Gene-gene and gene - clinical factors interaction in acute myocardial infarction: a new detailed risk chart.

AIMS: The complex pathogenesis of acute myocardial infarction (AMI) implicates phenotypic and genetic heterogeneity. In this pilot case-control study single nucleotide polymorphism (SNP) in several inflammatory genes, such as interleukin (IL)-1beta, IL-6, IL-10, alpha-1-antichymotrypsin (ACT), tumor necrosis factor alpha (TNF)-alpha and interferon gamma (IFN)-gamma genes along with SNPs of genes regulating vascular functions (vascular endothelial growth factor; VEGF) and cholesterol synthesis (hydroxy-methyl-glutaryl CoA reductase; HMGCR) were investigated. METHODS: Patients were genotyped with RT-PCR technique and data were analyzed with a new mathematical algorithm named Auto Contractive Map. RESULTS: The Auto Contractive Map (AutoCM), was applied in AMI patients with the aim to detect and evaluate the relationships among genetic factors, clinical variables and classical risk factors. Genes were selected because their strong regulatory effect on inflammation and SNP in these gene were located in the promoter region. In the connectivity map generated by AutoCM a group of variables was directly linked with the AMI status; these were: gender (male), early age at onset (50-65 years), HMGCR gene (CC wild type genotype), IL-1betaCT, IL-6 GG and VEGF CC genotypes. This direct link suggested a possible pathogenetic association with AMI. Other genetic, clinical and phenotypic variables were associated to the disease under a statistically defined hierarchy showed in the new connectivity map generated by AutoCM. CONCLUSION: These analyses suggested that genotypes of few inflammatory genes, a SNP in HMGCR gene, middle age, gender, low HDL and diabetes were very informative variables to predict the risk of AMI.

Tumor necrosis factor-alpha antagonists: differential clinical effects by different biotechnological molecules.

Inhibitors of tumor necrosis factor-alpha have deeply changed the therapy of several inflammatory human diseases. For instance, clinical management of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis have profoundly benefited after the introduction of new therapeutic tools, such as antagonist of TNF-alpha molecule. These drugs include etanercept, a soluble TNF-alpha receptor antagonist, three anti-TNF-alpha antibodies, adalimumab, infliximab, golimumab and certolizumab a humanized Fab fragment combined with polyethylene glycol. These compounds efficiently inhibit several TNF-alpha biological-mediated effects, however, they have also shown differential clinical efficacy in several trials from different autoimmune diseases. It is of clinical relevance that non-responders to one of these drugs often positively responded to another. Different mechanisms of action and diversity in pharmacokinetics of these three compounds may partially explain different clinical effects. However, partially diverse pathogenetic mechanisms in different diseases also contribute to differential therapeutic responses. Therefore, these apparently homogeneous agents can not be considered equivalent in their clinically efficacy. Differential therapeutic actions of these drugs may be advantageously used in clinical practice and further improve the great potential of individual TNF-alpha inhibitors.

Association between the polymorphisms of TLR4 and CD14 genes and Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. Inflammation plays a key role in AD and dissecting the genetics of inflammation may provide an answer to the possible treatment. Hence, the better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, and for its prevention and drug therapy. Accordingly, in the present study we evaluated whether the pro-inflammatory polymorphisms of lipopolysaccaride-receptors, +896A/G Toll-Like Receptor (TLR4) and -260C/T CD14, are risk factors for AD. The study included both 626 AD patients (427 women and 199 men; age range: 53-98 years; mean age: 74.88+/-8.44) from Northern Italy and age and gender matched controls. Our results demonstrate that the +896A/G TLR4 single nucleotide polymorphism (SNP) is associated with AD, whereas no association has been observed with -260C/T CD14 SNP. Furthermore, no differences have been observed evaluating the combined presence of +896A+TLR4/-260T+CD14 "high responder"(proinflammatory-profile). However, our results showing the involvement of TLR4 in AD pathophysiology, strengthen the suggestion that systemic inflammation plays a key role in AD. Carriers of high responder SNP, affected by mild cognitive impairment might, be the ideal target for a preventive treatment with biologics as monoclonal antibodies directed against the pro-inflammatory cytokines to decrease the level of systemic inflammation involved in AD pathophysiology.

Elevated plasma levels of alpha-1-anti-chymotrypsin in age-related cognitive decline and Alzheimer's disease: a potential therapeutic target.

alpha-1-antichymotrypsin (ACT), is an acute phase protein and a protease inhibitor produced by the liver and brain. ACT is involved in the pathogenesis of Alzheimer's disease (AD), since elevated ACT concentration was found in cerebrospinal fluid (CSF) and brain from AD. ACT has also been shown to influence amyloid deposition in vitro and in animal models of AD. In this investigation 830 healthy controls, 69 subjects with cognitive impairment and not dementia (CIND), 53 patients with severe clinical AD and 142 patients with mild AD were investigated. Plasma levels of ACT were measured with a new competitive immune enzyme linked immune-assay (ELISA). ACT levels were higher in AD patients than in CIND or controls. An age dependent increase of plasma ACT was present in both healthy elderly and CIND. Patients with mild clinical AD were followed up for two years and stratified according to the rate of clinical deterioration. CT plasma levels were elevated in AD patients that showed an accelerated rate of cognitive deterioration during the follow up; this increment being prominent in AD with the Apolipoprotein E (APOE) epsilon 4 allele. Therefore, increased peripheral ACT levels in APOE 4 positive patients appear to predict an accelerated clinical progression. Plasma ACT might be used as a surrogate marker to monitor the conversion of pre-dementia stages to AD and the progression of the disease. The development of compounds able to interfere with the ACT biological activity (protease inhibition and/or promotion of amyloid deposition) might have therapeutic relevance for the disease.

Oxidated low-density lipoproteins (oxLDL) and peroxides in plasma of Down syndrome patients.

A low prevalence of coronary artery disease is usually observed in adult Down syndrome (DS) subjects, and these patients rarely die because of atherosclerotic complications. High levels of oxLDL were found in plasma from children and adults with DS. Plasma oxLDL were still increased in elderly with DS, however, difference with controls was not statistically significant. Concentrations of plasma peroxides were significantly higher in children and adults with DS than controls. No differences between elderly DS subjects and controls were present. We speculated that increased levels of protective antiathero-sclerosis factors might be produced in young and adult DS subjects and these may explain low incidence of cardiovascular diseases in the syndrome. Up-regulation of vascular andothelial growth factor (VEGF)-mediated signals and increased nerve growth factor (NGF) expression might be two of these important protective factors.

Polymorphisms of fas gene: relationship with Alzheimer's disease and cognitive decline.

The Fas antigen (CD95) is a cell surface receptor that mediates cell apoptosis signalling. Recent investigations have shown that Fas-regulated apoptosis was linked to neurodegenerative lesions in the brain of patients with Alzheimer's disease (AD). Here data regarding the association of two polymorphisms of the Fas promoter region with AD patient's cognitive deterioration are reported. The polymorphism at position -1377 was associated with the risk of developing AD and with a differential rate of cognitive decline during a 2-year follow-up. The polymorphism at position -670 was not associated with the risk of AD and with the cognitive decline during the follow-up. Our data suggest that different genetic background in the Fas gene may influence the risk and clinical progression of the disease by affecting neurodegenerative processes leading to neuronal loss.

Altered vessel signalling molecules in subjects with Downs syndrome.

Downs syndrome (DS) is the most frequent human chromosomal abnormality and is associated with mental retardation. Some evidence indicates that certain inflammatory molecules may be increased in DS. Proinflammatory and vasoactive molecules in the blood of non demented subjects with DS were measured in the present investigation. Plasma levels of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1) and C reactive protein (CRP) were measured in child (2-14 years), adult (20-50 yrs) and elderly (> 60 yrs) DS subjects. Increased plasma levels of IL-6 and MCP-1 were present in DS. Plasma levels of VEGF were increased only in DS adults. Positive linear correlation between IL-6 and MCP-1 levels was present. However, no subclinical inflammation was apparent in DS, since neopterin and CRP levels were within the normal range. An altered regulation of these molecules might interfere with some processes involved in cognitive performances of DS subjects.

Interleukin-6 gene polymorphism is an age-dependent risk factor for myocardial infarction in men.

Several studies show that inflammatory components may contribute to atherosclerosis and increase the risk for myocardial infarction (MI). Interleukin-6 (IL-6) is a key pro-inflammatory and immune-modulatory cytokine of relevance for cardiovascular diseases. In this case-control study, 200 patients with MI and 257 healthy controls were genotyped for the polymorphism present in -174 promoter region of the IL-6 gene. Plasma concentrations of IL-6 and C-reactive protein (CRP) in a group of patients and controls were measured. The -174 C allele was associated with an increased risk of developing MI (OR = 2.886, c.i. = 1.801-4.624, P = 0.0001) in older patients, while no association was found in younger ones. The IL-6 plasma levels were higher in patients with MI carrying the CC genotype than in GG patients (CC carriers, IL-6 = 2.97 pg mL(-1) vs. GG carriers = 1.81 pg mL(-1), P = 0.016). A positive correlation of IL-6 levels with those of CRP in serum from patients with MI was also found. Data from this study suggest that the C allele of the promoter polymorphism in the IL-6 gene is a risk factor for MI in the elderly, and the production of the IL-6 is differentially affected by different genotypes of the IL-6 -174 promoter polymorphism.

Altered cytokine and acute phase response protein levels in the blood of children with Downs syndrome: relationship with dementia of Alzheimer's type.

Downs syndrome (DS) subjects are at high risk of developing Alzheimer's disease (AD). Patients with AD often show altered levels of some immune molecules in their peripheral blood which correlate with cognitive impairment. However, whether the altered peripheral immune phenotype is a late and secondary phenomenon associated with dementia or an early impairment linked to mechanisms controlling neurodegeneration of the central nervous system (CNS) is still an unanswered question. Here we studied immune molecules in the blood of non demented children with DS to investigate whether altered peripheral immune phenotype could be present in these subjects without dementia, many years before the presentation of clinical signs of cognitive deterioration. Plasma levels of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) were significantly higher in DS than in control children. Plasma levels of soluble intercellular adhesion molecule-3 (sICAM-3), soluble vascular cell adhesion molecule-1 (sVCAM-1) and C reactive protein (CRP) were also increased in DS. The increase of IL-6 and CRP from DS children was similar to that found in elderly patients with clinical AD. Peripheral altered immune phenotype in healthy young subjects with DS might be an early sign of CNS alterations leading many years later to cognitive deterioration and dementia.

alpha-1-Antichymotrypsin polymorphism in the gene promoter region affects survival and synapsis loss in Alzheimer's disease.

One-hundred-thirty-tree patients with neuropathologically confirmed Alzheimer's disease (AD) were genotyped for the polymorphic regions in the apolipoprotein Eepsilon (APOE)and a new polymorphism in the promoter region of the alpha-1-antichymotrypsin (ACT) gene. The ACT TT genotype was associated with a longer survival of AD patients, and among patients with the APOE epsilon4 allele, this genotype increased the duration of the disease. The ACT TT genotype was also associated with a late age at onset of the disease and a delayed age at death in patients without the APOE epsilon4 allele. This latter group of patients also showed increased levels of synaptophysin from the mid-frontal (MF) cortex area. ACT appears to play complex, multiple roles on AD and to affect synaptic plasticity in the AD brain of patients without the allele APOE epsilon4 allele.

Interleukin-10 promoter polymorphism in sporadic Alzheimer's disease.

Proinflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their high production have been shown to be associated with AD. Thus, AD patients display a proinflammatory genotype and the control of inflammation might play a protective role in AD development. By sequence-specific probes, we have evaluated the role of anti-inflammatory cytokine interleukin(IL)-10 in AD, by analysing in 132 AD patients and 213 healthy controls the prevalence of three different haplotypes, involving three single-nucleotide polymorphisms (SNPs) at -1082 (G-->A), -819 (C-->T) and -592 (C-->A) nucleotides of IL-10 promoter, associated with different IL-10 production. The percentage of -1082A carrier subjects was significantly increased among AD patients, and this increase was mainly due to the increase of ATA haplotype. Analysing these results according to the well-known genetic risk factor APOE-e4 allele, no significant differences were observed in SNP IL-10 allele distribution between AD patients carrying the genotype or not. So we may conclude that the presence of -1082A allele and in particular of -1082A/-819T/-592A haplotype, associated with a low production of anti-inflammatory cytokine IL-10, may be considered as an additive and independent genetic risk factor for AD.

Proapoptotic activated T-cells in the blood of children with Down's syndrome: relationship with dietary antigens and intestinal alterations.

Immune defects, thyroid abnormalities, infections and coeliac disease are often associated with Down's syndrome (DS). However, the basis of the immune defects is still unclear in DS. In the present study, we show that peripheral CD4 T-cells were decreased in children with DS, while mean values of cytotoxic CD8 T-cells were comparable with those from healthy children. Circulating activated (CD3/HLA-DR positive) T-cells were increased and a large proportion of purified T-cells from DS were also positive for APO-I/FAS (CD95) antigen. To further explore the functional status of circulating activated T-cells, enriched CD3 lymphocytes were cultured for 3 h and were tested for positivity to annexin-V (ANX-V) and propidium iodide. T-cells with the early apoptotic phenotype were increased in cell cultures from DS children. Plasma levels of inteleukin-6 (IL-6) were higher in DS children than in healthy children. The incidence of coeliac disease was also increased in this group of children. Most DS children showed increased levels of circulating IgG or IgA specific for gliadin, and their plasma IL-6 levels correlated with those of antigliadin IgG. The number of CD4 circulating cells was very low in DS children with coeliac disease, was low in those with serum antigliadin antibodies and was normal in DS without antigliadin antibodies. An overload of dietary antigens and impaired nutrient absorption secondary to altered functioning of the gastrointestinal mucosa might interfere with normal immune responses by inducing programmed cell death in CD4 T-cells.

[Analysis and comparative evaluations of the costs of supports and treatments of schizophrenia, affective psychosis, paranoia and neurosis]. / Analisi e valutazioni comparative dei costi dei trattamenti terapeutico-riabilitativi delle psicosi schizofreniche, delle psicosi affettive, della paranoia e dei disturbi nevrotici.

OBJECTIVE: The aim of the study was to show, trough the calculation of the direct costs of supports and treatments actually provided by a NHS Mental Health Department, the presence of associations between four diagnostic groups (schizophrenia, affective psychosis, paranoia and neurotic disorders) and their overall and items (community care, rehabilitation facilities and in-patients services) costs. SETTING: Mental Health Department and CSM "Scalo" (NHS Mental Centre), AUSL "Città di Bologna", Emilia-Romagna Region. DESIGN: Yearly direct costs were calculated for a sample (n = 75) of all patients (N = 745) who during 365 days had more than four contacts with CSM and also for four randomised diagnostic groups (n = 30 per group). MAIN OUTCOME MEASURES: We calculated unit costs of 15 types of services provided by CSM, selected according to the yearly number of services provided and the time spent by each health professional, and the in patient-cost per all days spent in a public or private sector hospital for psychiatric care. RESULTS: The statistic analysis, performed with the help of the Kruskal-Wallis test, showed significantly higher overall costs for the schizophrenic patients than the sample-group and the neurotic disorders-group; besides a significant difference in the item costs for rehabilitation facilities was found between the schizophrenic group and the paranoia, neurotic disorders groups and the sample one, whereas no significant differences in costs of inpatients services and drugs administration were tested between the groups. CONCLUSIONS: The results of our study allow to demonstrate that there are cost differences between the diagnosis (direct costs are highest for schizophrenic patients and lowest for those with neurotic disorders) and that the costs evaluation can be used to ensure appropriate provisions to Mental Health Department for support and treatment of a wide range of psychiatric disorders.

[Pattern of intervention and patients' satisfaction with community mental health services in Bologna]. / Assistiti e soddisfatti? Caratteristiche dell'assistenza e soddisfazione degli assistiti in un Centro di Salute Mentale di Bologna.

OBJECTIVE: To measure satisfaction with Community Mental Health Service (CSM) in patients and to check if it will be associated with some selected demographic and service variables. DESIGN: This study compares data from satisfaction scale administration in patients who attended CSM at least once every two months during 1998 and services that them have benefited from. SETTING: The Community Mental Health Service of Saragozza-Porto District in Bologna. Main outcome measures--Demographical, clinical and service variables taken from CSM informative system and Verona Service Satisfaction Scale (VSSS-32), a multidimensional instrument which measures satisfaction with community-based psychiatric service. RESULTS: Main results (145 subjects) pointed out higher satisfaction for technical and interpersonal skills of staff, information, drugs, help to get economical benefits and domiciliary care. Four issues stood out by comparing patients' satisfaction and their demographic, clinical and services' benefit features: 1) aged patients complained about high drugs costs and of contacts with other seriously ill patients into the waiting room; 2) relative's involvement was judged as insufficiently effective; 3) in young patients with serious mental disease high frequency of visits seemed to correlate with low satisfaction; 4) patients with complex pattern of intervention (including economical benefits) were the less satisfied ones with service's economical support. CONCLUSIONS: Patients' satisfaction differs according to their demographic and clinical features, but the pattern of intervention seems to influence their judgements too, sometimes in a incoherent way.

[A three-year long follow-up of a group of "everyday patients" in a mental health center]. / I "pazienti quotidiani": follow-up a tre anni di un gruppo di utenti alti utilizzatori di un centro di salute mentale cittadino.

OBJECTIVE: This research concerns those patients who most attend the community Mental Health Centre (CSM), hereby called "everyday patients". According to a previous research (Pileggi et al., 1992) a sample of patients mostly attending the Centre had been pointed out. Basing on the number of attendances, it emerged that some of those patients (57) had been on the average attending the Centre more than twice a week and, despite being only 10% of the total number of users, they had taken on a large share of the services offered by the Centre (30%). Therefore, those patients were the ones the Centre had been working for more intensely and continuously. Three years later, the object of this research is to check the assistance and clinical destiny of such patients and compare their patterns of attendances to those ones regarding the remainder of the CSM users. The hypothesis is that "everyday patients" are assisted by different and continuous treatments and that such a procedure prevents patients from dropping out and determines a strong reduction in relapses and less frequent attendances. DESIGN: Longitudinal study on a 42 patient sample (19 males, 23 females) on therapy at CSM. SETTING: Mental Health Centre, "Saragozza" District, Sanitary Unit of Bologna. MAIN OUTCOME MEASURES: The following elements have been examined: 1) social and demographic features; 2) duration of psychiatric history; 3) clinical diagnosis according to DSM-III-R, set by patients personal psychiatrist; 4) global functioning level as examined by two psychiatrists or psychologists from the Centre, using DSM-III-R Global Functioning Scale (GFS); 5) actions carried out and patterns of using the CSM services over the past 12 months. Concordance measures among independent examiners (Cohen K) and non-parametric variability measures for comparison between groups (Chi-square and Kruskal-Wallis tests) have been used. RESULTS AND CONCLUSION: Results partially confirm the original hypotheses. In particular, complicated services (psychological and pharmacological therapies and rehabilitation) are carried out for the most of "everyday patients" and much more intensely to them than to the remainder of the users. No drop-out has been found out, the global functioning level of the patients is good in most of cases and the number of necessary admissions to psychiatric wards has been reduced. However, the "attendance share" relevant to the sample of "everyday patients" is still high compared to the total number of the CSM users. Besides, discharge rate is nought.