Gene Therapy for Cardiovascular Disease

The last decade has seen substantial advances in the development of gene therapy strategies and vector technology for the treatment of a diverse number of diseases, with a view to translating the successes observed in animal models into the clinic. Perhaps the overwhelming drive for the increase in vascular gene transfer studies is the current lack of successful long-term pharmacological treatments for complex cardiovascular diseases. The increase in cardiovascular disease to epidemic proportions has also led many to conclude that drug therapy may have reached a plateau in its efficacy and that gene therapy may represent a realistic solution to a long-term problem. Here, we discuss gene delivery approaches and target diseases

Age, growth, mortality, and radiometric age validation of gray snapper (Lutjanus griseus) from Louisiana

The gray snapper (Lutjanus griseus) is a temperate and tropical reef fish that is found along the Gulf of Mexico and Atlantic coasts of the southeastern United States. The recreational fishery for gray snapper has developed rapidly in south Louisiana with the advent of harvest and seasonal restrictions on the established red snapper (L. campechanus) fishery. We examined the age and growth of gray snapper in Louisiana with the use of cross-sectioned sagittae. A total of 833 specimens, (441 males, 387 females, and 5 of unknown sex) were opportunistically sampled from the recreational fishery from August 1998 to August 2002. Males ranged in size from 222 to 732 mm total length (TL) and from 280 g to 5700 g total weight (TW) and females ranged from 254 to 756 mm TL and from 340 g to 5800 g TW. Both edge analysis and bomb radiocarbon analyses were used to validate otolith-based age estimates. Ages were estimated for 718 individuals; both males and females ranged from 1 to 28 years. The von Bertalanffy growth models derived from TL at age were Lt = 655.4{1–e[–0.23(t)]} for males, Lt = 657.3{1–e[– 0.21(t)]} for females, and L t = 656.4{1–e[– 0.22 (t)]} for all specimens of known sex. Catch curves were used to produce a total mortality (Z) estimate of 0.17. Estimates of M calculated with various methods ranged from 0.15 to 0.50; however we felt that M= 0.15 was the most appropriate estimate based on our estimate of Z. Full recruitment to the gray snapper recreational fishery began at age 4, was completed by age 8, and there was no discernible peak in the catch curve dome

Efficient transduction of primary vascular cells by the rare adenovirus serotype 49 vector

Neointima formation and vascular remodelling through vascular smooth muscle cell migration and proliferation can limit the long term success of coronary interventions, for example in coronary artery bypass grafting (CABG). Ex vivo gene therapy has the potential to reduce unnecessary cell proliferation and limit neointima formation in vascular pathologies. To date the species C adenovirus serotype 5 (Ad5) has been commonly used for pre-clinical gene therapy, however its suitability is potentially limited by relatively poor tropism for vascular cells and high levels of pre-existing immunity in the population. To avoid these limitations, novel species of adenovirus are being tested; here we investigate the potential of adenovirus 49 (Ad49) for use in gene therapy. Transduction of primary human vascular cells by a range of adenovirus serotypes was assessed; Ad49 demonstrated highest transduction of both vascular smooth muscle and endothelial cells. Gene transfer with Ad49 in vascular smooth muscle and endothelial cells was possible following short exposure times (*lt;1hr) and with low MOI which is clinically relevant. Ex vivo delivery to surplus CABG tissue showed efficient gene transfer with Ad49, consistent with the in vitro findings. Luminal infusion of Ad49GFP into intact CABG samples ex vivo resulted in efficient vessel transduction. In addition, no seroprevelance rates to Ad49 were observed in a Scottish cohort of patients from cardiovascular clinics, thus circumventing issues with pre-existing immunity. Our results show Ad49 has tropism for vascular cells in vitro and ex vivo and demonstrate Ad49 may be an improved vector for local vascular gene therapy compared to current alternatives

LABOR PRODUCTIVITY WITHIN THE AFRICAN AGRICULTURAL HOUSEHOLD: THE HOUSEHOLD PRODUCTION MODEL REVISITED

The benchmark concept is used to understand changes in farm household response to development dynamics. 1996-97 cropping seasons data from Cameroon is used to develop and test a "separate spheres" household model. Labor productivity for men and women is discussed, along with their implications for research and resource management policies.agriculture, labor productivity, gender, production, consumption, Consumer/Household Economics, Labor and Human Capital,

A Compact Starburst Core in the Dusty Lyman Break Galaxy Westphal-MD11

Using the IRAM Plateau de Bure Interferometer, we have searched for CO(3-2) emission from the dusty Lyman break galaxy Westphal-MD11 at z = 2.98. Our sensitive upper limit is surprisingly low relative to the system's 850 um flux density and implies a far-IR/CO luminosity ratio as elevated as those seen in local ultraluminous mergers. We conclude that the observed dust emission must originate in a compact structure radiating near its blackbody limit and that a relatively modest molecular gas reservoir must be fuelling an intense nuclear starburst (and/or deeply buried active nucleus) that may have been triggered by a major merger. In this regard, Westphal-MD11 contrasts strikingly with the lensed Lyman break galaxy MS1512-cB58, which is being observed apparently midway through an extended episode of more quiescent disk star formation.Comment: 5 pages, 1 figure (emulateapj), accepted by ApJ

Genomic analysis of Xenopus organizer function

BACKGROUND: Studies of the Xenopus organizer have laid the foundation for our understanding of the conserved signaling pathways that pattern vertebrate embryos during gastrulation. The two primary activities of the organizer, BMP and Wnt inhibition, can regulate a spectrum of genes that pattern essentially all aspects of the embryo during gastrulation. As our knowledge of organizer signaling grows, it is imperative that we begin knitting together our gene-level knowledge into genome-level signaling models. The goal of this paper was to identify complete lists of genes regulated by different aspects of organizer signaling, thereby providing a deeper understanding of the genomic mechanisms that underlie these complex and fundamental signaling events. RESULTS: To this end, we ectopically overexpress Noggin and Dkk-1, inhibitors of the BMP and Wnt pathways, respectively, within ventral tissues. After isolating embryonic ventral halves at early and late gastrulation, we analyze the transcriptional response to these molecules within the generated ectopic organizers using oligonucleotide microarrays. An efficient statistical analysis scheme, combined with a new Gene Ontology biological process annotation of the Xenopus genome, allows reliable and faithful clustering of molecules based upon their roles during gastrulation. From this data, we identify new organizer-related expression patterns for 19 genes. Moreover, our data sub-divides organizer genes into separate head and trunk organizing groups, which each show distinct responses to Noggin and Dkk-1 activity during gastrulation. CONCLUSION: Our data provides a genomic view of the cohorts of genes that respond to Noggin and Dkk-1 activity, allowing us to separate the role of each in organizer function. These patterns demonstrate a model where BMP inhibition plays a largely inductive role during early developmental stages, thereby initiating the suites of genes needed to pattern dorsal tissues. Meanwhile, Wnt inhibition acts later during gastrulation, and is essential for maintenance of organizer gene expression throughout gastrulation, a role which may depend on its ability to block the expression of a host of ventral, posterior, and lateral fate-specifying factors

Prescribing of inappropriate medicine in patients with limited life expectancy : a prospective study in a specialist palliative care unit

For patients with limited life expectancy – typically surviving for less than one year – polypharmacy is very common because medication is prescribed to manage acute symptoms associated with the life limiting illness (e.g. cancer) and to treat or prevent other long-term conditions (e.g. cardiovascular disease). As a consequence, this polypharmacy is linked with an increased risk of developing a drug-related toxicity due to the potential of drug-drug or drug-disease interactions. This risk is further heightened in patients with limited life expectancy owing to their unique and dynamic pharmacokinetic and pharmacodynamic parameters (e.g. variation in volume of distribution or altered drug excretion due to declining renal and/or hepatic function). In view of the potential for polypharmacy to cause harm in patients with limited life expectancy, it is essential to optimize patients’ medication to align with therapeutic goals and life expectancy. To date, however, there is a growing body of evidence that suggests inappropriate medication continues to be prescribed to patients with limited life expectancy

Toward a new Homestead Act: Designing a farmstead transfer and leasing program for high-value farming and farmstead preservation

Finding ways to make farming more accessible for would-be farmers involves working with existing landowners and potential tenants/buyers to educate both groups on the possibilities open to them. Surveys, focus groups and personal interviews were used to determine what tactics would be more effective in engaging both groups

An electrostatic mechanism for Ca(2+)-mediated regulation of gap junction channels.

Gap junction channels mediate intercellular signalling that is crucial in tissue development, homeostasis and pathologic states such as cardiac arrhythmias, cancer and trauma. To explore the mechanism by which Ca(2+) blocks intercellular communication during tissue injury, we determined the X-ray crystal structures of the human Cx26 gap junction channel with and without bound Ca(2+). The two structures were nearly identical, ruling out both a large-scale structural change and a local steric constriction of the pore. Ca(2+) coordination sites reside at the interfaces between adjacent subunits, near the entrance to the extracellular gap, where local, side chain conformational rearrangements enable Ca(2+)chelation. Computational analysis revealed that Ca(2+)-binding generates a positive electrostatic barrier that substantially inhibits permeation of cations such as K(+) into the pore. Our results provide structural evidence for a unique mechanism of channel regulation: ionic conduction block via an electrostatic barrier rather than steric occlusion of the channel pore

Control via electron count of the competition between magnetism and superconductivity in cobalt and nickel doped NaFeAs

Using a combination of neutron, muon and synchrotron techniques we show how the magnetic state in NaFeAs can be tuned into superconductivity by replacing Fe by either Co or Ni. Electron count is the dominant factor, since Ni-doping has double the effect of Co-doping for the same doping level. We follow the structural, magnetic and superconducting properties as a function of doping to show how the superconducting state evolves, concluding that the addition of 0.1 electrons per Fe atom is sufficient to traverse the superconducting domain, and that magnetic order coexists with superconductivity at doping levels less than 0.025 electrons per Fe atom.Comment: 4 pages, 6 figure