Performance of AAV8 vectors expressing human factor IX from a hepatic-selective promoter following intravenous injection into rats

Background: Vectors based on adeno-associated virus-8 (AAV8) have shown efficiency and efficacy for liver-directed gene therapy protocols following intravascular injection, particularly in relation to haemophilia gene therapy. AAV8 has also been proposed for gene therapy targeted at skeletal and cardiac muscle, again via intravascular injection. It is important to assess vector targeting at the level of virion accumulation and transgene expression in multiple species to ascertain potential issues relating to species variation in infectivity profiles. Methods: We used AAV8 vectors expressing human factor IX (FIX) from the liver-specific LP-1 promoter and administered this virus via the intravascular route of injection into 12 week old Wistar Kyoto rats. We assessed FIX levels in serum by ELISA and transgene expression at sacrifice by immunohistochemistry using anti-FIX antibodies. Vector DNA levels in organs we determined by real time PCR. Results: Administration of 1 × 1011 or 5 × 1011 scAAV8-LP1-hFIX vector particles/rat resulted in efficient production of physiological hFIX levels, respectively in blood assessed 4 weeks post-injection. This was maintained for the 4 month duration of the study. At 4 months we observed liver persistence of vector with minimal non-hepatic distribution. Conclusion: Our results demonstrate that AAV8 is a robust vector for delivering therapeutic genes into rat liver following intravascular injection

Letter from Mrs. T. E. McIntosh

Letter concerning engineering courses at Utah Agricultural College

Acupuncture's Effects in Treating the Sequelae of Acute and Chronic Spinal Cord Injuries: A Review of Allopathic and Traditional Chinese Medicine Literature

Each year, there are an estimated 12 000 individuals who sustain a spinal cord injury (SCI) in the United States. Improved understanding of the pathophysiology of SCI and its sequelae has over the past 50 years led to the development of medical treatments (especially urologic) that have enhanced short- and long-term survival from these injuries. The prevalence of individuals with SCI in this country is ~250 000 individuals; and beyond the incalculable personal consequences of these devastating neurologic injuries, substantial direct and indirect societal costs result from the sequelae of SCI including paralysis, sensory loss, chronic pain, decubiti and bladder and/or bowel incontinence. The purpose of this treatise is to review the allopathic and traditional Chinese medicine (TCM) literature available through MEDLINE, PubMed and eCAM search engines that discuss the potential uses of acupuncture to treat acute and chronic spinal cord injuries and their sequelae, and present the neurophysiologic mechanisms for acupuncture's beneficial effects. There is evidence that use of electroacupuncture in acute SCI may significantly improve long-term neurologic recovery from these injuries both in terms of motor, sensory and bowel/bladder function with essentially no risk. Acupuncture may even improve neurourologic function in individuals with chronic SCI, and help with management with chronic pain associated with these injuries

Multi-site mean-field theory for cold bosonic atoms in optical lattices

We present a detailed derivation of a multi-site mean-field theory (MSMFT) used to describe the Mott-insulator to superfluid transition of bosonic atoms in optical lattices. The approach is based on partitioning the lattice into small clusters which are decoupled by means of a mean field approximation. This approximation invokes local superfluid order parameters defined for each of the boundary sites of the cluster. The resulting MSMFT grand potential has a non-trivial topology as a function of the various order parameters. An understanding of this topology provides two different criteria for the determination of the Mott insulator superfluid phase boundaries. We apply this formalism to $d$-dimensional hypercubic lattices in one, two and three dimensions, and demonstrate the improvement in the estimation of the phase boundaries when MSMFT is utilized for increasingly larger clusters, with the best quantitative agreement found for $d=3$. The MSMFT is then used to examine a linear dimer chain in which the on-site energies within the dimer have an energy separation of $\Delta$. This system has a complicated phase diagram within the parameter space of the model, with many distinct Mott phases separated by superfluid regions.Comment: 30 pages, 23 figures, accepted for publication in Phys. Rev.

Explanatory debugging: Supporting end-user debugging of machine-learned programs

Many machine-learning algorithms learn rules of behavior from individual end users, such as task-oriented desktop organizers and handwriting recognizers. These rules form a “program” that tells the computer what to do when future inputs arrive. Little research has explored how an end user can debug these programs when they make mistakes. We present our progress toward enabling end users to debug these learned programs via a Natural Programming methodology. We began with a formative study exploring how users reason about and correct a text-classification program. From the results, we derived and prototyped a concept based on “explanatory debugging”, then empirically evaluated it. Our results contribute methods for exposing a learned program's logic to end users and for eliciting user corrections to improve the program's predictions

Neurogenic Bladder

Congenital anomalies such as meningomyelocele and diseases/damage of the central, peripheral, or autonomic nervous systems may produce neurogenic bladder dysfunction, which untreated can result in progressive renal damage, adverse physical effects including decubiti and urinary tract infections, and psychological and social sequelae related to urinary incontinence. A comprehensive bladder-retraining program that incorporates appropriate education, training, medication, and surgical interventions can mitigate the adverse consequences of neurogenic bladder dysfunction and improve both quantity and quality of life. The goals of bladder retraining for neurogenic bladder dysfunction are prevention of urinary incontinence, urinary tract infections, detrusor overdistension, and progressive upper urinary tract damage due to chronic, excessive detrusor pressures. Understanding the physiology and pathophysiology of micturition is essential to select appropriate pharmacologic and surgical interventions to achieve these goals. Future perspectives on potential pharmacological, surgical, and regenerative medicine options for treating neurogenic bladder dysfunction are also presented