PROSTAGLANDINS MEDIATE ARTERIOLAR DILATION TO INCREASED BLOOD-FLOW VELOCITY IN SKELETAL-MUSCLE MICROCIRCULATION

In cremaster muscle of pentobarbital-anesthetized rats, temporary occlusion of an arteriole increased red blood cell velocity (mean increase, 8.2 +/- 1.0 mm/sec from a control velocity of 7.9 +/- 0.7 mm/sec) in proximal parallel arteriolar branches (mean control diameter, 19.4 +/- 0.6 microns). Increases in flow velocity were consistently followed by proportional delayed (6-15 seconds) increases in arteriolar diameter (5.8 +/- 0.7 microns). Administration of NG-monomethyl-L-arginine (200 microM), an inhibitor of the synthesis of endothelium-derived relaxing factor that blocked the arteriolar responses to acetylcholine (1 microM) but not to arachidonic acid (10 microM), did not affect the dilation (mean increase, 8.9 +/- 1.1 microns) due to increases in red blood cell velocity (13.4 +/- 1.5 mm/sec). However, the cyclooxygenase inhibitor indomethacin (or meclofenamate), which completely blocked the dilator response to arachidonic acid but did not change the response to acetylcholine, inhibited the arteriolar dilation (mean increase, 0.3 +/- 0.2 micron) due to increases in red blood cell velocity (9.3 +/- 1.0 mm/sec). Inhibition of prostaglandin synthesis also reduced the increase in calculated blood flow by 57% during occlusion. These results suggest that the arterioles are sensitive to increases in blood flow velocity (wall shear stress), in response to which they release prostaglandins, eliciting vasodilation. The existence of this phenomenon in the skeletal muscle microcirculation suggests a new regulatory mechanism that, by modulation of vascular resistance in the microvascular network, has the role of normalizing wall shear stress and providing for substantial increases in tissue blood flow

ROLE OF ENDOTHELIUM-DERIVED PROSTAGLANDINS IN HYPOXIA-ELICITED ARTERIOLAR DILATION IN RAT SKELETAL-MUSCLE

The aims of the present study were to determine the response of rat cremaster muscle first-order arterioles to hypoxia and the role of endothelium-derived prostaglandins in the response. Isolated arterioles were cannulated, pressurized to 65 mm Hg, and studied in a no-flow condition in a bath containing Krebs' bicarbonate solution, pH 7.4, equilibrated with 21% O2-5% CO2-74% N2 (PO2, 150 mm Hg) or 95% N2-5% CO2 (Po2, 15 mm Hg [hypoxia]). Responses to hypoxia and vasoactive substances were studied before and after removal of the endothelium or blockade of prostaglandin synthesis by the administration of indomethacin (10(-5) M). Addition to the suffusion solution of arachidonic acid (10(-7) and 10(-6) M), prostaglandin E2 (10(-9) and 10(-8) M), acetylcholine (10(-8) and 10(-6) M), or sodium nitroprusside 10(-8) M) evoked significanT arteriolar dilation. When the bath Po2 was reduced from 150 to 15 mm Hg, arteriolar diameters increased by 58.8+/-9.3-mu-m (61%). Removal of the endothelium completely inhibited responses to hypoxia, acetylcholine, and arachidonic acid, whereas responses to sodium nitroprusside and prostaglandin E2 remained unaltered. In arterioles with an intact endothelium, indomethacin completely inhibited the responses to hypoxia and arachidonic acid, whereas responses to acetylcholine and sodium nitroprusside were unaltered. These findings support the conclusion that endothelium-derived prostaglandins mediate the arteriolar dilation to hypoxia in rat skeletal muscle arterioles

Heterogeneous loss of HIV transcription and proviral DNA from 8E5/LAV lymphoblastic leukemia cells revealed by RNA FISH:FLOW analyses

8E5/LAV cells harbor a single HIV provirus, and are used frequently to generate standards for HIV genome quantification. Using flow cytometry-based in situ mRNA hybridization validated by qPCR, we find that different batches of 8E5 cells contain varying numbers of cells lacking viral mRNA and/or viral genomes. These findings raise concerns for studies employing 8E5 cells for quantitation, and highlight the value of mRNA FISH and flow cytometry in the detection and enumeration of HIV-positive cells

LIPID MEDIATORS IN IMMUNE REGULATION AND RESOLUTION

We are all too familiar with the events that follow a bee sting – heat, redness, swelling and pain. These are Celsus’ four cardinal signs of inflammation that are driven by very well defined signals and hormones; in fact targeting the factors that drive this onset phase is the basis upon which most current anti‐inflammatory therapies were developed. We are also very well aware that within a few hours these cardinal signs normally disappear. In other words, inflammation resolves. When it does not, inflammation persists resulting in damaging chronic conditions. While inflammatory onset is actively driven so also is its resolution – years of research has identified novel internal counter‐regulatory signals that work together to switch off inflammation. Among these signals, lipids are potent signaling molecules that regulate an array of immune responses including vascular hyper reactivity and pain as well as leukocyte trafficking and clearance, so‐called resolution. Here, we collate bioactive lipid research to date and summarise the major pathways involved in their biosynthesis and their role in inflammation as well as resolution

Equivalent linear change in cognition between individuals with bipolar disorder and healthy controls over 5 years

ObjectivesCognitive dysfunction is a key feature of bipolar disorder (BD). However, not much is known about its temporal stability, as some studies have demonstrated a neurodegenerative model in BD while others have shown no change in cognitive functioning over time. Building upon our prior work, which examined the natural course of executive functioning, the current study aimed to investigate the natural course of memory, emotion processing, and fine motor dexterity over a 5‐year period in BD and healthy control (HC) samples.MethodsUsing a 5‐year longitudinal cohort, 90 individuals with BD and 17 HCs were administered a battery of neuropsychological tests at study baseline and at 1 and 5 years after study entry that captured four areas of cognitive performance: visual memory, auditory memory, emotion processing, and fine motor dexterity.ResultsLatent growth curve modeling showed no group differences in the slopes of any of the cognitive factors between the BD and HC groups. Age at baseline was negatively associated with visual memory, emotion processing, and fine motor dexterity. Education level was positively associated with auditory and visual memory and fine motor. Female gender was negatively associated with emotion processing.ConclusionsExtending our prior work on longitudinal evaluation of executive functioning, individuals with BD show similar linear change in other areas of cognitive functioning including memory, emotion processing, and fine motor dexterity as compared to unaffected HCs. Age, education, and gender may have some differential effects on cognitive changes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142144/1/bdi12532.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142144/2/bdi12532_am.pd

Ex Vivo Method for Assessing the Mouse Reproductive Tract Spontaneous Motility and a MATLAB-based Uterus Motion Tracking Algorithm for Data Analysis

Dysmenorrhea, or painful cramping, is the most common symptom associated with menses in females and its severity can hinder women's everyday lives. Here, we present an easy and inexpensive method that would be instrumental for testing new drugs decreasing uterine contractility. This method utilizes the unique ability of the entire mouse reproductive tract to exhibit spontaneous motility when maintained ex vivo in a Petri dish containing oxygenated Krebs buffer. This spontaneous motility resembles the wave-like myometrial activity of the human uterus, referred to as endometrial waves. To demonstrate the effectiveness of the method, we employed a well-known uterine relaxant drug, epinephrine. We demonstrate that the spontaneous motility of the entire mouse reproductive tract can be quickly and reversibly inhibited by 1 µM epinephrine in this Petri dish model. Documenting the changes of uterine motility can be easily done using an ordinary smart phone or a sophisticated digital camera. We developed a MATLAB-based algorithm allowing motion tracking to quantify spontaneous uterine motility changes by measuring the rate of uterine horn movements. A major advantage of this ex vivo approach is that the reproductive tract remains intact throughout the entire experiment, preserving all intrinsic intrauterine cellular interactions. The major limitation of this approach is that up to 10-20% of uteri may exhibit no spontaneous motility. Thus far, this is the first quantitative ex vivo method for assessing spontaneous uterine motility in a Petri dish model

Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma.

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B

The SPARC Water Vapor Assessment II: assessment of satellite measurements of upper tropospheric humidity

Nineteen limb-viewing data sets (occultation, passive thermal, and UV scattering) and two nadir upper tropospheric humidity (UTH) data sets are intercompared and also compared to frost-point hygrometer balloon sondes. The upper troposphere considered here covers the pressure range from 300-100 hPa. UTH is a challenging measurement, because concentrations vary between 2-1000 ppmv (parts per million by volume), with sharp changes in vertical gradients near the tropopause. Cloudiness in this region also makes the measurement challenging. The atmospheric temperature is also highly variable ranging from 180-250 K. The assessment of satellite-measured UTH is based on coincident comparisons with balloon frost-point hygrometer sondes, multi-month mapped comparisons, zonal mean time series comparisons, and coincident satellite-to-satellite comparisons. While the satellite fields show similar features in maps and time series, quantitatively they can differ by a factor of 2 in concentration, with strong dependencies on the amount of UTH. Additionally, time-lag response-corrected Vaisala RS92 radiosondes are compared to satellites and the frost-point hygrometer measurements. In summary, most satellite data sets reviewed here show on average similar to 30 % agreement amongst themselves and frost-point data but with an additional similar to 30 % variability about the mean bias. The Vaisala RS92 sonde, even with a time-lag correction, shows poor behavior for pressures less than 200 hPa