ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required to maintain normal apoE levels and lipidation in the central nervous system. In addition, ABCA1 has been reported to modulate ␤-amyloid (A␤) production in vitro. These observations raise the possibility that ABCA1 may play a role in the pathogenesis of Alzheimer disease. Here we report that the deficiency of ABCA1 does not affect soluble or guanidine-extractable A␤ levels in Tg-SwDI/B or amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with a dramatic reduction in soluble apoE levels in brain. Although this reduction in apoE was expected to reduce the amyloid burden in vivo, we observed that the parenchymal and vascular amyloid load was increased in Tg-SwDI/B animals and was not diminished in APP/ PS1 mice. Furthermore, we observed an increase in the proportion of apoE retained in the insoluble fraction, particularly in the APP/ PS1 model. These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo.Alzheimer disease (AD) 8 is the most common cause of senile dementia and currently affects ϳ40% of the population over 80 years of age. Clinically, AD is characterized by severe impairments in memory and executive cortical functions as well as difficulties in language, calculation, visuospatial perception, behavior, and judgment (1). Characteristic neuropathological hallmarks of AD include intraneuronal fibrillary tangles composed of hyperphosphorylated tau protein and amyloid deposits that are composed largely of A␤ peptides, apolipoprotein E (apoE), lipids, and other proteins that accumulate in the neural parenchyma and the cerebrovasculature (2, 3). A␤ peptides are a heterogeneous group of peptides 39 -43 amino acids in length that are proteolytically cleaved from amyloid precursor protein (APP) by ␥-and ␤-secretases (4, 5). A␤40 and A␤42 are the main A␤ species in the brain. A␤42 is less soluble and is present in all types of senile plaques, whereas A␤40 is the major species deposited in cerebral blood vessels (4 -7).Most affected individuals have late onset AD that typically manifests after 70 years of age. However, a number of families develop the disease in their 4th or 5th decades (8, 9). The cases of familial AD result from mutations within APP or secretase components (8, 10). For example, the Swedish mutation (K670M/N671L) increases the amount of A␤ peptide that is generated from APP (11, 12). Other APP mutations, including the Dutch (E693D) and Iowa (Q694N) mutations, alter the charge of the A␤ peptide and result in amyloid deposition predominantly in the cerebral blood vessels rather than in the parenchyma (13-16). In addition to mutations in APP, over 100 different mutations have been identified in presenilin-1 alone (17). However, less than 5% of the overall clinical burden of AD is caused by mutations in APP and presenilins combined.To date, the only well established risk factor for late-onset AD is apoE (18,19). In the hum...

Issues with the endoscope-assisted procedure primarily concerned the postoperative helmet regimen, specifically patient compliance (17.1% noncompliance rate) and minor skin breakdown (5.7%). The endoscope-assisted repair with postoperative helmet molding therapy is a cost-effective procedure with less operative risk and minimal postoperative morbidity. This is a valuable treatment option in younger patients with compliant caregivers.

Lipid trafficking in the brain is essential for the maintenance and repair of neuronal membranes, especially after neurotoxic insults. However, brain lipid metabolism is not completely understood. In plasma, LCAT catalyses the esterification of free cholesterol on circulating lipoproteins, a key step in the maturation of HDL. Brain lipoproteins are apolipoprotein E (apoE)-containing, HDL-like particles secreted initially as lipid-poor discs by glial cells. LCAT is synthesized within the brain, suggesting that it may play a key role in the maturation of these lipoproteins. Here we demonstrate that astrocytes are the primary producers of brain LCAT. This LCAT esterifies free cholesterol on nascent apoE-containing lipopoproteins secreted from glia. ApoE is the major LCAT activator in glia-conditioned media (GCM), and both the cholesterol transporter ABCA1 and apoE are required to generate glial LCAT substrate particles. LCAT deficiency leads to the appearance of abnormal ?8 nm particles in GCM, and exogenous LCAT restores the lipoprotein particle distribution to the wild-type (WT) pattern. In vivo, complete LCAT deficiency results in a dramatic increase in apoE-HDL and reduced apolipoprotein A-I (apoA-I)-HDL in murine cerebrospinal fluid (CSF). These data show that brain LCAT esterifies cholesterol on glial-derived apoE-lipoproteins, and influences CSF apoE and apoA-I levels. In plasma, LCAT is the sole enzyme capable of esterifying cholesterol in the circulation. LCAT is a 416 amino acid protein that circulates in plasma predominately bound to lipoproteins, where it catalyses the transfer of an unsaturated fatty acid from phosphatidylcholine, or lecithin, to the free b-hydroxyl residue of cholesterol to generate cholesterol esters (CE) and lysoPC (lysolecithin) (1). Esterification of lipoprotein cholesterol results in the segregation of CE into the lipoprotein core, an essential step in peripheral HDL maturation. Mutations in the human LCAT gene underlie two distinct metabolic diseases, Familial LCAT Deficiency and Fish Eye Disease, both of which present with low HDL levels (2).The preferred plasma substrate for circulating LCAT is free cholesterol found on HDL, and apolipoprotein A-I (apoA-I), the primary protein constituent of HDL, is considered the major physiological activator of LCAT (3). In vitro experiments show that other plasma apolipoproteins, including apolipoprotein E (apoE), apoC-I, and apoA-IV, are capable of activating LCAT, albeit less efficiently than apoA-I (3). Moreover, apoA-I, and to a lesser extent, apoE appear to be the predominant in vivo activators of LCAT, as a recent analysis of apoA-I-, apoE-, and double apoA-I/ apoE-deficient mice shows that the percentage of free cholesterol esterified in plasma drops to less than 2% of wildtype (WT) values after deletion of apoA-I and apoE (4).LCAT is synthesized mainly in liver, but is also abundant in brain and testes (5-8). Indeed, brain exhibits the second highest LCAT mRNA level after liver in rats and rhesus monkeys (6, 9). Brain LCAT ...

Nucleoside analogs can induce mitochondrial toxicity by inhibiting the human DNA polymerase gamma. This can lead to a wide range of clinical toxicities, from asymptomatic hyperlactatemia to death. Despite their technical and physiological variability, we propose that random venous lactate measurements can be useful to monitor the development of nucleoside-related mitochondrial toxicity. Recently, we have developed an assay that can measure changes in mitochondrial DNA levels in peripheral blood cells. Using this assay we have characterized changes in mitochondrial DNA (mtDNA) relative to nuclear DNA (nDNA) in peripheral blood cells of patients with symptomatic nucleoside-induced hyperlactatemia. Our results demonstrate that symptomatic hyperlactatemia was associated with markedly low mtDNA/nDNA ratios, which were on average 69% lower than HIV-uninfected controls and 45% lower than HIV-infected asymptomatic/antiretroviral naive controls. A statistically significant (p = .016) increase in mtDNA/nDNA ratio was observed following discontinuation of antiretroviral therapy. The mtDNA/nDNA ratio remained stable among selected patients who reintroduced antiretroviral therapy with stavudine (d4T)-sparing regimens. Of note, the decline in mtDNA preceded the increase in venous lactate levels. More recently we have evaluated changes in the mtDNA/nDNA ratio in relation to selected antiretroviral drug regimens in a cross-sectional study on a non-random sample of participants within the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program. Eligible patients had continuously received saquinavir plus ritonavir with either nevirapine (n = 20), lamivudine (n = 15), d4T (n = 53) or lamivudine + d4T (n = 69), for 4 to 30 months. d4T-sparing regimens were associated with a higher median mtDNA/nDNA ratio than d4T-containing regimens (p = .016), despite the fact that study patients had received d4T-containing regimens for a shorter median time than patients taking d4T-sparing regimens (13 versus 25 months, p = .002). In summary, mtDNA levels are significantly decreased among patients who develop symptomatic, nucleoside-related hyperlactatemia, an effect reversed upon therapy discontinuation. Furthermore, mtDNA/nDNA ratios were statistically significantly lower in patients taking d4T-containing regimens than in those taking selected d4T-sparing regimens in a population setting. These results suggest that measurement of this parameter should be investigated as a potential clinical management tool.

Active bowel dysfunction was seen in half of the children with a lower urinary tract condition. Constipation was more common in patients with dysfunctional voiding, while encopresis was significantly increased in those with idiopathic detrusor overactivity disorder and in those with dysfunctional voiding, severe urgency and detrusor overactivity. Anticholinergics, despite their constipating effect, given for treatment of detrusor overactivity resolved encopresis in most children with this bowel dysfunction.