate change, few have considered what public health interventions may be of most value in reducing the disease burden. We aimed to evaluate the effectiveness of public health interventions to reduce the disease burden of high priority climate sensitive diseases

Mobile evaporite enhances the cycle of physical–chemical erosion in badlands

Chemical weathering driven by physical erosion is a natural process that strongly affects chemical and solid matter budgets at the Earth's surface. However, the influence of extreme climatic erosion on chemical weathering dynamics is poorly understood. Badland landscapes formed in highly erodible substrates have the potential to respond to individual events on scales that are rapid enough for direct observation. Here, we assess the geochemical and grain-size composition of suspended sediment and riverine chemistry measurements collected from two catchments during the 2017 Nesat and Haitang typhoons in southwestern (SW) Taiwan. During the typhoons, the Na+ concentration covaried with suspended sediment concentration (SSC), which we attributed to sodium-induced deflocculation. Evaporite weathering at peak rainfall is succeeded by peak silicate weathering at maximum discharge. Overall, our observations suggest that initial weathering of near-surface evaporite enhances the physical erosion of silicate rock during extreme rainfall events.</p