Transgenic animal models of neurodegenerative diseases and their application to treatment development

Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressive accumulation of misfolded proteins with the formation of toxic oligomers. Previous studies show that while in Alzheimer's disease (AD) misfolded amyloid-beta protein accumulates both in the intracellular and extracellular space, in Lewy body disease (LBD), Parkinson's disease (PD), Multiple System Atrophy (MSA), Fronto-Temporal dementia (FTD), prion diseases, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat disorders (TNRD), the aggregated proteins accumulate in the plasma membrane and intracellularly. Protein misfolding and accumulation is the result of an altered balance between protein synthesis, aggregation rate and clearance. Based on these studies, considerable advances have been made in the past years in developing novel experimental models of neurodegenerative disorders. This has been in part driven by the identification of genetic mutations associated with familial forms of these conditions and gene polymorphisms associated with the more common sporadic variants of these diseases. Transgenic and knock out rodents and Drosophila as well as viral vector driven models of Alzheimer's disease (AD), PD, Huntington's disease (HD) and others have been developed, however the focus for this review will be on rodent models of AD, FTD, PD/LBD, and MSA. Promising therapeutic results have been obtained utilizing amyloid precursor protein (APP) transgenic (tg) models of AD to develop therapies including use of inhibitors of the APP-processing enzymes beta- and gamma-secretase as well as vaccine therapies.     

Granulocyte colony-stimulating factor crosses the placenta and stimulates fetal rat granulopoiesis

We studied the effect of recombinant human granulocyte colony- stimulating factor (rhG-CSF) administration to pregnant rats upon fetal and neonatal myelopoiesis. Pregnant rats were treated with rhG-CSF twice daily for 2, 4, and 6 days before parturition. rhG-CSF crossed the placenta and reached peak fetal serum concentrations 4 hours after administration. Peak fetal serum levels were 1,000-fold lower than levels detected in the dam. Hematopoietic effects of rhG-CSF were assessed by cytologic analysis of the newborn blood, spleen, bone marrow, thymus, and liver. White blood cell counts were increased twofold to fourfold in newborns. This increase was due to circulating numbers of polymorphonuclear cells (PMN). rhG-CSF induced a myeloid hyperplasia in the newborn marrow consisting of immature and mature myeloid cells in the day-2 and day-4 treated pups. Bone marrow of pups treated for 6 days contained mostly hyper-segmented PMN with little or no increase in myeloid precursors. An increase in the number of postmitotic (PMN, bands, and metamyelocytes) and mitotic (promyeloblasts, myeloblasts, and metamyeloblasts) myeloid cells in the spleen of neonates was observed. No change was detected in splenic lymphocytes or monocytes. No effect of rhG-CSF was noted in the newborn liver or thymus. These results demonstrate that maternally administered rhG-CSF crosses the placenta and specifically induces bone marrow and spleen myelopoiesis in the fetus and neonate. The significant myelopoietic effects of rhG-CSF at low concentrations in the fetus suggest an exquisite degree of developmental sensitivity to this cytokine and may provide enhanced defense mechanisms to the neonate.     

Homoscalarane sesterterpenes from Lendenfeldia frondosa.

The marine sponge Lendenfeldia frondosa, collected from the Solomon Islands, has yielded homoscalarane sesterterpenes. Two new metabolites, epihomoscalaralactone IIA [5] and homoscalarate II [10], were accompanied by two known metabolites, homoscalaralactone IIA [1] and homoscalaralactone IIB [7]. These structures were established by analysis of 2D nmr data, trends in 13C-nmr shifts, and comparison of experimental with molecular-mechanics-calculated nmr J's. Each of the alcohols 1, 2, and 3 was converted to its corresponding acetate, 2, 6, and 8, respectively. Compound 6 exhibited moderate anti-inflammatory activity.     

Influence of food on midazolam absorption

The influence of food on the absorption of midazolam, a new benzodiazepine derivative, was investigated in 18 healthy volunteers in a four-way, randomized, crossover study with a one-week washout period between treatments. Single 15-mg oral doses of midazolam were administered one hour before, with, and one hour after a standard meal as well as under fasting conditions (control). Following serial blood sampling over the next 24-hour period, midazolam plasma concentrations were determined by gas chromatography and mass spectrometry for pharmacokinetic evaluation. The maximum plasma concentration (Cmax), time of maximum concentration (tmax), lag time prior to absorption (tlag), area under the plasma concentration-time curve (AUC), and elimination rate constant of midazolam and 1-hydroxymethylmidazolam were determined. Significant changes in these parameters were not found when midazolam was taken one hour before or with a meal as compared with the control condition. Significant changes in the Cmax, tmax, and AUC parameters for both midazolam and its metabolite were seen when midazolam was ingested one hour after a meal: There was a delayed and reduced rate of absorption as well as a small reduction in the extent of absorption. Thus, ingestion of midazolam within one hour after a meal may result in a delay in the onset of the pharmacologic effect. These changes may be of some clinical significance in that they may potentially delay the onset of sleep.     

Stimulus investigative range in the perimetry of retinitis pigmentosa: some preliminary findings

The manipulation of perimetric stimulus parameters over a given dynamic range has been reported to provide diagnostic information additional to that of changes in differential sensitivity. Preliminary studies (Flanagan et al., 1984a) have indicated that the perimetric response in retinitis pigmentosa behaves atypically over a range of stimulus combinations and strategies. The current study investigated the perimetric response of 17 retinitis pigmentosa patients of various genetic types over a range of stimulus parameters (target size, presentation time and background luminance) and test strategies (kinetic and threshold static) using the Octopus automated perimeter, the Goldmann and Tubinger bowl perimeters and the Dicon Autoperimeter 3000. Statokinetic dissociation was found to be present with large target sizes at 10 asb and 31.5 asb bowl luminances. Some patients demonstrated enhanced sensitivity to shorter stimulus presentations.     

Peer Reviewed: State-Level Prevalence of Cigarette Smoking and Treatment Advice, by Disability Status, United States, 2004

Introduction

To our knowledge, no study has determined whether smoking prevalence is higher among people with disabilities than among people without disabilities across all U.S. states. Neither do we know whether people with disabilities and people without disabilities receive the same quality of advice about tobacco-cessation treatment from medical providers.

Methods

We analyzed data from the 2004 Behavioral Risk Factor Surveillance System to estimate differences between people with and people without disabilities in smoking prevalence and the receipt of tobacco-cessation treatment advice from medical providers.

Results

We found that smoking prevalence for people with disabilities was approximately 50% higher than for people without disabilities. Smokers with disabilities were more likely than smokers without disabilities to have visited a medical provider at least once in the previous 12 months and to have received medical advice to quit. More than 40% of smokers with disabilities who were advised to quit, however, reported not being told about the types of tobacco-cessation treatment available.

Conclusion

Ensuring that people with disabilities are included in state-based smoking cessation programs gives states an opportunity to eliminate health disparities and to improve the health and wellness of this group. Ways to reduce unmet preventive health care needs of people with disabilities include provider adoption of the Public Health Service''s clinical practice guideline for treating tobacco use and dependence and the provision of smoking cessation services that include counseling and effective pharmaceutical treatment.