Histamine release after intravenous application of short-acting hypnotics. A comparison of etomidate, Althesin (CT1341) and propanidid

The subject of histamine release was investigated in 16 volunteers by means of plasma histamine determination after the administration of etornidate, Althesin, propanidid, and Cremophor EL. Althesin and propanidid caused release of histamine in various degrees of frequency. Blood pressure changes were rather pronounced with both anaesthetic agents; tachycardia reached its maximum in the first and second minute, which seems to be an argument against histamine release as the underlying cause of this reaction. Histamine was, indeed, only released to such an extent (with the exception of one borderline case) that no clinical symptoms other than secretion of gastric juice and erythema were to be expected. After the application of etomidate and Cremophor EL an increase in plasma histamine was not detectable. Changes in the differential blood picture in terms of a decrease in basophils only occurred after Althesin and propanidid; not, however, after etomidate and Cremophor EL. Etomidate is, therefore, the first hypnotic drug for intravenous application which is unlikely to cause chemical histamine release

Electronic tuneability of a structurally rigid surface intermetallic and Kondo lattice: CePt5_5 / Pt(111)

We present an extensive study of structure, composition, electronic and magnetic properties of Ce--Pt surface intermetallic phases on Pt(111) as a function of their thickness. The sequence of structural phases appearing in low energy electron diffraction (LEED) may invariably be attributed to a single underlying intermetallic atomic lattice. Findings from both microscopic and spectroscopic methods, respectively, prove compatible with CePt$_5$ formation when their characteristic probing depth is adequately taken into account. The intermetallic film thickness serves as an effective tuning parameter which brings about characteristic variations of the Cerium valence and related properties. Soft x-ray absorption (XAS) and magnetic circular dichroism (XMCD) prove well suited to trace the changing Ce valence and to assess relevant aspects of Kondo physics in the CePt$_5$ surface intermetallic. We find characteristic Kondo scales of the order of 10$^2$ K and evidence for considerable magnetic Kondo screening of the local Ce $4f$ moments. CePt$_5$/Pt(111) and related systems therefore appear to be promising candidates for further studies of low-dimensional Kondo lattices at surfaces.Comment: 14 pages, 11 figure

Absence of P2Y2 receptor does not prevent bone destruction in a murine model of muscle paralysis-induced bone loss

Increased incidence of bone fractures in the elderly is associated with gradual sarcopenia. Similar deterioration of bone quality is seen with prolonged bed rest, spinal cord injuries or in astronauts exposed to microgravity and, preceded by loss of muscle mass. Signaling mechanisms involving uridine-5′-triphosphate (UTP) regulate bone homeostasis via P2Y2 receptors on osteoblasts and osteoclasts, whilst dictating the bone cells’ response to mechanical loading. We hypothesized that muscle paralysis-induced loss of bone quality would be prevented in P2Y2 receptor knockout (KO) mice. Female mice injected with botulinum toxin (BTX) in the hind limb developed muscle paralysis and femoral DXA analysis showed reduction in bone mineral density (<10%), bone mineral content (<16%) and bone area (<6%) in wildtype (WT) compared to KO littermates (with <13%, <21%, <9% respectively). The femoral metaphyseal strength was reduced equally in both WT and KO (<37%) and <11% in diaphysis region of KO, compared to the saline injected controls. Tibial micro-CT showed reduced cortical thickness (12% in WT vs. 9% in KO), trabecular bone volume (38% in both WT and KO), trabecular thickness (22% in WT vs. 27% in KO) and increased SMI (26% in WT vs. 19% in KO) after BTX. Tibial histomorphometry showed reduced formation in KO (16%) but unchanged resorption in both WT and KO. Furthermore, analyses of DXA and bone strength after regaining the muscle function showed partial bone recovery in the KO but no difference in the bone recovery in WT mice. Primary osteoblasts from KO mice displayed increased viability and alkaline phosphatase activity but, impaired bone nodule formation. Significantly more TRAP-positive osteoclasts were generated from KO mice but displayed reduced resorptive function. Our data showed that hind limb paralysis with a single dose of BTX caused profound bone loss after 3 weeks, and an incomplete reversal of bone loss by week 19. Our findings indicate no role of the P2Y2 receptor in the bone loss after a period of skeletal unloading in mice or, in the bone recovery after restoration of muscle function

A Family of Nonlinear Fourth Order Equations of Gradient Flow Type

Global existence and long-time behavior of solutions to a family of nonlinear fourth order evolution equations on $R^d$ are studied. These equations constitute gradient flows for the perturbed information functionals $F[u] = 1/(2\alpha) \int | D (u^\alpha) |^2 dx + \lambda/2 \int |x|^2 u dx$ with respect to the $L^2$-Wasserstein metric. The value of $\alpha$ ranges from $\alpha=1/2$, corresponding to a simplified quantum drift diffusion model, to $\alpha=1$, corresponding to a thin film type equation.Comment: 33 pages, no figure

Chronic Fluid Flow Is an Environmental Modifier of Renal Epithelial Function

Although solitary or sensory cilia are present in most cells of the body and their existence has been known since the sixties, very little is been known about their functions. One suspected function is fluid flow sensing- physical bending of cilia produces an influx of Ca++, which can then result in a variety of activated signaling pathways. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a progressive disease, typically appearing in the 5th decade of life and is one of the most common monogenetic inherited human diseases, affecting approximately 600,000 people in the United States. Because ADPKD is a slowly progressing disease, I asked how fluid flow may act, via the primary cilium, to alter epithelial physiology during the course of cell turnover. I performed an experiment to determine under what conditions fluid flow can result in a change of function of renal epithelial tissue. A wildtype epithelial cell line derived the cortical collecting duct of a heterozygous offspring of the Immortomouse (Charles River Laboratory) was selected as our model system. Gentle orbital shaking was used to induce physiologically relevant fluid flow, and periodic measurements of the transepithelial Sodium current were performed. At the conclusion of the experiment, mechanosensitive proteins of interest were visualized by immunostaining. I found that fluid flow, in itself, modifies the transepithelial sodium current, cell proliferation, and the actin cytoskeleton. These results significantly impact the understanding of both the mechanosensation function of primary cilia as well as the understanding of ADPKD disease progression

North Pacific deglacial hypoxic events linked to abrupt ocean warming

Marine sediments from the North Pacific document two episodes of expansion and strengthening of the subsurface oxygen minimum zone (OMZ) accompanied by seafloor hypoxia during the last deglacial transition. The mechanisms driving this hypoxia remain under debate. We present a new high-resolution alkenone palaeotemperature reconstruction from the Gulf of Alaska that reveals two abrupt warming events of 4–5 degrees Celsius at the onset of the Bølling and Holocene intervals that coincide with sudden shifts to hypoxia at intermediate depths. The presence of diatomaceous laminations and hypoxia-tolerant benthic foraminiferal species, peaks in redox-sensitive trace metals, and enhanced ¹⁵N/¹⁴N ratio of organic matter, collectively suggest association with high export production. A decrease in ¹⁸O/¹⁶O values of benthic foraminifera accompanying the most severe deoxygenation event indicates subsurface warming of up to about 2 degrees Celsius. We infer that abrupt warming triggered expansion of the North Pacific OMZ through reduced oxygen solubility and increased marine productivity via physiological effects; following initiation of hypoxia, remobilization of iron from hypoxic sediments could have provided a positive feedback on ocean deoxygenation through increased nutrient utilization and carbon export. Such a biogeochemical amplification process implies high sensitivity of OMZ expansion to warming

An Intact Kidney Slice Model to Investigate Vasa Recta Properties and Function in situ

Background: Medullary blood flow is via vasa recta capillaries, which possess contractile pericytes. In vitro studies using isolated descending vasa recta show that pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in ‘live’ kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. Results: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10–30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E2) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L-NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). Conclusions: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow

Past abrupt changes, tipping points and cascading impacts in the Earth system

The geological record shows that abrupt changes in the Earth system can occur on timescales short enough to challenge the capacity of human societies to adapt to environmental pressures. In many cases, abrupt changes arise from slow changes in one component of the Earth system that eventually pass a critical threshold, or tipping point, after which impacts cascade through coupled climate–ecological–social systems. The chance of detecting abrupt changes and tipping points increases with the length of observations. The geological record provides the only long-term information we have on the conditions and processes that can drive physical, ecological and social systems into new states or organizational structures that may be irreversible within human time frames. Here, we use well-documented abrupt changes of the past 30 kyr to illustrate how their impacts cascade through the Earth system. We review useful indicators of upcoming abrupt changes, or early warning signals, and provide a perspective on the contributions of palaeoclimate science to the understanding of abrupt changes in the Earth system

Loss of apical monocilia on collecting duct principal cells impairs ATP secretion across the apical cell surface and ATP-dependent and flow-induced calcium signals

Renal epithelial cells release ATP constitutively under basal conditions and release higher quantities of purine nucleotide in response to stimuli. ATP filtered at the glomerulus, secreted by epithelial cells along the nephron, and released serosally by macula densa cells for feedback signaling to afferent arterioles within the glomerulus has important physiological signaling roles within kidneys. In autosomal recessive polycystic kidney disease (ARPKD) mice and humans, collecting duct epithelial cells lack an apical central cilium or express dysfunctional proteins within that monocilium. Collecting duct principal cells derived from an Oak Ridge polycystic kidney (orpkTg737) mouse model of ARPKD lack a well-formed apical central cilium, thought to be a sensory organelle. We compared these cells grown as polarized cell monolayers on permeable supports to the same cells where the apical monocilium was genetically rescued with the wild-type Tg737 gene that encodes Polaris, a protein essential to cilia formation. Constitutive ATP release under basal conditions was low and not different in mutant versus rescued monolayers. However, genetically rescued principal cell monolayers released ATP three- to fivefold more robustly in response to ionomycin. Principal cell monolayers with fully formed apical monocilia responded three- to fivefold greater to hypotonicity than mutant monolayers lacking monocilia. In support of the idea that monocilia are sensory organelles, intentionally harsh pipetting of medium directly onto the center of the monolayer induced ATP release in genetically rescued monolayers that possessed apical monocilia. Mechanical stimulation was much less effective, however, on mutant orpk collecting duct principal cell monolayers that lacked apical central monocilia. Our data also show that an increase in cytosolic free Ca2+ primes the ATP pool that is released in response to mechanical stimuli. It also appears that hypotonic cell swelling and mechanical pipetting stimuli trigger release of a common ATP pool. Cilium-competent monolayers responded to flow with an increase in cell Ca2+ derived from both extracellular and intracellular stores. This flow-induced Ca2+ signal was less robust in cilium-deficient monolayers. Flow-induced Ca2+ signals in both preparations were attenuated by extracellular gadolinium and by extracellular apyrase, an ATPase/ADPase. Taken together, these data suggest that apical monocilia are sensory organelles and that their presence in the apical membrane facilitates the formation of a mature ATP secretion apparatus responsive to chemical, osmotic, and mechanical stimuli. The cilium and autocrine ATP signaling appear to work in concert to control cell Ca2+. Loss of a cilium-dedicated autocrine purinergic signaling system may be a critical underlying etiology for ARPKD and may lead to disinhibition and/or upregulation of multiple sodium (Na+) absorptive mechanisms and a resultant severe hypertensive phenotype in ARPKD and, possibly, other diseases