Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by beta-amyloid (A beta) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5' region of CH25H revealed three common haplotypes, CH25Hchi2, CH25Hchi3 and CH25Hchi4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hchi4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain A beta deposits in carriers of CH25Hchi4 and CH25Hchi3 haplotypes, whereas no A beta deposits were present in CH25Hchi2 carriers. Together, these results are compatible with a role of CH25Hchi4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain A beta deposition.     

Auditory steady-state responses in infants with perinatal brain injury

Infants with perinatal brain injury present impairments in motor, visual, auditory, and cognitive functions. The most useful methods for detecting auditory alterations are auditory brainstem responses and otoacoustic emissions. Auditory steady-state responses have been reported as a reliable and objective technique for evaluating the hearing threshold. Auditory brainstem responses and auditory steady-state responses were carried out in 53 infants with perinatal brain injury and abnormal neurologic findings. With auditory brainstem responses, 33 (62.26%) infants presented normal and 20 abnormal results; 8 (15.09%) exhibited mild alterations, 8 (15.09%) moderate, and 4 (7.54%) severe alterations. With auditory steady-state responses, 17 (32.0%) infants were normal and 36 (67.9%) had abnormal results. When auditory steady-state responses were compared with auditory brainstem responses gold standard, the assessment gave 100% sensitivity, 51.51% specificity, 55.55% positive predictive value, and 100% negative predictive value. Abnormalities were mild in 21 (39.6%) infants, moderate in 10 (18.9%), and 5 (9.4%) exhibited severe hearing loss. We conclude that hearing loss is a frequent abnormality in infants with perinatal brain injury, and auditory steady-state responses have a high sensitivity for detecting hearing impairment, which is more evident in mild hearing loss for specific frequencies.     

Assessment of capacity to consent to research among older persons with schizophrenia, Alzheimer disease, or diabetes mellitus: comparison of a 3-item questionnaire with a comprehensive standardized capacity instrument

CONTEXT: Considerable discussion surrounds issues related to the capacities of neuropsychiatric patients to consent to research, yet few empirical investigations have directly compared decisional capacity among patients with a serious mental illness with that among patients with neurologic or medical conditions. Also, as requirements for formal assessment of decisional capacity are becoming more common, there is a clear need to identify efficient screening methods. OBJECTIVES: To compare decisional capacity among 3 diagnostic groups, and to examine the degree to which impaired understanding can be detected with a brief set of screening questions. SETTING: Outpatient veterans hospital clinic and university-based neuropsychiatric research centers. DESIGN/ PARTICIPANTS: Cross-sectional comparison of decisional capacity among older (>/=60 years) outpatients with schizophrenia (n = 35), mild to moderate Alzheimer disease (n = 30), and type 2 diabetes mellitus (n = 36), and determination of sensitivity and specificity of a screening measure. MAIN OUTCOME MEASURES: Three-item decisional capacity questionnaire and the MacArthur Competence Assessment Tool for Clinical Research. RESULTS: Patients with diabetes mellitus performed the best on the capacity instruments, patients with Alzheimer disease had the worst performance, and patients with schizophrenia were intermediate. However, there was considerable heterogeneity within each group. Even within diagnostic groups, the level of cognitive functioning (measured with the Mini-Mental State Examination) was generally the best predictor of decisional capacity (particularly in the understanding component). The 3-item questionnaire was sensitive to impaired understanding as measured with the MacArthur Competence Assessment Tool for Clinical Research understanding subscale. CONCLUSIONS: Decisional capacity differed among the 3 groups; there was considerable heterogeneity even within each diagnostic group, so individualized consideration of capacity may be warranted. The level of cognitive deficits is 1 potential marker of which participants should receive comprehensive capacity evaluations, but sensitive brief questionnaires targeting key aspects of disclosed information may also provide an effective means of screening for participants warranting comprehensive capacity evaluations.     

Ventricular rate stabilization for the prevention of pause dependent ventricular tachyarrhythmias: results from a prospective study in 309 ICD recipients

Reviews of stored electrograms from ICDs revealed a 5-30% incidence of short-long-short intervals preceding the onset of recurrent ventricular tachyarrhythmias. Rate stabilization by dedicated antibradycardia pacing algorithms has, therefore, been suggested to prevent onset of pause dependent tachyarrhythmias. However, the clinical efficacy of this approach has not been studied systematically. In a prospective multicenter crossover study, patients were randomized to activation or deactivation of an implemented ventricular rate stabilization algorithm (VRS) after first implant of a dual chamber ICD. After 3 months, all patients were crossed over to the alternate programming. The rate of appropriate spontaneous VA episodes was compared between VRS On and VRS Off. Stored electrograms were reviewed for evaluation of the mode of onset of tachyarrhythmias. Overall efficacy analysis was based on 309 patients enrolled in the study. Forty percent (124/309) of the patients experienced 4,973 VA episodes. Based on an intention-to-treat analysis, VRS Off and On arrhythmia incidence was 10.2 and 6.6 normalized to 3 months, respectively (risk reduction 35%; P = 0.18) On an on-treatment basis, a reduction from 9.0 episodes to 8.1 episodes (10% risk reduction, P = 0.24) was seen. In an extended Cox model adjusting for confounding variables, the relative risk for recurrent episodes was 0.92 during VRS On compared to Off (95% CI: 0.58-1.48; P = 0.74). During VRS Off, pause dependent onset was documented in only 36 (8%) of 427 visually analyzed episodes. There was no significant reduction in the incidence of recurrent ventricular tachyarrhythmias with VRS On compared to the Off programming in this prospective study.     

Negative charge distribution and density on the surface of oxygenated normal and sickle red cells

Negative charges on the external surface of red cells were visualized by colloidal iron hydroxide labelling of 50% of the membrane area after osmotic hemolysis and glutaraldehyde fixation. Counts were made over randomly selected areas on electron micrographs at 350,000 x magnification. Statistical analyses showed that at the 95% level of confidence there was no significant difference between oxygenated normal (AA) and sickle (SS) cells in either the distribution or the density of negative charges.     

Prevalence of risk factors for cardiovascular disease in Canadians 55 to 74 years of age: results from the Canadian Heart Health Surveys, 1986-1992

BACKGROUND: By 2016, the proportion of Canadians older than 65 years of age will increase to 16%, and there will be an increase in the absolute number of cases of cardiovascular disease in older Canadians. The Canadian Heart Health Surveys database provides information about this population upon which health policy related to cardiovascular disease can be based. This paper presents for the first time population-based data on the risk factors for cardiovascular disease in older Canadians. METHODS: Canadians from all 10 provinces participated in surveys of cardiovascular risk factors; health insurance registries were used as sampling frames. In each province, probability samples of 2200 adults 18 to 74 years old not living in institutions, on reserves or in military camps were asked to participate in interviews and to undergo testing at clinics for major risk factors for cardiovascular disease. RESULTS: A total of 2739 men (response rate 70%) and 2617 women (response rate 66%) aged 55 to 74 years participated in the survey and also provided follow-up clinical measurements at the clinic. Overall, 52% of participants were hypertensive, 26% had isolated systolic hypertension, and 30% had a total blood cholesterol level of 6.2 mmol/L or greater. Rates of current smoking were lower in women than men (17% v. 22%). Overall, 87% of men and 78% of women who were current smokers smoked at least 10 cigarettes per day. Only slightly more than half of participants exercised at least once a week for at least 15 minutes, and almost half had a body mass index of 27 or greater. In only 4% was no major risk factor for cardiovascular disease detected. INTERPRETATION: Significant numbers of older Canadians have one or more major risk factors for cardiovascular disease. Many of these risk factors are amenable to modification.     

Autoantibodies against bactericidal/permeability-increasing protein in patients with cystic fibrosis

Cystic fibrosis (CF), a genetic disorder, is characterized by chronic pulmonary infection/inflammation which leads to respiratory failure. The presence of anti-neutrophil cytoplasmic autoantibodies (ANCA) has previously been observed in the sera of patients with CF. In view of the known relationship of ANCA with primary vasculitis and of their putative pathogenetic role in these disorders, we studied the presence, specificity and isotype of ANCA and their clinical associations in 66 adult CF patients. None of the 66 CF samples had autoantibodies to the major ANCA antigens, proteinase 3 or myeloperoxidase. However, 60/66 (91%) CF samples contained IgG and 55/66 (83%) IgA, autoantibodies to bactericidal/permeability increasing protein (BPI), a recently characterized ANCA specificity. All the IgA anti-BPI-positive samples were also IgG anti-BPI-positive. The autoantibody specificity was confirmed by inhibition assay and immunoblotting of CF sera against a neutrophil granule preparation. Furthermore, in this cross-sectional study, anti-BPI levels were inversely correlated with the observed reductions in FEV1 and FVC (IgA anti-BPI and FEV1: r = 0.508, <it>p</it> &lt; 0.0001), and both IgG and IgA anti-BPI levels were higher in CF patients with secondary vasculitis (<it>n</it> = 6) than in those without (<it>p</it> &lt; 0.05). ANCA with specificity for BPI were present in the majority of CF sera in this study and autoimmune processes may be associated with the development of pulmonary injury in CF.      

Salivary levels of Epstein-Barr virus DNA correlate with subgingival levels, not severity of periodontitis

Objective:  The aim of this study was to determine the presence and quantity of human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA in the saliva of patients with periodontitis, and investigate the correlation between these factors.
Methods:  Presence and amounts of viral DNA in saliva and subgingival plaque samples, from healthy and disease sites, of 65 adults diagnosed with chronic periodontitis were determined using quantitative real-time polymerase chain reaction.
Results:  Epstein-Barr virus DNA was detected in saliva of 81.5% (53/65) of patients at a median concentration of 4325 copies ml⁻¹. CMV DNA was detected in saliva of one individual (1.5%) at low copy number. Patients who had EBV in saliva were 10 times more likely to have EBV in subgingival plaque than patients lacking EBV in saliva (odds ratio = 10.1, 95% confidence interval = 2.6–39.5; P  = 0.0009). EBV DNA burden in saliva positively correlated with the amounts detected in plaque and with amounts detected in increasing number of affected sites ( P  < 0.0001). EBV DNA presence and quantity in saliva did not correlate with increasing severity of disease as measured by periodontal indices.
Conclusions:  Epstein-Barr virus DNA presence and burden in saliva are associated with its presence and burden in subgingival plaque, but presence and burden in saliva does not correlate with periodontal disease severity.     

Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation

In an attempt to decrease the relapse rate after bone marrow transplantation (BMT) for advanced acute leukemia, we initiated studies using 131I-labeled anti-CD45 antibody (BC8) to deliver radiation specifically to hematopoietic tissues, followed by a standard transplant preparative regimen. Biodistribution studies were performed in 23 patients using 0.5 mg/kg trace 131I-labeled BC8 antibody. The BC8 antibody was cleared rapidly from plasma with an initial disappearance half-time of 1.5 +/- 0.2 hours, presumably reflecting rapid antigen- specific binding. The mean radiation absorbed doses (cGy/mCi131I administered) were as follows: marrow, 7.1 +/- 0.8; spleen, 10.8 +/- 1.4; liver, 2.7 +/- 0.2; lungs, 2.1 +/- 0.1; kidneys, 0.7 +/- 0.1; and total body, 0.4 +/- 0.03. Patients with acute myelogenous leukemia (AML) in relapse had a higher marrow dose (11.4 cGy/mCi) than those in remission (5.2 cGy/mCi; P = .001) because of higher uptake and longer retention of radionuclide in marrow. Twenty patients were treated with a dose of 131I estimated to deliver 3.5 Gy (level 1) to 7 Gy (level 3) to liver, with marrow doses of 4 to 30 Gy and spleen doses of 7 to 60 Gy, followed by 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI). Nine of 13 patients with AML or refractory anemia with excess blasts (RAEB) and two of seven with acute lymphocytic leukemia (ALL) are alive disease-free at 8 to 41 months (median, 17 months) after BMT. Toxicity has not been measurably greater than that of CY/TBI alone, and the maximum tolerated dose has not been reached. This study demonstrates that with the use of 131I-BC8 substantially greater doses of radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation.