Treatment of olfactory dysfunction, II: studies with minocycline

OBJECTIVES/HYPOTHESIS: The treatment of anosmia has changed minimally since the early 1970s, despite dramatic advances in the understanding of the molecular biology of olfaction. Recent studies from the authors' laboratory have suggested that most common causes of clinical olfactory dysfunction, including rhinosinusitis, appear to be associated with increased apoptotic death of olfactory sensory neurons. This appears to result in a decline in the number of functioning mature olfactory sensory neurons, despite the capacity of the olfactory epithelium for regeneration. The current study evaluated the ability of the antibiotic minocycline to inhibit olfactory sensory neuron apoptosis. This drug is known to inhibit apoptosis separate from its anti-infective properties. Olfactory sensory neuron apoptosis was triggered by surgical deafferentation ("bulbectomy"), the standard experimental model. Earlier studies have indicated that bulbectomy and sinusitis invoke similar proteolytic enzyme cascades in olfactory sensory neurons. STUDY DESIGN: Histological analysis of animal olfactory tissue. METHODS: Mice underwent unilateral olfactory bulbectomy to induce apoptotic olfactory sensory neuron death, with and without 45 mg/kg intraperitoneal minocycline given 12 hours before surgery and every 12 hours until death. Mice were killed at 2 and 4 days after bulbectomy and assessed for activation of capsase-3 and olfactory sensory neuron survival by immunohistochemical analysis. RESULTS: Minocycline resulted in partial suppression of cell death at 2 days after surgery when compared with untreated animals. CONCLUSION: Minocycline inhibits olfactory sensory neuron death in the face of a potent pro-apoptotic stimulus. This drug is well tolerated and is currently undergoing human trials for the management of a variety of neurological disorders associated with apoptosis. The current results suggest that minocycline may be efficacious in the management of peripheral olfactory loss as well.     

Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22

PURPOSE: To report results of linkage analysis in a large family with autosomal dominant (AD) febrile seizures (FS) and epilepsy. BACKGROUND: AD FS and epilepsy is clinically and genetically a heterogeneous group of epilepsies, frequently inherited. The most notable, generalized epilepsy with febrile seizures plus (GEFS+), is characterized by heterogeneous phenotypes including FS persisting beyond the usual age of remission or coexisting with afebrile seizures. Mutations in three subunits of sodium channel genes and one GABA(A)-receptor subunit gene have been identified in some GEFS+ pedigrees. Six genetic loci for FS have been reported so far, but the molecular basis of FS remains unknown. METHODS: We identified a five-generation family with 13 individuals affected by FS. Evidence was found for coexisting afebrile seizures in some affected individuals. Evaluation included a detailed history and neurologic examination, as well as collection of DNA. After excluding previously identified loci associated with FS and epilepsy, a genome-wide search was performed. RESULTS: Two affected individuals reported only a single FS, whereas the other affected individuals had a history of repeated FS. Coexisting afebrile seizures developed in three individuals. The mode of inheritance was consistent with AD inheritance with an incomplete penetrance. Tight linkage to a group of markers on chromosome 21q22 was identified with flanking markers D21S1909 and D21S1444, and maximum 2-point lod score 3.35 for markers D21S1910 and D21S1894. We excluded four ion-channel genes within this 6.5-cM locus as a cause of FS and epilepsy in this family. CONCLUSIONS: We report a novel locus on chromosome 21q22 for AD FS. Identification of the gene causing epilepsy on chromosome 21q22 will advance our understanding of inherited epilepsy and FS, and possibly other types of epilepsies.     

Cardiac magnetic resonance imaging assessment of regional and global left atrial function before and after catheter ablation for atrial fibrillation

Background  

Ablation of the left atrium and pulmonary veins antrum (PVAI) can be an effective treatment of atrial fibrillation (AF). However, there is discrepancy in the literature regarding the effect extensive ablation has on left atrial (LA) function. We sought to evaluate the effect that AF ablation procedures has on global and regional wall motion as assessed by cardiovascular magnetic resonance imaging (MRI).     

Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease

Several recent case-control studies have examined the association between single nucleotide polymorphisms (SNPs) in the promoter region of the apolipoprotein E gene (APOE) and risk of Alzheimer disease (AD), with conflicting results. We assessed the relation between five APOE region SNPs and risk of AD in both case-control and family-based analyses. We observed a statistically significant association with the +5361T allele in the overall case-control analysis (P value=0.04) after adjusting for the known effect of the APOE-4 allele. Further analysis revealed this association to be limited to carriers of the APOE-4 allele. Age-stratified analyses in the patients with age at onset of 80 years or greater and age-matched controls showed that the –219T allele (P value=0.009) and the +113C allele (P value=0.03) are associated with increased risk of AD. Despite these findings, haplotype and family-based association analyses were unable to provide evidence that the APOE region SNPs influenced risk of AD independent of the APOE-4 allele. In addition to risk, we tested for association between the SNPs and age at onset of AD, but found no association in the case-control or family based analyses. In conclusion, SNPs +5361, or a SNP in strong linkage disequilibrium, may confer some additional risk for developing AD beyond the risk due to APOE-4; however, the effect independent of APOE-4 is likely to be small.     

Comparing student and patient simulated malingerers' performance on standard neuropsychological measures to detect feigned cognitive deficits

Despite the proliferation of studies investigating methods for detecting malingering, important questions that remain unanswered. Specifically, many studies use students to simulate malingering; however, it is unclear whether this is an appropriate analog group. In addition, many studies have focused on the development of cognitive measures designed to detect malingering, rather than pursuing whether current neuropsychological measures are effective. Results of the present investigation suggest that student malingerers are significantly more difficult to detect than non-neurological patients instructed to malinger. The findings also provide further support for the recent evidence that standard neuropsychological measures are useful in detecting malingering.