Role of the genetic polymorphism of inflammatory cytokines in patients with Alzheimer's disease.

Alzheimer\u2019s disease (AD) is a dementia characterized by neuronal loss, atrophy, gliosis and clinically by progressive cognitive impairment. In the last years several experimental evidences both \u201cin vitro\u201d and \u201cin vivo\u201d have suggested a possible involvement of the immune system in the pathogenesis and/or in the progression of the disease. Considering the relative low quantity of studies about multiple cytokine gene polymorphisms in AD, we were prompted to studying the panel polymorphism of related cytokine genes in an AD group of patients and in a control healthy group. In a case control, using a unified method of genotyping (PCR\u2013SSP methodology), we have examined 22 polymorphisms in 13 cytokine genes in 63 caucasian AD patients with medium\u2013high level of dementia (Mini Mental State Examination MMSE <24) and 65 normal controls belonging to the same ethnic group matched by age and gender affected by non inflammatory neuropsychiatric diseases. The patients and the control group did not shown any symptoms or signs of inflammatory process. Polymorphisms in the genes for IL-1A, IL-1\u3b2, IL-2, IL-4, IL-6, IL-10, IL-12, IFN-\u3b3, TGF-\u3b2, TNF-\u3b1 and for the cytokine receptors IL-1R, IL-1RA, IL-4RA were investigated. Angiotensin I-converting enzyme (ACE) gene polymorphism was carried out only in the group of patients to evaluate a possible association with known genetic risk factors for AD and cerebrovascular diseases. Our analysis showed an highly significant presence in AD patients when compared to controls of some alleles belonging to the anti-inflammatory cytokine gene IL-4 (C allele for the -590 promoter and T allele for the -1098, p <0.0006 and p <0.0005, respectively). Statistically no difference was evident for the D allele of the ACE gene in the group of demented patients. Although our observations suggest the presence of a pro-inflammatory environment in AD patients with MMSE <24, which is sustained by a low expression of anti-inflammatory cytokine genes, it is important to underline that these results could not apply to AD patients belonging to different ethnic groups, as the ethnic characteristics can influence the study of polymorphisms. Large cohort studies are necessary in order to assess the true association of some cytokine alleles or extended haplotypes with AD

Role of apolipoprotein e alleles as risk factors in patients with medium-high level of dementia assessed by an MMSE <24.

Alzheimer\u2019s disease is a dementia characterized by neuronal loss, athrophy, gliosis and clinically by progressive cognitive impairment. The apolipoprotein E type 4 allele is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease. Aim of this study was to evaluate and compare genotypic and allelic polymorphism of APO-E gene in a sample caucasoid AD patients with Mini Mental State Examination <24 and cognitively - normal control individuals

ACE and PAI-1 gene polymorphisms in renal transplant recipients.

Extracellular matrix accumulation in renal tissue is the hallmark of progressive renal function loss in a variety of renal diseases, including renal allograft. Several studies have recently suggested a role for both the Renin-Angiotensin (RAS) and the Fibrinolytic System as modulators of extracellular matrix turnover. We investigated whether the genetic polymorphisms of the RAS components (insertion/deletion: I/D polymorphism of the ACE gene) and of the Fibrinolytic System (insertion/deletion: 4G/5G polymorphism of the PAI-1 gene) could have any influence on kidney graft survival (GS) in a recipient cohort. DNA was extracted from 130 adult recipients (mean age 49 years) who reached a minimum of one year GS (mean follow-up 5.25 +/- 3.64 years) after receiving a kidney graft in our center. A PCR technique was utilized for ACE and PAI-1 genotyping. Our results have shown that: 1. Actuarial GS at 10 years in recipients with ACE/II genotype was higher than in recipients with ACE/DD genotype (87% vs 54.5%, p <0.05); 2. Analyzing the ACE/DD group (n = 49) in relation to PAI-1 polymorphism, we observed that the actuarial GS of the 4G/5G genotype was higher than the homozygous conditions (4G/5G 81.9% vs 4G/4G 25.8% vs 5G/5G 27.3%; p <0.05); 3. ACE/DD genotype combined with homozygosity in the PAI-1 genotype is associated with a shorter kidney GS than ACE/II and ACE/ID genotypes (p <0.01). In conclusion, the association of ACE/DD genotype with homozygosity in PAI-1 gene polymorphism seems to in?uence negatively the long\u2013term kidney GS, thus suggesting a crucial role of a genetic environment in the progression of chronic kidney graft damage

ACE and PAI-1 gene polymorphisms in renal transplant recipients.

Extracellular matrix accumulation in renal tissue is the hallmark of progressive renal function loss in a variety of renal diseases, including renal allograft. Several studies have recently suggested a role for both the Renin-Angiotensin (RAS) and the Fibrinolytic System as modulators of extracellular matrix turnover. We investigated whether the genetic polymorphisms of the RAS components (insertion/deletion: I/D polymorphism of the Angiotensin I-converting enzyme (ACE) gene) and genetic polymorphisms of the Fibrinolytic System (insertion/deletion: 4G/5G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene could have any influence on kidney graft survival in a recipient cohort. DNA was extracted from 130 adult recipients (mean age 49 years) who reached a minimum of one year GS (mean follow-up 5.25 +/- 3.64 years) after receiving a kidney graft in our center. A polymerase chain reaction (PCR) technique was utilized for ACE and PAI-1 genotyping. Our results have shown that: 1. actuarial graft survival at 5 and 10 years in recipients with ACE/II genotype was lightly higher although not reaching the statistical significance (p &lt;0.4, p&lt;0.06, respectively) than in recipients with ACE/DD genotype (88% vs 86% and 72% vs 55%, respectively); 2. actuarial graft survival at 5 and 10 years in recipients with PAI-1/4G5G genotype was higher than in recipients with PAI-1/4G4G and PAI-1/5G5G genotype (89% vs 81% vs 82% and 77% vs 45% vs 49%, respectively, with 4G5G genotype vs 4G4G genotype, p&lt; 0.04); this observation indicated for 4G4G group a worse outcome in long term graft survival. In conclusion, the association of ACE/DD genotype with homozygosity in PAI-1 gene polymorphism seems to influence negatively the long-term kidney graft survival, thus suggesting a crucial role of a genetic environment in the progression of chronic kidney graft damage

A study of HLA class I and class II 4-digit allele level in Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are represented by rare but life-threatening cutaneous adverse reactions to different drugs. Previous studies have found that in a Han Chinese population from Taiwan and other Asian Countries, a strong genetic association between HLA-class I alleles (B*15:02, B*58:01) and SJS and TEN was induced by carbamazepine and allopurinol, respectively. To identify genetic markers that covered the MHC region, we carried out a case-control association enrolling 20 Caucasian patients with SJS/TEN. Our patient series included 10 cases related to paracetamol, 7 to allopurinol and 3 to different drugs (plaquenil, itraconazol, nabumetone). Healthy controls were represented by 115 Caucasian bone marrow or stem cell donors. The HLA-A*, B*, C*, DRB1*, DQB1*, DQA1* and DPB1* genotyping were determined. The frequencies of HLA-A*33:03 as well as C*03:02 and C*08:01 were significantly higher in SJS/TEN patient subgroup showing allopurinol drug-induced severe cutaneous adverse reactions (SCAR) as compared to controls (28.6% vs 0%, P=0.00002, Pc=0.0011; 28.6% vs 0%, P=0.00002, Pc=0.001; 28.6% vs 0%, P=0.00002, Pc=0.001, respectively). In the same subgroup the frequencies of B*58:01, DRB1*15:02 and DRB1*13:02 alleles, although considerably higher than in control group (42.8% vs 5.2%, P=0.003; 28.6% vs 1.7%, P=0.005; 28.6% vs 3.5%, P=0.037, respectively), appeared no more statistically different after P correction (Pc=0.248; Pc=0.29; Pc=1.00, respectively). In addition, in 10 of the 20 SJS/TEN patient subgroup with paracetamol-induced SCAR no statistically significant association with HLA alleles could be found. However, in the same SJS/TEN patient subgroup showing allopurinol drug-induced SCAR, haplotype analysis indicated that B*58:01, DRB1*13:02 and DRB1*15:02 alleles, that in a single allele analysis lost statistical significance after P correction, may still confer susceptibility, because the B*58:01-DRB1*13:02 and DRB1*15:02-DQB1*05:02 are positively associated with the disease (14.2% vs 0.43%, P= 0.00001, Pc=0.00028; 14.2% vs 0.43%, P=0.00001, Pc=0.00028, respectively). Our results show that in contrast to SCAR-related to paracetamol, where HLA alleles do not appear to be involved, HLA molecules behave as a strong risk factor for SCAR-related to allopurinol even when a limited number of patients are considered

Therapeutic management and costs of severe haemophilia A patients with inhibitors in Italy

Haemophilia A (HA) patients with high responding inhibitors require therapies with bypassing agents to control bleedings or Immune Tolerance Induction (ITI) to attempt inhibitor eradication and restore FVIII therapy. The aim of this study was to assess the therapeutic management and product consumption of HA inhibitor patients and the relative costs in Italy. A retrospective survey was performed utilizing data from the National Registry of Congenital Coagulopathies and from a specific questionnaire on product consumption of HA inhibitor patients over the year 2011. Among HA patients, 10% had currently detectable inhibitors; 24% of patients were undergoing ITI (mostly children) and 76% utilized bypassing agents. Patients on ITI consumed 45,000,000 IU of FVIII (median consumption/patient of 1,200,000 IU year(-1)). Patients receiving bypassing agents utilized 21,000,000 IU of aPCC (median consumption/patient of 360,000 IU year(-1)), and 38,000 mg of rFVIIa (median consumption/patient of 440 mg year(-1)). The annual cost/patient on ITI and on bypassing agents therapy was analysed. Recombinant products represented the product of choice for children therapies in >90% of the cases. FVIII prophylaxis of severe HA patients without inhibitor costs about half than therapy with bypassing agents and is three times less expensive than prophylaxis with such agents. Therefore, the possibility to restore FVIII prophylaxis, having eradicated the inhibitor through ITI, can justify the high costs of ITI treatment needed in the short term. Consistent with this notion, over the last years a 50% increase in the number of patients undergoing ITI in Italy was registered

Therapeutic management and costs of severe haemophilia A patients with inhibitors in Italy

Haemophilia A (HA) patients with high responding inhibitors require therapies with bypassing agents to control bleedings or Immune Tolerance Induction (ITI) to attempt inhibitor eradication and restore FVIII therapy. The aim of this study was to assess the therapeutic management and product consumption of HA inhibitor patients and the relative costs in Italy. A retrospective survey was performed utilizing data from the National Registry of Congenital Coagulopathies and from a specific questionnaire on product consumption of HA inhibitor patients over the year 2011. Among HA patients, 10% had currently detectable inhibitors; 24% of patients were undergoing ITI (mostly children) and 76% utilized bypassing agents. Patients on ITI consumed 45 000 000 IU of FVIII (median consumption/patient of 1 200 000 IU year−1). Patients receiving bypassing agents utilized 21 000 000 IU of aPCC (median consumption/patient of 360 000 IU year−1), and 38 000 mg of rFVIIa (median consumption/patient of 440 mg year−1). The annual cost/patient on ITI and on bypassing agents therapy was analysed. Recombinant products represen-ted the product of choice for children therapies in >90% of the cases. FVIII prophylaxis of severe HA patients without inhibitor costs about half than therapy with bypassing agents and is three times less expensive than prophylaxis with such agents. Therefore, the possibility to restore FVIII prophylaxis, having eradicated the inhibitor through ITI, can justify the high costs of ITI treatment needed in the short term. Consistent with this notion, over the last years a 50% increase in the number of patients undergoing ITI in Italy was registered

Therapeutic management and costs of severe haemophilia A patients with inhibitors in Italy

Haemophilia A (HA) patients with high responding inhibitors require therapies with bypassing agents to control bleedings or Immune Tolerance Induction (ITI) to attempt inhibitor eradication and restore FVIII therapy. The aim of this study was to assess the therapeutic management and product consumption of HA inhibitor patients and the relative costs in Italy. A retrospective survey was performed utilizing data from the National Registry of Congenital Coagulopathies and from a specific questionnaire on product consumption of HA inhibitor patients over the year 2011. Among HA patients, 10% had currently detectable inhibitors; 24% of patients were undergoing ITI (mostly children) and 76% utilized bypassing agents. Patients on ITI consumed 45,000,000 IU of FVIII (median consumption/patient of 1,200,000 IU year(-1)). Patients receiving bypassing agents utilized 21,000,000 IU of aPCC (median consumption/patient of 360,000 IU year(-1)), and 38,000 mg of rFVIIa (median consumption/patient of 440 mg year(-1)). The annual cost/patient on ITI and on bypassing agents therapy was analysed. Recombinant products represented the product of choice for children therapies in >90% of the cases. FVIII prophylaxis of severe HA patients without inhibitor costs about half than therapy with bypassing agents and is three times less expensive than prophylaxis with such agents. Therefore, the possibility to restore FVIII prophylaxis, having eradicated the inhibitor through ITI, can justify the high costs of ITI treatment needed in the short term. Consistent with this notion, over the last years a 50% increase in the number of patients undergoing ITI in Italy was registered