Pigs Transgenic For Human Dominant Mutations Of The GUCY2D Gene

Purpose: Studies on large animal models are an important step to test new therapeutical strategies before human application. Considering the importance of cone function for human vision and the paucity of large animal models for cone dystrophies having an enriched cone region, we propose to develop a pig model for cone degeneration. With a lentiviral-directed transgenesis, we obtained pigs transgenic for a cone-dominant mutant gene described in a human cone dystrophy.Methods: Lentiviral vectors encoding the human double mutant GUCY2DE837D/R838S cDNA under the control of a region of the pig arrestin-3 promoter (Arr3) was produced and used for lentiviral-derived transgenesis in pigs. PCR-genotyping and southern blotting determined the genotype of pigs born after injection of the vector at the zygote stage. Retina function analysis was performed by ERG and behavioral tests at 11, 24 and 54 weeks of age. OCT and histological analyses were performed to describe the retina morphology.Results: The ratio of transgenic pigs born after lentiviral-directed transgenesis was close to 50%. Transgenic pigs with 3 to 5 transgene copies per cell clearly present a reduced photopic response from 3 months of age on. Except for one pig, which has 6 integrated transgene copies, no dramatic decrease in general mobility was observed even at 6 months of age. OCT examinations reveal no major changes in the ONL structure of the 6-months old pigs. The retina morphology was well conserved in the 2 pigs sacrificed (3 and 6 months old) except a noticeable displacement of some cone nuclei in the outer segment layer.Conclusions: Lentiviral-directed transgenesis is a rapid and straightforward method to engineer transgenic pigs. Some Arr3-GUCY2DE837D/R838S pigs show signs of retinal dysfunction but further work is needed to describe the progression of the disease in this model.

Epidemic: Responding to America's Prescription Drug Abuse Crisis, 2011

Prescription drug abuse is the Nation’s fastest-growing drug problem. While there has been a marked decrease in the use of some illegal drugs like cocaine, data from the National Survey on Drug Use and Health (NSDUH) show that nearly one-third of people aged 12 and over who used drugs for the first time in 2009 began by using a prescription drug non-medically.1 The same survey found that over 70 percent of people who abused prescription pain relievers got them from friends or relatives, while approximately 5 percent got them from a drug dealer or from the Internet.2 Additionally, the latest Monitoring the Future study—the Nation’s largest survey of drug use among young people—showed that prescription drugs are the second most-abused category of drugs after marijuana.3 In our military, illicit drug use increased from 5 percent to 12 percent among active duty service members over a three-year period from 2005 to 2008, primarily attributed to prescription drug abuse.

Reducing Prescription Drug Abuse in Iowa, January 5, 2011

Prescription drug abuse is the nation’s fastest-growing drug problem, as outlined by the White House Office of National Drug Control Policy’s 2011 national plan “Responding to America’s Prescription Drug Abuse Crisis.” The urgency of the challenge is underscored in other reports, including a recent analysis by the Centers for Disease Control (CDC) that said: “Overdoses involving prescription painkillers are at epidemic levels and now kill more Americans than heroin and cocaine combined.” According to the CDC, more than 40 people die in America every day from overdoses involving narcotic pain relievers such as hydrocodone (Vicodin), oxycodone (Oxycontin), methadone and oxymorphone (Opana). In Iowa, the situation is similar, at least in some ways. Prescription drug abuse is one of the fastest-growing forms of substance abuse in our state too, though its scope is smaller and on a more manageable scale when compared with most other states. The Iowa Department of Public Health, Bureau of Vital Statistics, reports the drug overdose deaths of at least 130 Iowans over the last three years (2008-2010) due to non-heroin opioids (i.e., prescription pain relievers such as oxycodone, hydrocodone and methadone), nearly as many as for the previous eight years combined (149 from 2000-2007).

The Impact of Senate File 169 on Meth Abuse in Iowa A Report to the Legislature by Drug Policy, January 17, 2006

This report is respectfully submitted in satisfaction of the following Senate File 169 requirement, as approved by the 2005 Iowa Legislature: “The Drug Policy Coordinator shall report, in a joint meeting, to the Committee on Judiciary of the Senate and the Committee on Public Safety of the House of Representatives in January 2006 and in January 2007, the effects of this Act on methamphetamine abuse and related criminal activity.” (*Please note that all data contained in this document are preliminary, based on the most recent information available to the Governor’s Office of Drug Control Policy.)

Substance Abuse, Report to the Board of Corrections, 2006

This report, however, goes beyond documentation of the problem. It describes how the Iowa Department of Corrections is addressing substance abuse among the offender population through the provision of treatment, and monitoring for current drug and alcohol usage. All information was obtained from the Iowa Corrections Offender Network (ICON) with many of the reports obtained via the Iowa Justice Data Warehouse.

Community-Based Corrections Substance Abuse Treatment for the Higher Risk Offender, Iowa Department of Corrections Performance Audit Report, September 2007

The performance audit conducted by the Department of Management concerned the licensed substance abuse treatment programs in Department of Corrections’ institutions. This report uses the same methodology, modified for community-based corrections populations, to examine the delivery of substance abuse treatment for higher risk offenders under field supervision, and all offenders who were assigned to community corrections residential facilities.

Membrane-destabilizing activity of pH-responsive cationic lysine-based surfactants: role of charge position and alkyl chain length

Many strategies for treating diseases require the delivery of drugs into the cell cytoplasm following internalization within endosomal vesicles. Thus, compounds triggered by low pH to disrupt membranes and release endosomal contents into the cytosol are of particular interest. Here, we report novel cationic lysine-based surfactants (hydrochloride salts of N¿- and N¿-acyl lysine methyl ester) that differ in the position of the positive charge and the length of the alkyl chain. Amino acid-based surfactants could be promising novel biomaterials in drug delivery systems, given their biocompatible properties and low cytotoxic potential. We examined their ability to disrupt the cell membrane in a range of pH values, concentrations and incubation times, using a standard hemolysis assay as a model of endosomal membranes. Furthermore, we addressed the mechanism of surfactant-mediated membrane destabilization, including the effects of each surfactant on erythrocyte morphology as a function of pH. We found that only surfactants with the positive charge on the ¿-amino group of lysine showed pH-sensitive hemolytic activity and improved kinetics within the endosomal pH range, indicating that the positive charge position is critical for pH-responsive behavior. Moreover, our results showed that an increase in the alkyl chain length from 14 to 16 carbon atoms was associated with a lower ability to disrupt cell membranes. Knowledge on modulating surfactant-lipid bilayer interactions may help us to develop more efficient biocompatible amino acid-based drug delivery devices.

Sampling Position under No-Tillage System Affects the Results of Soil Physical Properties

ABSTRACT Understanding the spatial behavior of soil physical properties under no-tillage system (NT) is required for the adoption and maintenance of a sustainable soil management system. The aims of this study were to quantify soil bulk density (BD), porosity in the soil macropore domain (PORp) and in the soil matrix domain (PORm), air capacity in the soil matrix (ACm), field capacity (FC), and soil water storage capacity (FC/TP) in the row (R), interrow (IR), and intermediate position between R and IR (designated IP) in the 0.0-0.10 and 0.10-0.20 m soil layers under NT; and to verify if these soil properties have systematic variation in sampling positions related to rows and interrows of corn. Soil sampling was carried out in transect perpendicular to the corn rows in which 40 sampling points were selected at each position (R, IR, IP) and in each soil layer, obtaining undisturbed samples to determine the aforementioned soil physical properties. The influence of sampling position on systematic variation of soil physical properties was evaluated by spectral analysis. In the 0.0-0.1 m layer, tilling the crop rows at the time of planting led to differences in BD, PORp, ACm, FC and FC/TP only in the R position. In the R position, the FC/TP ratio was considered close to ideal (0.66), indicating good water and air availability at this sampling position. The R position also showed BD values lower than the critical bulk density that restricts root growth, suggesting good soil physical conditions for seed germination and plant establishment. Spectral analysis indicated that there was systematic variation in soil physical properties evaluated in the 0.0-0.1 m layer, except for PORm. These results indicated that the soil physical properties evaluated in the 0.0-0.1 m layer were associated with soil position in the rows and interrows of corn. Thus, proper assessment of soil physical properties under NT must take into consideration the sampling positions and previous location of crop rows and interrows.

Autofluorescence Study In NR2E3 p.G56R-linked Autosomal Dominant Retinitis Pigmentosa In A Single Kindred

Purpose: To date, the genotype/phenotype correlation of p.G56R-linked autosomal dominant retinitis pigmentosa (ADRP) is limited to less than 10 kindred. The purpose of this study is to report an unusual appearance of fundus autofluorescence (AF) with NR2E3 p.G56R-linked ADRP in a single kindred.Methods: Patients were enrolled among three generations in a previously unreported family. Molecular diagnosis was performed on all exons of NR2E3 and a p.G56R mutation was identified in affected family members only. Examinations included fundus photography, visual fields, optical coherence tomography, AF, near-infrared AF and ISCEV-standard electrophysiology (ERG).Results: Among 10 examined family members, 5 were affected. The youngest and oldest patients were 16 and 65 years old, respectively. Fundus examination revealed a range of retinal disorder from normal to optic nerve pallor, attenuated arterial caliber and bone spicule-like pigment deposits. In all patients, AF showed a double hyperfluorescent ring; an inner paramacular ring which extension was comparable among patients and an outer ring along the vascular arcades which extended towards periphery in older patients and became hypofluorescent. Maximal scotopic ERGs when recordable showed an increased a/b wave ratio.Conclusions: A double hyperfluorescent ring on AF is an uncommon observation and might be a specific clinical finding in NR2E3 p.G56R-linked ADRP. The consistency of that finding in all affected members of our 3-generation family confirms a previous study. Further analysis is required to determine whether AF changes are associated with particular retinal layer abnormalities.

Review of the Iowa Department of Human Services Drug Testing Process for Drug Testing of a Person Responsible for the Care of a Child in Child Abuse Cases, December 1, 2008

This report outlines the current drug testing practices, guidelines, programs and initiatives as currently implemented by the Department regarding the process for drug testing of a person responsible for the care of a child in child abuse cases.

Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene.

We report a Spanish family with autosomal-dominant non-neuropathic hereditary amyloidosis with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disease is caused by a previously unreported deletion/insertion mutation in exon 4 of the apolipoprotein AI (apoAI) gene encoding loss of residues 60-71 of normal mature apoAI and insertion at that position of two new residues, ValThr. Affected individuals are heterozygous for this mutation and have both normal apoAI and variant molecules bearing one extra positive charge, as predicted from the DNA sequence. The amyloid fibrils are composed exclusively of NH2-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wild-type sequence. Amyloid fibrils derived from the other three known amyloidogenic apoAI variants are also composed of similar NH2-terminal fragments. All known amyloidogenic apoAI variants carry one extra positive charge in this region, suggesting that it may be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, this is the first deletion mutation to be described in association with hereditary amyloidosis and it significantly extends the value of the apoAI model for investigation of molecular mechanisms of amyloid fibrillogenesis.

Delinquency-Related Systems in Iowa: Substance Abuse, Mental Health, Education and Job Traning, April 2006

This report was developed to provide summary information to allow state agency staff, practitioners and juvenile justice system officials to access specific sections of Iowa’s Three Year Plan. It includes the “Service Network” section of Iowa’s 2006 Juvenile Justice and Delinquency Prevention Act formula grant Three-Year Plan. The complete Three Year Plan serves as Iowa’s application for Juvenile Justice and Delinquency Prevention Act formula grant funding. The information included in this report overviews some of the systems and services that relate to Iowa’s delinquency and CINA systems. The systems and services discussed include substance abuse , mental health, alternative or special education, and job training.

Iowa Elder Abuse Initiative Demonstration Projects Fiscal Year 2001-2011

In 2001, the Iowa Legislature approved approximately $475,000 to fund strategies for elder abuse detection, training and services in an effort to evaluate Iowa’s adult abuse system. This endeavor became known as Iowa’s Elder Abuse Initiative (EAI) demonstration projects. These projects were located in 4 of the 13 Area Agencies on Aging and available in 22 of Iowa’s 99 counties. The EAI focused on the prevention, intervention, detection, and reporting of elder abuse, neglect and exploitation by presenting elders with options to enhance their lifestyle choices.