Safety and efficacy of intrathecal ziconotide in the management of severe chronic pain

Ziconotide is a conopeptide intrathecal (IT) analgesic which is approved by the US Food and Drug Administration (FDA) for the management of severe chronic pain. It is a synthetic equivalent of a naturally occurring conopeptide found in the venom of the fish-eating marine cone snail and provides analgesia via binding to N-type voltage-sensitive calcium channels in the spinal cord. As ziconotide is a peptide, it is expected to be completely degraded by endopeptidases and exopeptidases (Phase I hydrolytic enzymes) widely located throughout the body, and not by other Phase I biotransformation processes (including the cytochrome P450 system) or by Phase II conjugation reactions. Thus, IT administration, low plasma ziconotide concentrations, and metabolism by ubiquitous peptidases make metabolic interactions of other drugs with ziconotide unlikely. Side effects of ziconotide which tend to occur more commonly at higher doses may include: nausea, vomiting, confusion, postural hypotension, abnormal gait, urinary retention, nystagmus/amblyopia, drowsiness/somnolence (reduced level of consciousness), dizziness or lightheadedness, weakness, visual problems (eg, double vision), elevation of serum creatine kinase, or vestibular side effects. Initially, when ziconotide was first administered to human subjects, titration schedules were overly aggressive and led to an abundance of adverse effects. Subsequently, clinicians have gained appreciation for ziconotide’s relatively narrow therapeutic window. With appropriate usage multiple studies have shown ziconotide to be a safe and effective intrathecal analgesic alone or in combination with other intrathecal analgesics

Final report for DOE Grant No. DE-FG02-07ER64404 - Field Investigations of Microbially Facilitated Calcite Precipitation for Immobilization of Strontium-90 and Other Trace Metals in the Subsurface

Subsurface radionuclide and metal contaminants throughout the U.S. Department of Energy (DOE) complex pose one of DOEâÃÂÃÂs greatest challenges for long-term stewardship. One promising stabilization mechanism for divalent ions, such as the short-lived radionuclide 90Sr, is co-precipitation in calcite. We have previously found that that nutrient addition can stimulate microbial ureolytic activity that this activity accelerates calcite precipitation and co-precipitation of Sr, and that higher calcite precipitation rates can result in increased Sr partitioning. We have conducted integrated field, laboratory, and computational research to evaluate the relationships between ureolysis and calcite precipitation rates and trace metal partitioning under environmentally relevant conditions, and investigated the coupling between flow/flux manipulations and precipitate distribution. A field experimental campaign conducted at the Integrated Field Research Challenge (IFRC) site located at Rifle, CO was based on a continuous recirculation design; water extracted from a down-gradient well was amended with urea and molasses (a carbon and electron donor) and re-injected into an up-gradient well. The goal of the recirculation design and simultaneous injection of urea and molasses was to uniformly accelerate the hydrolysis of urea and calcite precipitation over the entire inter-wellbore zone. The urea-molasses recirculation phase lasted, with brief interruptions for geophysical surveys, for 12 days followed by long-term monitoring which continued for 13 months. Following the recirculation phase we found persistent increases in urease activity (as determined from 14C labeled laboratory urea hydrolysis rates) in the upper portion of the inter-wellbore zone. We also observed an initial increase (approximately 2 weeks) in urea concentration associated with injection activities followed by decreasing urea concentration and associated increases in ammonium and dissolved inorganic carbon (DIC) following the termination of injection. Based on the loss of urea and the appearance of ammonium, a first order rate constant for urea hydrolysis of 0.18 day-1 rate with an associate Rf for ammonium of 11 were estimated. This rate constant is approximately 6 times higher than estimated for previous field experiments conducted in eastern Idaho. Additionally, DIC carbon isotope ratios were measured for the groundwater. Injected urea had a ÃÂô13C of 40.7ÃÂñ0.4 âÃÂð compared to background groundwater DIC of ÃÂô13C of -16.6ÃÂñ0.2âÃÂð. Observed decreases in groundwater DIC ÃÂô13C of up to -19.8âÃÂð followed temporal trends similar to those observed for ammonium and suggest that both the increase in ammonium and the sift in ÃÂô13C are the result of urea hydrolysis. Although direct observation of calcite precipitation was not possible because of the high pre-existing calcite content in the site sediments, an observed ÃÂô13C decrease for solid carbonates from sediment samples collect following urea injection (compared to pre-injection values) is likely the result of the incorporation of inorganic carbon derived from urea hydrolysis into newly formed solid carbonates

Complete Spontaneous Regression of Pulmonary Metastatic Melanoma

Complete spontaneous regression of melanoma metastatic to the lungs is a rare event. objective . To report a case of biopsy-proven melanoma metastatic to the lung with complete spontaneous regression. methods . Multidisciplinary case report. results . A 35-year-old white female was diagnosed with metastatic melanoma to the lung. A pleural biopsy confirmed the diagnosis. Partial spontaneous regression was noted by a staging computed tomography scan prior to enrollment in an investiga-tional protocol. Complete spontaneous regression occurred over 5 months without any form of conventional or alternative therapy, and the patient remains disease-free 3 years after diagnosis. conclusions . Our case represents the seventh case of complete spontaneous regression of melanoma metastatic to the lung, and the only case with histologic confirmation of both the primary and pulmonary metastatic lesions. The patient was pregnant twice between the time of her initial diagnosis of primary melanoma and pulmonary metastatic disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75559/1/j.1524-4725.1998.tb04275.x.pd

Type II Quasars from the Sloan Digital Sky Survey: V. Imaging host galaxies with the Hubble Space Telescope

Type II quasars are luminous Active Galactic Nuclei whose centers are obscured by large amounts of gas and dust. In this paper we present 3-band HST images of nine type II quasars with redshifts 0.2 < z < 0.4 selected from the Sloan Digital Sky Survey based on their emission line properties. The intrinsic luminosities of these AGN are estimated to be -24 > M_B > -26, but optical obscuration allows their host galaxies to be studied unencumbered by bright nuclei. Each object has been imaged in three continuum filters (`UV', `blue' and `yellow') placed between the strong emission lines. The spectacular, high quality images reveal a wealth of details about the structure of the host galaxies and their environments. Six of the nine galaxies in the sample are ellipticals with de Vaucouleurs light profiles, one object has a well-defined disk component and the remaining two have marginal disks. Stellar populations of type II quasar hosts are more luminous (by a median of 0.3-0.7 mag, depending on the wavelength) and bluer (by about 0.4 mag) than are M* galaxies at the same redshift. When smooth fits to stellar light are subtracted from the images, we find both positive and negative residuals that become more prominent toward shorter wavelengths. We argue that the negative residuals are due to kpc-scale dust obscuration, while most positive residuals are due to the light from the nucleus scattered off interstellar material in the host galaxy. Scattered light makes a significant contribution to the broad band continuum emission and can be the dominant component of the extended emission in the UV in extreme cases.Comment: 51 pages, including 12 grey scale figures, 4 color figures, 5 tables. In press in AJ. Version with higher-resolution images available at http://www.astro.princeton.edu/~nadia/qso2.html. (Minor changes in response to the referee report

A study of National Health Service management of chronic osteoarthritis and low back pain

AIM: To describe treatment and referral patterns and National Health Service resource use in patients with chronic pain associated with low back pain or osteoarthritis, from a Primary Care perspective. BACKGROUND: Osteoarthritis and low back pain are the two commonest debilitating causes of chronic pain, with high health and social costs, and particularly important in primary care. Understanding current practice and resource use in their management will inform health service and educational requirements and the design and optimisation of future care. METHOD: Multi-centre, retrospective, descriptive study of adults (⩾18 years) with chronic pain arising from low back pain or osteoarthritis, identified through primary care records. Five general practices in Scotland, England (two), Northern Ireland and Wales. All patients with a diagnosis of low back pain or osteoarthritis made on or before 01/09/2006 who had received three or more prescriptions for pain medication were identified and a sub-sample randomly selected then consented to an in-depth review of their medical records (n=264). Data on management of chronic pain were collected retrospectively from patients’ records for three years from diagnosis (‘newly diagnosed’ patients) or for the most recent three years (‘established’ patients). FINDINGS: Patients received a wide variety of pain medications with no overall common prescribing pattern. GP visits represented the majority of the resource use and ‘newly diagnosed’ patients were significantly more likely to visit their GP for pain management than ‘established’ patients. Although ‘newly diagnosed’ patients had more referrals outside the GP practice, the number of visits to secondary care for pain management was similar for both groups. CONCLUSION: This retrospective study confirmed the complexity of managing these causes of chronic pain and the associated high resource use. It provides an in-depth picture of prescribing and referral patterns and of resource use

Algorithm Selection Framework for Cyber Attack Detection

The number of cyber threats against both wired and wireless computer systems and other components of the Internet of Things continues to increase annually. In this work, an algorithm selection framework is employed on the NSL-KDD data set and a novel paradigm of machine learning taxonomy is presented. The framework uses a combination of user input and meta-features to select the best algorithm to detect cyber attacks on a network. Performance is compared between a rule-of-thumb strategy and a meta-learning strategy. The framework removes the conjecture of the common trial-and-error algorithm selection method. The framework recommends five algorithms from the taxonomy. Both strategies recommend a high-performing algorithm, though not the best performing. The work demonstrates the close connectedness between algorithm selection and the taxonomy for which it is premised.Comment: 6 pages, 7 figures, 1 table, accepted to WiseML '2

The cardiac-restricted protein ADP-ribosylhydrolase-like 1 is essential for heart chamber outgrowth and acts on muscle actin filament assembly

AbstractAdprhl1, a member of the ADP-ribosylhydrolase protein family, is expressed exclusively in the developing heart of all vertebrates. In the amphibian Xenopus laevis, distribution of its mRNA is biased towards actively growing chamber myocardium. Morpholino oligonucleotide-mediated knockdown of all Adprhl1 variants inhibits striated myofibril assembly and prevents outgrowth of the ventricle. The resulting ventricles retain normal electrical conduction and express markers of chamber muscle differentiation but are functionally inert. Using a cardiac-specific Gal4 binary expression system, we show that the abundance of Adprhl1 protein in tadpole hearts is tightly controlled through a negative regulatory mechanism targeting the 5′-coding sequence of Xenopus adprhl1. Over-expression of full length (40kDa) Adprhl1 variants modified to escape such repression, also disrupts cardiac myofibrillogenesis. Disarrayed myofibrils persist that show extensive branching, with sarcomere division occurring at the actin-Z-disc boundary. Ultimately, Adprhl1-positive cells contain thin actin threads, connected to numerous circular branch points. Recombinant Adprhl1 can localize to stripes adjacent to the Z-disc, suggesting a direct role for Adprhl1 in modifying Z-disc and actin dynamics as heart chambers grow. Modelling the structure of Adprhl1 suggests this cardiac-specific protein is a pseudoenzyme, lacking key residues necessary for ADP-ribosylhydrolase catalytic activity

Light and smell stimulus protocol reduced negative frontal EEG asymmetry and improved mood

Light and smell have both been shown to induce beneficial changes to human psychophysiology. Bright light therapy has been shown to have a positive impact on anxiety and depression and smell has also been shown to have positive effects on mood, stress, anxiety and depression. We developed a method for the delivery of integrated light and smell stimulation to try to optimise positive psychophysiological benefit. We tested its effectiveness on a physiological measure, EEG frontal alpha asymmetry (FA) and a psychological paradigm, the POMS test, both of which have been used as a measure of emotional state and mood. Light, pleasant smell, combined light+smell and a no stimulus control were delivered for 90s while the frontal alpha asymmetry (FA) was monitored. Smell and light+smell caused significant reductions in negative FA during stimulation. Exposure to a longer 15 min nonadaptive light+smell stimulus protocol reduced negative FA and decreased negative affect (POMS). The effects were greater in the negative FA group. Both the physiological (EEG) and psychometric (POMS) data indicate that integrated light and smell stimulation can reduce negative affect and reduce a marker for anxiety/ depression. This light+smell sensory stimulation protocol could offer a safe treatment for depression/anxiety