Italian Project on Epidemiology of Alzheimer's disease (I.PR.E.A.): study design and methodology of cross-sectional survey

BACKGROUND AND AIMS: The purpose of this paper is to describe the design and diagnostic procedures of the multicenter community-based prospective Italian Project on the Epidemiology of Alzheimer's disease (I.PR.E.A.). The study is aimed at estimating the prevalence and incidence of Alzheimer's disease (AD) in the preclinical phase, examining the natural history of cognitive decline without dementia (mainly AD) in the Italian population, and identifying risk factors or health determinants related or associated with various health outcomes. METHODS: Both cross-sectional and longitudinal phases will be performed in 4800 elderly subjects aged 65-84 years. The sample will be selected from the registries of 12 Italian rural and urban municipalities, with an interval of one year between examinations. The study population will undergo several screening examinations, including personal and informant interviews by means of a structured ad hoc questionnaire, physical and neurological examination, laboratory tests, genetic markers and a neuropsychological battery. Neuroimaging screening will also be carried out in a subgroup of subjects positive for cognitive impairment without dementia. The longitudinal phase will include all subjects who, during the cross-sectional survey, are identified as affected by cognitive impairment without dementia, and will aim at assessing the incidence and natural history of cognitive impairment without dementia and the degree of disease progression from the earliest stage. This is the first systematic prospective study on the preclinical phase of AD in Italy.     

SURGERY FOR ASYMPTOMATIC CAROTID ARTERY STENOSIS

SUMMARY The recent European Carotid Surgery Trial (ECST) and North American Symptomatic Carotid Endarterectomy Trial (NASCET) have clearly defined a population who benefit from carotid artery endarterectomy (CAE). However these trials used different criteria to identify >70% stenosis of the internal carotid artery (ICA). The role of CAE in asymptomatic ICA stenosis has been investigated by the Carotid Artery Stenosis with Asymptomatic Narrowing Operation Versus Aspirin (CASANOVA) study, the Veterans Administration Asymptomatic Carotid Study (VAACS) and the Asymptomatic Carotid Artery Stenosis (ACAS) trials, all of which have design limitations. The Asymptomatic Carotid Stenosis Trial (ACST) is still recruiting patients but until the natural history of asymptomatic ICA disease is understood, the role of surgical intervention will continue to be controversial.     

The effect of sulphasalazine on neutrophil superoxide generation in rheumatoid arthritis

The production of superoxide by the peripheral blood neutrophils of 19 patients with active rheumatoid arthritis was measured during treatment with sulphasalazine (SASP). The response to drug treatment was determined by change in plasma viscosity, CRP, early morning stiffness and articular index over a 10-point scale. Of the 19 patients studied, eight were considered to have responded well to SASP and seven to have responded poorly or not at all. Over the treatment period, plateau levels of superoxide production fell in seven of the eight responders (P = 0.028) compared with a non-significant fall in 3/7 of the non- responder groups. The initial rate of superoxide production also fell in the responder group, but this was not statistically significant. Initial values in both the responder and non-responder groups were comparable with those seen for normal controls. Analysis of drug levels showed all patients to be compliant with drug treatment; however, drug levels and neutrophil activity were not correlated. Studies of the effect of SASP and sulphapyridine on superoxide production in vitro showed no difference between good and poor responders. These results suggest that there is no inherent difference between good and poor responders regarding the susceptibility of their neutrophils to SASP. SASP's action on neutrophils, therefore, appears not to be its main mechanism of disease-modifying activity in RA.      

Identification of normal human peripheral blood monocytes and liver as sites of synthesis of coagulation factor XIII a-chain

Factor XIII is the fibrin-stabilizing factor that covalently cross- links fibrin monomers to form a highly organized, stable fibrin clot. The plasma form of factor XIII is a heterodimer, a2b2, consisting of two a-chains and two b-chains; the intracellular form, such as in platelets and placenta, is a dimer, a2, consisting of a-chains only. The catalytic function of factor XIII, a transglutaminase, resides in the a-chain. To address questions regarding sites of synthesis of factor XIII a-chain, an EcoRI restriction fragment from the protein- coding region of the factor XIII a-chain cDNA was used as a probe for Northern blot analysis. The cDNA probe showed hybridization with a single approximately 4.0-kilobase (kb) message in poly (A)+ mRNA prepared from normal human peripheral blood monocytes and normal human liver. The results demonstrate conclusively that factor XIII a-chains are actively synthesized in circulating monocytes and in liver. To our knowledge, these data represent the first demonstration of synthesis of any blood coagulation factor in primary uncultured and unstimulated monocytes or macrophage cells.     

A K-ras oncogene increases resistance to sulindac-induced apoptosis in rat enterocytes

BACKGROUND & AIMS: Mutations of c-K-ras occur commonly in colonic neoplasms. The aim of this study was to determine how c-K-ras mutations alter the responses to the chemopreventive agent sulindac. METHODS: The parental rat intestinal cell line IEC-18 and c-K-ras-transformed derivatives were treated with sulindac sulfide. Cell cycle distribution was determined by flow-cytometric analysis (fluorescence-activated cell sorter), apoptosis by DNA fragmentation (laddering), flow cytometry, and microscopy, and changes in gene expression by immunoblotting. RESULTS: Sulindac sulfide inhibited cell growth and induced apoptosis in a time- and dose-dependent manner more rapidly in and at lower concentrations in parental cells than ras-transformed cells. Expression of the sulindac sulfide arrested cells in G0/G1, but cells entered apoptosis throughout the cell cycle. Proapoptotic protein Bak was relatively high in untreated parental cells and increased markedly after sulindac sulfide but was low in untreated ras-transformed cells and did not increase after sulindac sulfide. Expression of other Bcl-2 family members was unchanged after sulindac sulfide. However, sulindac sulfide reduced levels of cyclin D1 protein and cyclin E- and cyclin D1- associated kinase activity. CONCLUSIONS: c-K-ras-transformed enterocytes are relatively resistant to sulindac sulfide-induced growth inhibition and apoptosis, which may result from specific reduction of bak expression. (Gastroenterology 1997 Dec;113(6):1892-900)     

Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma

The blood of most patients with active multiple myeloma (MM) contains cells related to the bone marrow tumor. However, identifying clonal cells in the blood of patients with monoclonal gammopathy of undetermined significance (MGUS) has been difficult. In this study, we analyzed blood mononuclear cells (BMNCs) from 16 patients with MGUS, 2 with amyloidosis, 8 with smoldering MM (SMM), 2 with indolent MM (IMM), and 15 with active MM using three different methods to detect and quantitate clonal cells, ie, immunofluorescence microscopy (IM) for monoclonal plasma cells, three-color flow cytometry (FC) for CD38(+)CD45- CD45(dim) cells, and the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). Using ASO-PCR, we were able to detect clonal cells in the blood in 13 of 16 patients with MGUS, 2 of 2 with amyloid, 6 of 8 with SMM, 2 of 2 with IMM, and 13 of 15 with MM. In 9 of the 13 patients with MGUS with blood involvement, the number of clonal cells was very small ( < 0.04% of the BMNCs). The median percentage of clonal cells as determined by ASO-PCR was 0.02 for MGUS, 0.02 for SMM, and 0.24 for MM. Clonal plasma cells or CD38+CD45- CD45(dim) cells were identified by IM or FC in 6 of 16 MGUS patients, 4 of 8 with SMM, and 11 of 15 with MM. In all cases in which IM or FC detected clonal cells, the ASO-PCR was positive. This study shows that, by using ASO-PCR, clonal cells can be found at very low levels in the blood in most patients with MGUS. However, the number of clonal cells in the blood of MGUS patients is less than those with overt MM (P = .006). In contrast to MGUS, patients with active MM are more likely to have identifiable clonal circulating plasma cells (P = .05).