Focal Atrophy and Cerebrovascular Disease Increase Dementia Risk among Cognitively Normal Older Adults

BACKGROUND AND PURPOSE: This study investigated the association of medial temporal lobe (MTL) atrophy and cerebrovascular disease (white matter hyperintensities [WMH], subclinical infarcts) with the risk of developing Alzheimer's disease (AD) among cognitively normal older adults. METHODS: Risk of developing AD was examined for 155 cognitively normal older adults (77.4 years, 60% women, 81% white). The MTL volumes and the presence of WMH and of subclinical infarcts were determined from brain magnetic resonance imaging (MRI) at the beginning of the study. Follow-up cognitive evaluations (average 4.3 years) identified those who developed AD. RESULTS: The presence of either MTL atrophy or subclinical infarcts was independently and significantly associated with a greater risk to develop AD (OR [95% CI]: 4.4 [1.5, 12.3] and 2.7 [1.0, 7.1], respectively). In addition, those participants with both MTL atrophy and at least one brain infarct had a 7-fold increase in the risk of developing AD (OR [95% CI]: 7.0 [1.5, 33.1]), compared to those who had neither of these conditions. CONCLUSIONS: In cognitively normal older adults, markers of neurodegeneration (as reflected by MTL atrophy) and of cerebrovascular disease (as reflected by infarcts on MRI) independently contribute to the risk to develop AD.     

Serum levels of C1 subunits in rheumatoid arthritis

Modifications of radial immunodiffusion and of hemolytic assays of C1q are described, which enable the results of these assays to be in agreement with those obtained by hydroxyproline assay. Using these assays, we show that C1q serum levels are significantly increased in rheumatoid arthritis (RA) and that the excess C1q levels in this disease are not accompanied by increased levels of C1r and C1s. Active RA is therefore characterized by increased levels of hemolytically active C1q that has a physiologically active stem region unbound to C1r and C1s.     

Extended long-term culture reveals a highly quiescent and primitive human hematopoietic progenitor population

Long-term culture-initiating cells (LTC-IC) are hematopoietic progenitors able to generate colony-forming unit-cells (CFU) after 5 to 8 weeks (35 to 60 days) of culture on bone marrow (BM) stroma and represent the most primitive progenitors currently detectable in vitro. We have recently reported that long-term cultures initiated with CD34+CD38- cells from BM or cord blood are able to continue generating CFU for at least 100 days, ie, beyond the standard LTC-IC period. In this report, single-cell cultures from cord blood and retroviral marking of cord blood and BM were used to study whether the subpopulation of CD34+CD38- cells able to generate CFU beyond 60 days ("extended long-term culture-initiating cells" or ELTC-IC) are functionally distinct from LTC-IC in terms of timing of initial clonal proliferation and generative capacity. All cord blood LTC-IC formed clones of greater than 50 cells by day 30. In contrast, cord blood ELTC- IC proliferated later in culture, 50% forming clones after day 30. Although efficient retroviral marking of LTC-IC was seen (25% to 45%), marking of ELTC-IC was inefficient (< 1%), consistent with a more quiescent progenitor population. There was a positive correlation between time of clonal proliferation and generative capacity. ELTC-IC generated threefold to fourfold more progeny than did LTC-IC (P < .002). These studies show that there is a functional hierarchy of progenitors in long-term culture which correlates with their level of quiescence. By extending the LTC-IC assay, a more primitive progenitor may be studied that may be functionally closer to the human long-term repopulation stem cell in vivo.     

The spectrum of MR detectable cortical microinfarcts: a classification study with 7-tesla postmortem MRI and histopathology

Cerebral microinfarcts (CMIs) are common neuropathologic findings in aging and dementia. We explored the spectrum of cortical CMIs that can be visualized with 7T magnetic resonance imaging (MRI). Thirty-three coronal brain slices of 11 individuals with neuropathologically confirmed dementia were subjected to a high-resolution postmortem 7T MRI protocol. First, we identified all visible small (⩽5 mm) intracortical and juxtacortical lesions on postmortem MRI. Lesions were classified as CMI or nonCMI based on histology, and their MR features were recorded. Thirty lesions were identified on the initial MRI evaluation, of which twenty-three could be matched with histology. Histopathology classified 12 lesions as CMIs, all of which were located intracortically. On the basis of their MR features, they could be classified as chronic gliotic CMIs—with or without cavitation or hemorrhagic components—and acute CMIs. Eleven MRI identified lesions were not of ischemic nature and most commonly enlarged or atypically shaped perivascular spaces. Their MRI features were similar to gliotic CMIs with or without cavitation, but these ‘CMI mimics'' were always located juxtacortically. 7T postmortem MRI distinguishes different histopathologic types of cortical CMIs, with distinctive MR characteristics. On the basis of our findings, we propose in vivo rating criteria for the detection of intracortical CMIs.     

二尖瓣疾病左心室充盈压的多普勒评估

由于在瓣膜区域、左心室松弛性和僵直性等方面易于发生混淆．传统多普勒测量对二尖瓣疾病病人左心房压的预测上受到限制。然而，在犬和临床研究中，组织多普勒成像所测定的充盈早期二尖瓣血流速率起始段和房室环的充盈早期速率之间的时间窗（time interval between the onset of early diastolic mitral inflow velocity and annular early diastolic velocity，TE-Ea）与左心室舒张时间常数（time constant of left ventricular relaxation，t）良好相关，并且不受上述瓣膜区域、左心室舒张和僵直等变量的影响。因此在病人人群中开展这项研究，检验其用途。     

Effect of atorvastatin on endothelium-dependent vasodilation in postmenopausal women with average serum cholesterol levels

After menopause, most healthy women show an impairment of peripheral vasodilation and an increase of plasma cholesterol levels. Statins have been shown to improve endothelial function in hypercholesterolemic men and women. The present study tests whether atorvastatin (10 mg) influences endothelium-dependent vasodilation in postmenopausal normocholesterolemic women. Twenty-eight healthy, postmenopausal women (mean age 51 +/- 2 years) with serum total cholesterol and low-density lipoprotein cholesterol within the desirable range entered a double-blind, single-crossover study. Postmenopausal women were randomized to receive either atorvastatin (10 mg/day) or placebo for 10 days and then crossed to the complementary treatment. Endothelium-dependent and -independent responses were assessed by means of strain-gauge plethysmography before and after intra-arterial infusion of acethylcholine (ACh) and sodium nitroprusside, in comparison to physiologic saline. The nitric oxide pathway was evaluated by repeating the infusion of ACh during admininstration of L-arginine and (G)-monomethyl-L-arginine (L-NMMA). Serum lipoproteins were not significantly modified by the active treatment. The vasodilation induced by ACh was significantly higher in the atorvastatin-treated women compared with the placebo-treated group (24 +/- 3 vs 13 +/- 2 ml/100 ml tissue/min, p <0.01). In contrast, responses to the endothelium-independent vasodilator sodium nitroprusside were not significantly modified by atorvastatin. The ACh-stimulated vasodilation induced by atorvastatin was additionally potentiated by L-arginine (800 +/- 105% vs 370 +/- 60%, p <0.05) and blunted by L-NMMA. No correlation was found between changes in plasma cholesterol and improvement in forearm blood flow. Our data show that the beneficial effect of atorvastatin on endothelium-dependent vasodilation is independent from changes in the lipid profile.     

The significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation

Despite matching for serologically defined HLA-A, B, DR antigens, acute graft-versus-host disease (GVHD) is a major complication contributing to increased morbidity and mortality in patients who undergo marrow transplantation from unrelated donors. The extent to which unrecognized mismatching for alleles that encode DR1-DR18 contribute to the increased risk of acute GVHD and overall survival is unknown. We analyzed 364 patients and their HLA-A, B, DR serologically matched donors to determine whether molecular typing of DRB1 alleles can allow more accurate donor/recipient matching and thereby improve clinical outcome after marrow transplantation. DRB1 alleles were typed by sequence-specific oligonucleotide probe hybridization methods. Selected alleles were confirmed by DNA sequencing. Of the 364 pairs, 305 were matched and 59 were mismatched for DRB1. The probability of moderate to severe acute GVHD was .48 for the matched and .70 for the mismatched patients. Compared with mismatched patients, the estimated relative risk (RR) of GVHD for matched patients was .58 (95% confidence interval [CI], .40 to .85). DRB1 matching decreased the risk of transplant- related mortality (RR, .66; 95% CI, .44 to .97) and was associated with decreased overall mortality (RR, .71; 95% CI, .51 to 1.0). Therefore, matching DRB1 alleles of the donor and recipient decreases the risk of acute GVHD and improves survival after unrelated marrow transplantation. These results indicate that prospective matching of patients and donors for DRB1 alleles is warranted.