Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms

Randomized, open-label, phase 1/2a study to determine the maximum tolerated dose of intraventricular sustained release nimodipine for subarachnoid hemorrhage (NEWTON [Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage])

BACKGROUND AND PURPOSE—: We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. METHODS—: Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. RESULTS—: Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P=0.027) enteral nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). CONCLUSIONS—: EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. CLINICAL TRIAL REGISTRATION—: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01893190

Stratigraphy and sedimentology of early Pennsylvanian red beds at Lower Cove, Nova Scotia, Canada: the Little River Formation with redefinition of the Joggins Formation

The coastal cliffs along the eastern shore of Chignecto Bay, Nova Scotia contain one of the finest Carboniferous sections in the world. In 1843, Sir William Logan measured the entire section as the first project of the Geological Survey of Canada, and defined eight stratigraphic divisions. We have re-measured a section corresponding almost exactly with Logan’s Division 5 in bed-by-bed detail. The strata are exposed in the wave-cut platform and low-relief bluffs of a 2 km-long section at Lower Cove, near Joggins, north and south of Little River. This 635.8 metre-thick succession until now has been included within the basal part of the Joggins Formation, and overlies the Boss Point Formation. However, the studied strata are lithologically distinct, and are formally recognized as the new Little River Formation. This formation is bounded by regionally important surfaces and is traceable inland for 30 kilometres from its Lower Cove type section. Facies analysis indicates that it represents the deposits of a well-drained alluvial plain dissected by shallow rivers characterized by flashy flow. It can be clearly distinguished from the underlying Boss Point Formation (Logan’s Division 6) by its much smaller channels, and from the overlying Joggins Formation (Logan’s Division 4) by lack of coal seams and bivalve-bearing limestone beds. Palynological assemblages indicate that the Little River Formation is of probable late Namurian to basal Westphalian (basal Langsettian) age, and is a likely time-equivalent of the informal Grand-Anse formation of southeast New Brunswick. Resumé Les falaises côtières longeant le rivage oriental de la baie Chignectou, en Nouvelle-Écosse, abritent l’un des stratotypes carbonifères les plus intéressants dans le monde. Sir William Logan avait mesuré en 1843 l’ensemble du stratotype dans le cadre du premier projet de la Commission géologique du Canada et il avait défini huit divisions stratigraphiques. Nous avons mesuré à nouveau un stratotype correspondant presque exactement dans ses détails couche par couche à la division 5 de Logan. Les strates affleurent dans une plate-forme d’érosion et des falaises de relief émoussé d’un secteur de deux kilomètres de longueur à l’anse Lower, près de Joggins, au nord et au sud de la rivière Little. Cette succession de 635,8 mètres d’épaisseur avait jusqu’à maintenant été incluse à l’intérieur de la partie basale de la Formation de Joggins et elle recouvre la Formation de Boss Point. Les strates étudiées sont cependant lithologiquement distinctes et on les reconnaît officiellement en tant que nouvelle Formation de Little River. Cette formation est limitée par des surfaces importantes à l’échelle régionale; on peut la retracer à l’intérieur des terres sur 30 kilomètres à partir de son stratotype de l’anse Lower. Une analyse du faciès révèle qu’il représente les dépôts d’une plaine alluviale bien drainée, sectionnée par des rivières peu profondes caractérisées par des crues éclair. On peut nettement la distinguer de la Formation sous-jacente de Boss Point (division 6 de Logan), grâce à ses canaux beaucoup plus petits, ainsi que de la Formation sus-jacente de Joggins (division 4 de Logan), par l’absence de couches houillères et de couches de calcaire abritant des lamellibranches. Les assemblages palynologiques révèlent que la Formation de Little River remonte probablement à la période du Namurien tardif au Westphalien basal (Langsettien basal) et qu’elle constitue vraisemblablement un équivalent chronologique de la Formation officieuse de Grande-Anse dans le sud-est du Nouveau-Brunswick

Identification of Alternative Transcripts Encoding the Essential Murine Gammaherpesvirus Lytic Transactivator RTA

The essential immediate early transcriptional activator RTA, encoded by gene 50, is conserved among all characterized gammaherpesviruses. Analyses of a recombinant murine gammaherpesvirus 68 (MHV68) lacking both of the known gene 50 promoters (G50DblKo) revealed that this mutant retained the ability to replicate in the simian kidney epithelial cell line Vero but not in permissive murine fibroblasts following low-multiplicity infection. However, G50DblKo replication in permissive fibroblasts was partially rescued by high-multiplicity infection. In addition, replication of the G50DblKo virus was rescued by growth on mouse embryonic fibroblasts (MEFs) isolated from IFN-α/βR(−/−) mice, while growth on Vero cells was suppressed by the addition of alpha interferon (IFN-α). 5′ rapid amplification of cDNA ends (RACE) analyses of RNAs prepared from G50DblKo and wild-type MHV68-infected murine macrophages identified three novel gene 50 transcripts initiating from 2 transcription initiation sites located upstream of the currently defined proximal and distal gene 50 promoters. In transient promoter assays, neither of the newly identified gene 50 promoters exhibited sensitivity to IFN-α treatment. Furthermore, in a single-step growth analysis RTA levels were higher at early times postinfection with the G50DblKo mutant than with wild-type virus but ultimately fell below the levels of RTA expressed by wild-type virus at later times in infection. Infection of mice with the MHV68 G50DblKo virus demonstrated that this mutant virus was able to establish latency in the spleen and peritoneal exudate cells (PECs) of C57BL/6 mice with about 1/10 the efficiency of wild-type virus or marker rescue virus. However, despite the ability to establish latency, the G50DblKo virus mutant was severely impaired in its ability to reactivate from either latently infected splenocytes or PECs. Consistent with the ability to rescue replication of the G50DblKo mutant by growth on type I interferon receptor null MEFs, infection of IFN-α/βR(−/−) mice with the G50DblKo mutant virus demonstrated partial rescue of (i) acute virus replication in the lungs, (ii) establishment of latency, and (iii) reactivation from latency. The identification of additional gene 50/RTA transcripts highlights the complex mechanisms involved in controlling expression of RTA, likely reflecting time-dependent and/or cell-specific roles of different gene 50 promoters in controlling virus replication. Furthermore, the newly identified gene 50 transcripts may also act as negative regulators that modulate RTA expression. IMPORTANCE The viral transcription factor RTA, encoded by open reading frame 50 (Orf50), is well conserved among all known gammaherpesviruses and is essential for both virus replication and reactivation from latently infected cells. Previous studies have shown that regulation of gene 50 transcription is complex. The studies reported here describe the presence of additional alternatively initiated, spliced transcripts that encode RTA. Understanding how expression of this essential viral gene product is regulated may identify new strategies for interfering with infection in the setting of gammaherpesvirus-induced diseases

Noise and performance of propellers for light aircraft : final report

July 1980Project Manager: G. P. Succi ; Contributors: E.E. Larrabee, P.D. [i.e. P. B.] Dunbeck, D.H. Munro, J.A. Zimmer; Principal Investigators: K.U. Ingard, J.L. KerrebrockIncludes bibliographical references (pages 22-23)Final report. February 24, 1978 to July 31, 1980Introduction and Summary: The project "Noise and Performance of Propellers for Light Aircraft," Contract #NASl-15154 between NASA Langley and MIT, has now been completed, and the main results obtained are summarized in this report and its appendices. The primary practical objective of the study was to explore the possibility of reducing the noise from a general aviation type propeller without altering significantly its aerodynamic performance or the engine characteristics. After an extensive study of this question, involving aerodynamic and acoustic theory, design, construction and wind tunnel testing of model propellers, design and manufacturing of full scale propellers and, finally, flight tests, we are pleased to report that for one of the propellers tested an overall reduction of 4.8 dBA as measured in a flight test was achieved.The theory deals with aerodynamics and acoustics of lightly loaded propellers with subsonic tip speeds and includes studies of the effects of sweeping the blades, altering the radial load distribution, and changing the number of blades. These studies lead to new insight into the general problem of sound generation from moving bodies. Of particular value are the algorithms, which are well suited for computer coding. The wind tunnel tests involved three propellers, 1/4 scale, including a replica of a fixed pitch propeller used on a 150 HP single engine airplane. The other two propellers were designed to have the peak radial load distribution shifted inboard. The acoustic wind tunnel which was used in these tests enabled measurement not only of the radiated sound field but also the thrust and torque of the propeller. In addition, the load distribution was determined indirectly from wake surveys.Sound pressure signatures were obtained at different locations and speeds (up to a tip Mach number of 0.75) and compared with theoretical predictions in which only the shape and motion of the propeller were needed as input parameters; no empirical adjustments were made. Agreement to within a few percent was obtained throughout except in the presence of a transonic "buzz" instability which was encountered within a narrow speed range. On the basis of the theoretical analysis and its verification in the model tests, a two-bladed fixed pitch propeller was designed for a 150 HP single engine airplane. Flight tests with this propeller indicated about the same performance as the production propeller for that airplane, but the maximum sound level during a full power flyover at 1000 feet was found to be 4.8 dBA lower. A second propeller, with three blades and fixed pitch, was designed for the Ohio State University 180 HP single engine airplane.Flight tests of this propeller have not yet been made at this time.NASA Contract NAS1-1515

Development of a rapid serological assay for the diagnosis of strongyloidiasis using a novel diffraction-based biosensor technology.

BACKGROUND: Strongyloidiasis is a persistent human parasitic infection caused by the intestinal nematode, Strongyloides stercoralis. The parasite has a world-wide distribution, particularly in tropical and subtropical regions with poor sanitary conditions. Since individuals with strongyloidiasis are typically asymptomatic, the infection can persist for decades without detection. Problems arise when individuals with unrecognized S. stercoralis infection are immunosuppressed, which can lead to hyper-infection syndrome and disseminated disease with an associated high mortality if untreated. Therefore a rapid, sensitive and easy to use method of diagnosing Strongyloides infection may improve the clinical management of this disease. METHODOLOGY/PRINCIPAL FINDINGS: An immunological assay for diagnosing strongyloidiasis was developed on a novel diffraction-based optical bionsensor technology. The test employs a 31-kDa recombinant antigen called NIE derived from Strongyloides stercoralis L3-stage larvae. Assay performance was tested using retrospectively collected sera from patients with parasitologically confirmed strongyloidiasis and control sera from healthy individuals or those with other parasitoses including schistosomiasis, trichinosis, echinococcosis or amebiasis who were seronegative using the NIE ELISA assay. If we consider the control group as the true negative group, the assay readily differentiated S. stercoralis-infected patients from controls detecting 96.3% of the positive cases, and with no cross reactivity observed in the control group These results were in excellent agreement (κ = 0.98) with results obtained by an NIE-based enzyme-linked immunosorbent assay (ELISA). A further 44 sera from patients with suspected S. stercoralis infection were analyzed and showed 91% agreement with the NIE ELISA. CONCLUSIONS/SIGNIFICANCE: In summary, this test provides high sensitivity detection of serum IgG against the NIE Strongyloides antigen. The assay is easy to perform and provides results in less than 30 minutes, making this platform amenable to rapid near-patient screening with minimal technical expertise

Survivin-induced abnormal ploidy contributes to cystic kidney and aneurysm formation

BACKGROUND: Cystic kidneys and vascular aneurysms are clinical manifestations seen in patients with polycystic kidney disease, a cilia-associated pathology (ciliopathy). Survivin overexpression is associated with cancer, but the clinical pathology associated with survivin downregulation or knockout has never been studied before. The present studies aim to examine whether and how cilia function (Pkd1 or Pkd2) and structure (Tg737) play a role in cystic kidney and aneurysm through survivin downregulation. METHODS AND RESULTS: Cysts and aneurysms from polycystic kidney disease patients, Pkd mouse, and zebrafish models are characterized by chromosome instability and low survivin expression. This triggers cytokinesis defects and formation of nuclear polyploidy or aneuploidy. In vivo conditional mouse and zebrafish models confirm that survivin gene deletion in the kidneys results in a cystic phenotype. As in hypertensive Pkd1, Pkd2, and Tg737 models, aneurysm formation can also be induced in vascular-specific normotensive survivin mice. Survivin knockout also contributes to abnormal oriented cell division in both kidney and vasculature. Furthermore, survivin expression and ciliary localization are regulated by flow-induced cilia activation through protein kinase C, Akt and nuclear factor-κB. Circumventing ciliary function by re-expressing survivin can rescue polycystic kidney disease phenotypes. CONCLUSIONS: For the first time, our studies offer a unifying mechanism that explains both renal and vascular phenotypes in polycystic kidney disease. Although primary cilia dysfunction accounts for aneurysm formation and hypertension, hypertension itself does not cause aneurysm. Furthermore, aneurysm formation and cyst formation share a common cellular and molecular pathway involving cilia function or structure, survivin expression, cytokinesis, cell ploidy, symmetrical cell division, and tissue architecture orientation

Validation of Aura Microwave Limb Sounder OH measurements with Fourier Transform Ultra-Violet Spectrometer total OH column measurements at Table Mountain, California

The first seasonal and interannual validation of OH measurements from the Aura Microwave Limb Sounder (MLS) has been conducted using ground-based OH column measurements from the Fourier Transform Ultra-Violet Spectrometer (FTUVS) over the Jet Propulsion Laboratory's Table Mountain Facility (TMF) during 2004–2007. To compare with FTUVS total column measurements, MLS OH vertical profiles over TMF are integrated to obtain partial OH columns above 21.5 hPa, which covers nearly 90% of the total column. The tropospheric OH and the lower stratopheric OH not measured by MLS are estimated using GEOS (Goddard Earth Observing System)-Chem and a Harvard 2-D model implemented within GEOS-Chem, respectively. A number of field observations and calculations from a photochemical box model are compared to OH profiles from these models to estimate the variability in the lower atmospheric OH and thus the uncertainty in the combined total OH columns from MLS and models. In general, the combined total OH columns agree extremely well with TMF total OH columns, especially during seasons with high OH. In winter with low OH, the combined columns are often higher than TMF measurements. A slightly weaker seasonal variation is observed by MLS relative to TMF. OH columns from TMF and the combined total columns from MLS and models are highly correlated, resulting in a mean slope of 0.969 with a statistically insignificant intercept. This study therefore suggests that column abundances derived from MLS vertical profiles have been validated to within the mutual systematic uncertainties of the MLS and FTUVS measurements