Abnormal processing of amyloid precursor protein (APP), in particular the generation of beta-amyloid (Abeta) peptides, has been implicated in the pathogenesis of Alzheimer's disease. This study examined the consequences of deleting the APP gene on hippocampal synaptic plasticity, and upon the biophysical properties of morphologically identified neurones in APP-null mice. The hippocampus of APP-null mice had a characteristic increase in gliosis throughout the CA1 region and a disruption of staining for the dendritic marker MAP2 and the presynaptic marker synaptophysin. The disruption of MAP2 staining was associated with a significant reduction in overall dendritic length and projection depth of biocytin labeled CA1 neurones. In two groups of APP-null mice that were examined at 8-12 months, and 20-24 months of age, there was an impairment in the formation of long-term potentiation (LTP) in the CA1 region compared to isogenic age matched controls. This LTP deficit was not associated with an alteration in the amplitude of EPSPs at low stimulus frequencies (0.033 Hz) or facilitation during a 100 Hz stimulus train, but was associated with a reduction in post-tetanic potentiation. Paired-pulse depression of GABA-mediated inhibitory post-synaptic currents was also attenuated in APP-null mice. These data demonstrate that the impaired synaptic plasticity in APP deficient mice is associated with abnormal neuronal morphology and synaptic function within the hippocampus.

Aging↗

PubMed1999

A retrospective investigation of an intensive outpatient substance abuse treatment program.

Outpatient treatment for chemical dependency has been found to be both clinically effective and cost efficient. The purpose of this retrospective investigation was to evaluate program completion data and variables related to attrition for an intensive outpatient substance abuse treatment program. Subjects were 488 clients enrolled in the Smithers Evening Rehabilitation Program between 1991 and 1995. Client drug preference was found to be an important factor related to treatment retention, with cocaine abusers having the highest attrition rates. In addition, increasing age was an advantage in predicting who would complete the initial phase of treatment. Implications for programmatic changes, clinical practice, and future research are considered.

Adult↗

PubMed1999

Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus.

OBJECTIVE: The host immune response and low vector efficiency have been key impediments to effective cystic fibrosis transmembrane regulator (CFTR) gene transfer for cystic fibrosis (CF). An adeno-associated virus vector (AAV-CFTR) was used in a phase I dose-escalation study to transfer CFTR cDNA into respiratory epithelial cells of the maxillary sinus of 10 CF patients. STUDY DESIGN: A prospective, randomized, unblinded, dose-escalation, within-subjects, phase I clinical trial of AAV-CFTR was conducted. PATIENTS: Ten patients with previous bilateral maxillary antrostomies were treated. MAIN OUTCOME MEASURES: Safety, gene transfer as measured by semiquantitative polymerase chain reaction (PCR), and sinus transepithelial potential difference (TEPD) were measured. RESULTS: The highest level of gene transfer was observed in the range of 0.1-1 AAV-CFTR vector copy per cell in biopsy specimens obtained 2 weeks after treatment. When tested, persistence was observed in one patient for 41 days and in another for 10 weeks. Dose-dependent changes in TEPD responses to pharmacologic intervention were observed following treatments. Little or no inflammatory or immune responses were observed. CONCLUSION: AAV-CFTR administration to the maxillary sinus results in successful, dose-dependent gene transfer to the maxillary sinus and alterations in sinus TEPD suggestive of a functional effect, with little or no cytopathic or host immune response. Further study is warranted for AAV vectors as they may prove useful for CFTR gene transfer and other in vivo gene transfer therapies. A prospective, randomized, double-blind, placebo-controlled, within-subjects, phase II clinical trial of the effect AAV-CFTR on clinical recurrence of sinusitis will determine the clinical efficacy of AAV gene therapy for CF.

Adult↗

PubMed1999