Investigating neuroepigenetic alterations in chronic low back pain with positron emission tomography.

ABSTRACT: Epigenetics has gained considerable interest as potential mediators of molecular alterations that could underlie the prolonged sensitization of nociceptors, neurons, and glia in response to various environmental stimuli. Histone acetylation and deacetylation, key processes in modulating chromatin, influence gene expression; elevated histone acetylation enhances transcriptional activity, whereas decreased acetylation leads to DNA condensation and gene repression. Altered levels of histone deacetylase (HDAC) have been detected in various animal pain models, and HDAC inhibitors have demonstrated analgesic effects in these models, indicating HDACs' involvement in chronic pain pathways. However, animal studies have predominantly examined epigenetic modulation within the spinal cord after pain induction, which may not fully reflect the complexity of chronic pain in humans. Moreover, methodological limitations have previously impeded an in-depth study of epigenetic changes in the human brain. In this study, we employed [11C]Martinostat, an HDAC-selective radiotracer, positron emission tomography to assess HDAC availability in the brains of 23 patients with chronic low back pain (cLBP) and 11 age-matched and sex-matched controls. Our data revealed a significant reduction of [11C]Martinostat binding in several brain regions associated with pain processing in patients with cLBP relative to controls, highlighting the promising potential of targeting HDAC modulation as a therapeutic strategy for cLBP.

Statewide school-located influenza vaccination program for children 5-13 years of age, Hawaii, USA.

New guidance recommends annual influenza vaccination for all children 5-18 years of age in the United States. During 2007-2008, Hawaii offered inactivated and live attenuated influenza vaccine at school-located clinics for grades kindergarten through 8. Most (90%) public and private schools participated, and 622 clinics were conducted at 340 schools. Of 132,775 children 5-13 years of age, 60,760 (46%) were vaccinated. The proportion vaccinated peaked at 54% for those 6 years of age and declined for older cohorts. More than 90% of schoolchildren transited the clinic in <10 minutes. A total of 16,920 staff-hours were expended; estimated cost per dose administered was $27 and included vaccine purchase and administration, health staffing resources, printing costs, data management, and promotion. This program demonstrates the feasibility of conducting mass school-located influenza vaccination programs in public and private schools statewide, as might be indicated to respond to pandemic influenza.

Cdk5 is a key factor in tau aggregation and tangle formation in vivo.

Tau aggregation is a common feature of neurodegenerative diseases such as Alzheimer's disease, and hyperphosphorylation of tau has been implicated as a fundamental pathogenic mechanism in this process. To examine the impact of cdk5 in tau aggregation and tangle formation, we crossed transgenic mice overexpressing the cdk5 activator p25, with transgenic mice overexpressing mutant (P301L) human tau. Tau was hyperphosphorylated at several sites in the double transgenics, and there was a highly significant accumulation of aggregated tau in brainstem and cortex. This was accompanied by increased numbers of silver-stained neurofibrillary tangles (NFTs). Insoluble tau was also associated with active GSK. Thus, cdk5 can initiate a major impact on tau pathology progression that probably involves several kinases. Kinase inhibitors may thus be beneficial therapeutically.

Leptospirosis on Oahu: an outbreak associated with flooding of a university campus.

On October 31, 2004, a stream overflowed, flooding the University of Hawaii (UH) campus. On November 19, 2004, a possible flood-related leptospirosis case (Patient 1) was reported to the Hawaii State Department of Health (HDOH). Surveillance for febrile illness was established through an Internet questionnaire. Active case finding was conducted among groups involved in the flood clean-up. Free leptospirosis testing was offered by HDOH. Patient 1's illness was confirmed as leptospirosis by microscopic agglutination testing. A total of 271 persons responded to the Internet survey, of whom 90 (33%) reported a febrile illness within 30 days of contact with flood water. Forty-eight respondents (18%) were tested for leptospirosis. One additional acute leptospirosis case was identified. Patient 2 was epidemiologically linked to Patient 1. Health care providers should maintain a high level of suspicion for leptospirosis after flooding events, and local public health officials should promote leptospirosis awareness among flood-affected populations.

Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo.

Epidemiology, in vitro, and in vivo studies strongly implicate a role for cholesterol in the pathogenesis of Alzheimer's disease (AD). We have examined the impact of aberrant intracellular cholesterol transport on the processing of the amyloid precursor protein (APP) in a mouse model of Niemann-Pick type C (NPC) disease. In the NPC mouse brain, cholesterol accumulates in late endosomes/lysosomes. This was associated with the accumulation of beta-C-terminal fragments (CTFs) of APP, but the level of beta-secretase and its activity were not affected. Alpha-secretase activity and secreted APPalpha generation were also not affected, suggesting CTFs increased because of decreased clearance. The level of presenilin-1 (PS-1) was unchanged, but gamma-secretase activity was greatly enhanced, which correlated with an increase in Abeta40 and Abeta42 levels. These events were associated with abnormal distribution of PS-1 in the endosomal system. Our results show that aberrant cholesterol trafficking is associated with the potentiation of APP processing components in vivo, leading to an overall increase in Abeta levels.

Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to beta-amyloid.

Plaques containing beta-amyloid (Abeta) peptides are one of the pathological features of Alzheimer's disease, and the reduction of Abeta is considered a primary therapeutic target. Amyloid clearance by anti-Abeta antibodies has been reported after immunization, and recent data have shown that the antibodies may act as a peripheral sink for Abeta, thus altering the periphery/brain dynamics. Here we show that peripheral treatment with an agent that has high affinity for Abeta (gelsolin or GM1) but that is unrelated to an antibody or immune modulator reduced the level of Abeta in the brain, most likely because of a peripherally acting effect. We propose that in general, compounds that sequester plasma Abeta could reduce or prevent brain amyloidosis, which would enable the development of new therapeutic agents that are not limited by the need to penetrate the brain or evoke an immune response.

Brain damage results in down-regulation of N-acetylaspartate as a neuronal osmolyte.

N-acetyl-L-aspartate (NAA) is present in the vertebrate brain, where its concentration is one of the highest of all free amino acids. Although NAA is synthesized and stored primarily in neurons, it is not hydrolyzed in these cells. However, after its regulated release into extracellular fluid, neuronal NAA is hydrolyzed by amidohydrolase II that is present in oligodendrocytes. About 30% of neurons do not contain appreciable amounts of NAA, but its prominence in 1H nuclear magnetic resonance spectroscopic (MRS) studies has led to its wide use as a neuronal marker in diagnostic human medicine as both an indicator of brain pathology, and of disease progression in a variety of central nervous system (CNS) diseases. Loss of NAA has been interpreted as indicating either loss of neurons, or loss of neuron viability. In this investigation, the upregulation of NAA in early stages of construction of the CNS, and its downregulation in experimentally induced damage models of the CNS is reported. The results of this study indicate that the buildup of NAA is not required for viability of neurons in monocellular cultures, and that NAA is lost from multicellular cultured brain slice explants that contain viable neurons. Thus, loss of NAA does not necessarily indicate either loss of neurons or their function. The NAA system, when present in the brain, appears to reflect a high degree of cellular integration, and therefore may be a unique metabolic construct of the intact vertebrate brain.

Co-localization of cholesterol, apolipoprotein E and fibrillar Abeta in amyloid plaques.

Recent evidence strongly suggests a role for cholesterol and apolipoprotein E in the etiology of Alzheimer's disease. We have demonstrated the co-localization of cholesterol and apolipoprotein E with beta-amyloid immunoreactivity and thioflavin S immunofluorescence in AD type plaques of a transgenic mouse model. Cholesterol and apolipoprotein E co-localized to the core of thioflavin S-positive (fibrillar) plaques, but not thioflavin S-negative (diffuse) plaques from an early age. By 18 months of age, there was extensive coverage of fibrillar plaques immunopositive for apolipoprotein E and cholesterol oxidase. These findings support evidence that cholesterol and apolipoprotein E are involved in fibrillar plaque formation or maintenance, and suggest that cholesterol may impact amyloid formation extracellularly, as well as through an intracellular effect.

Distribution of eosinophilic meningitis cases attributable to Angiostrongylus cantonensis, Hawaii.

During November 2004-January 2005, 5 cases of eosinophilic meningitis (EM) attributable to Angiostrongylus cantonensis infection were reported in Hawaii. To determine if this temporal clustering reflected an increased incidence, we ascertained EM and A. cantonensis cases by systematic review of statewide laboratory and medical records for January 2001-February 2005 and generalized the data to population estimates. We identified 83 EM cases; 24 (29%) were attributed to A. cantonensis infection, which was included in the discharge diagnoses for only 2 cases. Comparison of A. cantonensis infection incidence rates (per 100,000 person-years) for the baseline (January 2001-October 2004) and cluster (November 2004-February 2005) periods showed statistically significant increases for the state as a whole (0.3 vs. 2.1), the Big Island of Hawaii (1.1 vs. 7.4), and Maui County (0.4 vs. 4.3). These findings underscore the need to consider the diagnosis of A. cantonensis infection, especially in the state of Hawaii.

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo.

Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically.