Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model.

BACKGROUND AND PURPOSE: cAMP and pharmacological inhibition of PDE4, which degrades it, are promising therapeutic targets for the treatment of spinal cord injury (SCI). Using our previously described in vitro SCI model, we studied the mechanisms by which cAMP modulators promote neurite outgrowth and myelination using enantiomers of the PDE4-specific inhibitor rolipram and other modulators of downstream signalling effectors. EXPERIMENTAL APPROACH: Rat mixed neural cell myelinating cultures were cut with a scalpel and treated with enantiomers of the PDE4-specific inhibitor rolipram, Epac agonists and PKA antagonists. Neurite outgrowth, density and myelination were assessed by immunocytochemistry and cytokine levels analysed by qPCR. KEY RESULTS: Inhibition of the high-affinity rolipram-binding state (HARBS), rather than the low-affinity rolipram binding state (LARBS) PDE4 conformer promoted neurite outgrowth and myelination. These effects were mediated through the activation of Epac and not through PKA. Expression of the chemokine CXCL10, known to inhibit myelination, was markedly elevated in astrocytes after Rho inhibition and this was blocked by inhibition of Rho kinase or PDE4. CONCLUSIONS AND IMPLICATIONS: PDE4 inhibitors targeted at the HARBS conformer or Epac agonists may provide promising novel targets for the treatment of SCI. Our study demonstrates the differential mechanisms of action of these compounds, as well as the benefit of a combined pharmacological approach and highlighting potential promising targets for the treatment of SCI. These findings need to be confirmed in vivo.

Science potential from a Europa lander.

The prospect of a future soft landing on the surface of Europa is enticing, as it would create science opportunities that could not be achieved through flyby or orbital remote sensing, with direct relevance to Europa's potential habitability. Here, we summarize the science of a Europa lander concept, as developed by our NASA-commissioned Science Definition Team. The science concept concentrates on observations that can best be achieved by in situ examination of Europa from its surface. We discuss the suggested science objectives and investigations for a Europa lander mission, along with a model planning payload of instruments that could address these objectives. The highest priority is active sampling of Europa's non-ice material from at least two different depths (0.5-2 cm and 5-10 cm) to understand its detailed composition and chemistry and the specific nature of salts, any organic materials, and other contaminants. A secondary focus is geophysical prospecting of Europa, through seismology and magnetometry, to probe the satellite's ice shell and ocean. Finally, the surface geology can be characterized in situ at a human scale. A Europa lander could take advantage of the complex radiation environment of the satellite, landing where modeling suggests that radiation is about an order of magnitude less intense than in other regions. However, to choose a landing site that is safe and would yield the maximum science return, thorough reconnaissance of Europa would be required prior to selecting a scientifically optimized landing site.

MAPKs and their relevance to arthritis and inflammation.

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which imbalances in pro- and anti-inflammatory cytokines promote the induction of autoimmunity, inflammation and joint destruction. The importance of inflammatory cytokines in the pathogenesis of RA has been underscored by the success of biologics that act to block the effects of cytokines, such as tumour necrosis factor-alpha, interleukin (IL)-1 or IL-6, in treating disease. Mitogen-activated protein kinases (MAPKs) have been implicated as playing key regulatory roles in the production of these pro-inflammatory cytokines and downstream signalling events leading to joint inflammation and destruction. This article reviews the evidence that MAPKs play important roles in the pathogenesis of RA and discusses their therapeutic potential as drug targets.

Discovery of gaseous S2 in Io's Pele plume.

Spectroscopy of Io's Pele plume against Jupiter by the Hubble Space Telescope in October 1999 revealed absorption due to S2 gas, with a column density of 1.0 +/- 0.2 x 10(16) per square centimeter, and probably also SO(2) gas with a column density of 7 +/- 3 x 10(16) per square centimeter. This SO2/S2 ratio (3 to 12) is expected from equilibration with silicate magmas near the quartz-fayalite-magnetite or wüstite-magnetite buffers. Condensed S3 and S4, probable coloring agents in Pele's red plume deposits, may form by polymerization of the S2, which is unstable to ultraviolet photolysis. Diffuse red deposits near other Io volcanoes suggest that venting and polymerization of S2 gas is a widespread feature of Io volcanism.

Effects of 3 analgesic regimens on the perception of pain after removal of femoral artery sheaths.

BACKGROUND: Effective pain management after removal of femoral artery sheaths after percutaneous transluminal coronary angioplasty is highly individualized and requires frequent, accurate assessment and administration of analgesics as needed. OBJECTIVE: To determine which of 3 analgesic regimens is most effective in decreasing patients' perception of pain with the fewest side effects after removal of a femoral artery sheath. SAMPLE: 130 adult who had undergone percutaneous transluminal coronary angioplasty and were in an 8-bed cardiac short-stay unit in a 1400-bed acute care hospital. METHOD: Patients were randomized to receive either intravenous morphine, intravenous fentanyl, subcutaneous lidocaine around the sheath site, or an intravenous placebo before sheath removal. Rescue analgesia (intravenous fentanyl) was made available to all groups. Patients used a visual analog scale to assess pain within 10 minutes before, 1 minute after, and 20 minutes after sheath removal. Pain levels, frequency of side effects, and use of rescue analgesia were compared among groups. RESULTS: Age, sex, number of stents, and frequency of hematomas did not differ significantly among groups. Pain ratings, use of rescue analgesia, and side effects (nausea, vomiting, or vasovagal symptoms) were not significantly different among treatment groups. Ratings of pain were slightly higher immediately after sheath removal in all groups. CONCLUSION: For most patients, removal of femoral artery sheaths and manual compression for hemostasis are relatively pain-free. Pain scores among patients given analgesia with subcutaneous lidocaine, intravenous morphine, or intravenous fentanyl were not significantly different from pain scores among control patients.

Far-ultraviolet imaging spectroscopy of Io's atmosphere with HST/STIS.

Well-resolved far-ultraviolet spectroscopic images of O I, S I, and previously undetected H ILyman-alpha emission from Io were obtained with the Hubble space telescope imaging spectrograph (STIS). Detected O I and S I lines (1250 to 1500 angstroms) have bright equatorial spots (up to 2.5 kilorayleighs) that shift position with jovian magnetic field orientation; limb glow that is brighter on the hemisphere facing the jovian magnetic equator; and faint diffuse emission extending to approximately 20 Io radii. All O I and S I features brightened by approximately 50 percent in the last two images, concurrently with a ground-based observation of increased iogenic [O I] 6300-angstrom emission. The H ILyman-alpha emission, consisting of a small, approximately 2-kilorayleigh patch near each pole, has a different morphology and time variation.

Fluorescent hydroxyl emissions from Saturn's ring atmosphere.

Just before earth passed through Saturn's ring plane on 10 August 1995, the Hubble Space Telescope Faint Object Spectrograph detected ultraviolet fluorescent emissions from a tenuous atmosphere of OH molecules enveloping the rings. Brightnesses decrease with increasing distance above the rings, implying a scale height of about 0.45 Saturn radii (Rs). A spatial scan 0.28Rs above the A and B rings indicates OH column densities of about 10(13) cm(-2) and number densities of up to 700 cm(-3). Saturn's rings must produce roughly 10(25) to 10(29) OH molecules per second to maintain the observed OH distribution.

HST spectroscopic observations of Jupiter after the collision of comet Shoemaker-Levy 9.

Ultraviolet spectra obtained with the Hubble Space Telescope identified at least 10 molecules and atoms in the perturbed stratosphere near the G impact site, most never before observed in Jupiter. The large mass of sulfur-containing material, more than 10(14) grams in S2 alone, indicates that many of the sulfur-containing molecules S2, CS2, CS, H2S, and S+ may be derived from a sulfur-bearing parent molecule native to Jupiter. If so, the fragment must have penetrated at least as deep as the predicted NH4SH cloud at a pressure of approximately 1 to 2 bars. Stratospheric NH3 was also observed, which is consistent with fragment penetration below the cloud tops. Approximately 10(7) grams of neutral and ionized metals were observed in emission, including Mg II, Mg I, Si I, Fe I, and Fe II. Oxygen-containing molecules were conspicuous by their absence; upper limits for SO2, SO, CO, SiO, and H2O are derived.

Response of the Io plasma torus to comet Shoemaker-Levy 9.

Spectroscopic and imaging observations of the Io plasma torus were made in June and July 1994 in conjunction with the encounter of periodic comet Shoemaker-Levy 9 with Jupiter. Characteristic emissions from sulfur and oxygen ions showed a decline of about 30 percent in the extreme ultraviolet and an increase of about 40 percent in the far ultraviolet relative to preimpact observations. Changes in the extreme ultraviolet may be indicative of small changes in the torus electron temperature as a result of quenching of electrons by dust associated with the comet passage. However, no new emission features indicative of fragment dust within the torus were detected. The characteristic torus morphology seen in ground-based imaging was typical of that observed in the past.

Detection of an oxygen atmosphere on Jupiter's moon Europa.

Europa, the second large satellite out from Jupiter, is roughly the size of Earth's Moon, but unlike the Moon, it has water ice on its surface. There have been suggestions that an oxygen atmosphere should accumulate around such a body, through reactions which break up the water molecules and form molecular hydrogen and oxygen. The lighter H2 molecules would escape from Europa relatively easily, leaving behind an atmosphere rich in oxygen. Here we report the detection of atomic oxygen emission from Europa, which we interpret as being produced by the simultaneous dissociation and excitation of atmospheric O2 by electrons from Jupiter's magnetosphere. Europa's molecular oxygen atmosphere is very tenuous, with a surface pressure about 10(-11) that of the Earth's atmosphere at sea level.

Femoral arterial sheath removal after PTCA: a cross-Canada survey.

A cross-sectional survey was conducted to examine current Canadian practices in the nursing and medical management of femoral arterial sheath removal (SR) after PTCA (percutaneous transluminal coronary angioplasty). The purposes of the study were to (a) investigate the roles of the nurses and physicians in SR, (b) assess the length of time arterial sheaths are left in place and patients kept on bedrest, and (c) describe the routine medical protocols used for pain and anticoagulation therapy. Of the 35 hospitals that perform PTCA in Canada, 30 responded to the survey (response rate of 86%). Nurses had primary responsibility for SR in 13% of the sites and shared responsibility with physicians for SR in a further 10% of the institutions. When nurses were trained to remove sheaths, they assumed responsibility for the adjunctive steps to establish hemostasis. One third of hospitals removed sheaths in 4 hours or less; approximately 75% of them removed sheaths in 6 hours or less after PTCA. Patients are kept on bedrest for 6 hours or less following hemostasis in half, and 8 hours or less at three-quarters of the hospitals. Post-PTCA and pre-SR anticoagulant monitoring was used in almost half of the sites. Premedication for SR varied from no premedication to combinations of three intravenous medications plus local anaesthetic. Survey results showed that in almost one quarter of the Canadian institutions where PTCA is performed, nurses play a role in SR. Results also showed that there is no uniformity in post-PTCA SR across Canada and that further research is needed to identify the optimum approach to managing this common cardiovascular procedure.

PTCA in elderly patients: hospital events.

BACKGROUND: Medical treatment of the elderly is changing to include the aggressive management of coronary artery disease with percutaneous transluminal coronary angioplasty. OBJECTIVE: The purpose of this study was to review major hospital events of patients aged 70 years or more, who underwent a first percutaneous transluminal coronary angioplasty. METHODS: A retrospective medical record review was done of 246 consecutive patients of 70 years or more, from January 1985 to December 1988, at a tertiary care community hospital. Adverse events and the factors that influenced outcome were identified. RESULTS: Of 246 patients (age range, 70-85 years, mean = 73.6), 19 died, 4 had a cerebral vascular accident, 11 had a transfusion and 11 underwent coronary artery bypass grafting. Sixteen patients had acute vessel closure and 8 died. Twenty-five patients had one event and 21 patients had more than one. DISCUSSION: The event rate after percutaneous transluminal coronary angioplasty in the elderly is high. CONCLUSIONS: Knowledge of the factors that influence adverse events (diagnostic category, success of procedure, degree of coronary artery disease and age) will assist the critical care team to plan and implement appropriate care.

Successful limb salvage with prostaglandin infusion: a review of ergotamine toxicity.

OBJECTIVE: A case of severe acute peripheral arterial insufficiency secondary to ergotamine toxicity treated successfully with intravenously administered prostaglandin is presented to highlight the features of this condition and to demonstrate the efficacy of treatment with prostaglandin infusion. CLINICAL FEATURES: A 35-year-old unemployed Caucasian woman with a background of polypharmacy abuse and recurrent migraines presented to St Vincent's Hospital Emergency Department with limb-threatening ischaemia of both legs secondary to chronic ergotamine overuse. INTERVENTION AND OUTCOME: A prostaglandin infusion was started and a dramatic and rapid improvement of her peripheral circulation occurred within six hours. CONCLUSION: Ergotamine toxicity is an uncommon but well documented cause of peripheral vascular insufficiency that should be recognised and treated aggressively because its sequelae can be disastrous. Intravenously administered prostaglandin proved to be successful in this case and is a logical choice as first-line therapy for ergotamine toxicity.

The coexistence of obstruction at the ureteropelvic and ureterovesical junctions.

Obstructions at the ureteropelvic junction and ureterovesical junction were found to coexist in 14 children seen over an 11-year period. The coexistence of these two conditions made the diagnosis of each difficult. In only three children were both diagnoses made preoperatively; in the others, the second diagnosis was either suspected at surgery or was made on postoperative uroradiologic studies. Of five children in whom the initial diagnosis was obstruction at the ureteropelvic junction, only two have needed surgery for obstruction at the ureterovesical junction. Seven children had an initial diagnosis of obstruction at the ureterovesical junction, and all required subsequent pyeloplasty to relieve coexisting obstruction at the ureteropelvic junction. Therefore, our experience suggests that when both obstructions are known to exist or are suspected preoperatively, it is advisable to repair the stenosis at the ureteropelvic junction first, as distal ureteral surgery may not be necessary.

Transient aortic arch syndrome with dysphasia due to ergotism.

A 55-year-old woman with an aortic arch syndrome of acute onset and dysphasia, resulting from the excessive administration of ergotamine tartrate suppositories, is described. Complete resolution of symptoms and return of upper limb and carotid artery pulses to normal occurred within four days of cessation of the ergot derivative. Lower limb involvement was conspicuously absent in this case.