A cross-sectional study to identify a set of risk factors for caprine herpesvirus 1 infection.

BACKGROUND: Caprine herpesvirus 1 (CpHV-1) causes neonatal mortality and reproductive failure in goats. Despite its impact on herd reproductive performance, few studies have investigated the risk factors associated with CpHV-1 infection. The aim of this cross-sectional study was to identify potential herd- and host-level risk factors associated with CpHV-1 prevalence in a goat population with heterogeneous seropositivity for CpHV-1. RESULTS: Blood samples and individual data from 4542 goats were collected from 255 herds in Piedmont, Italy. Enzyme-linked immunosorbent assay (ELISA) and serum neutralization tests were carried out to detect antibodies against CpHV-1. A mixed-effects model was applied to identify any statistical association between CpHV-1 seropositivity and a set of putative host-level and herd-level risk factors. A total of 630 samples tested were found positive by ELISA (prevalence = 13.9%; 95% confidence interval (CI) 12.9-14.9). Of the 255 tested herds, 85 were classified as positive for the presence of at least one gB-positive animal (herd prevalence 33.3%, 95% CI 27.5-39.2), with a within-herd prevalence between 0.7 and 100% (Q1 = 17.6%; median = 32.3%; Q3 = 50%) (Q = quartiles). The prevalence ratios showed a statistical association with the following risk factors: breeds other than Saanen, older age, larger herd size, meat and extensive herds, and co-existence of CAEV-infected animals. CONCLUSIONS: Results from this cross sectional study may help to elucidate the natural history of the infection and inform targeted strategies to control a disease with a potentially important impact on animal health and goat farming economy.

Serological and virological survey of hepatitis E virus in wild boar populations in northwestern Italy: detection of HEV subtypes 3e and 3f.

Although rare in developed countries, most acquired human cases of hepatitis E virus (HEV) infection are associated with travel to developing countries where HEV is endemic. Increasingly, however, sporadic, non-travel-related HEV cases have been reported in developed countries. In Italy, only two studies to date have investigated the presence of HEV in wild boars. Here, we report a serological and virological survey of HEV in wild boar populations in northwestern Italy. During the hunting season, 594 serum and 320 liver samples were collected and screened for antibodies to HEV and HEV RNA. Overall, the seroprevalence was 4.9 %, and HEV RNA was detected in 12 liver samples (p = 3.7 %). No serum samples tested positive for HEV RNA. Phylogenetic analysis of the ORF2 region revealed that the isolates clustered within genotype 3, subtypes 3e and 3f, and were closely related to HEV strains previously detected in domestic pigs farmed in the same geographic area. Although the routes of viral transmission are still poorly understood, our data show that HEV genotypes 3e and 3f circulate in wild boars in northwestern Italy. Also, they provide evidence that autochthonous HEV infections in Italy could also be linked to wild boar populations, suggesting an increased risk for domestically acquired HEV infection in humans through wild animals. The HEV sequences determined in this study may be useful for comparing present and future human isolates to identify transmission events between wild boar, humans, and farmed pigs. Similarly to other more commonly known zoonotic agents, HEV should be included in national or regional disease surveillance programs for wild animals.

Heterozygosity for lysosomal acid lipase E8SJM mutation and serum lipid concentrations.

BACKGROUND AND AIM: The complete absence of the lysosomal acid lipase (LAL) enzyme function causes Wolman's Disease that is fatal within the first six months of life. Subtotal defects cause Cholesteryl ester storage disease (CESD), an autosomal recessive disorder leading to hepatic steatosis, fibrosis, micronodular cirrhosis, combined hyperlipidemia with low HDL-cholesterol, increased risk for atherosclerosis, premature death. Since the frequency of the Exon 8 splice junction mutation (c.894 G > A, E8SJM), the CESD leading mutation, is not rare in the general population (allele frequency 0.0025), we investigated the impact of this mutation on serum lipid profile in E8SJM carriers. METHODS AND RESULTS: We collected E8SJM carriers both form genetic study-population analysis and from Outpatient Lipid Clinics and then we assessed their serum lipid profile. We found thirteen individuals heterozygote for E8SJM. Most of them were Germans, three Spanish and two Italian. We found a significant increase in total cholesterol levels in both sexes with E8SJM mutation, leading to a significant increase in LDL cholesterol in males. CONCLUSIONS: Our results show that LAL E8SJM carriers have an alteration in lipid profile with a Polygenic Hypercholesterolemia phenotype, leading to an increase in cardiovascular risk profile.

Leucine 10 allelic variant in signal peptide of PCSK9 increases the LDL cholesterol-lowering effect of statins in patients with familial hypercholesterolaemia.

BACKGROUND AND AIMS: In the normal population, carriers of an additional leucine residue in a stretch of nine leucines in the signal peptide of PCSK9 (L10) have lower total (TC) and low-density lipoprotein cholesterol (LDL-C) than homozygotes for the wild-type allele (L9/L9). A similar effect was detected in familial hypercholesterolaemia (FH) patients with the p.C681X mutation of LDL-receptor (LDLR). We investigated the effect of L10 variant on basal lipid profile and response to statins in molecularly characterised FH patients. METHODS AND RESULTS: Plasma lipids were determined in 322 FH patients screened for the L9/L10/L11 polymorphism and in a subgroup of 54 patients carrying the same LDLR mutation (p.Q474HfsX63). Plasma lipids were also determined in 42 FH patients carrying the L10 variant and in a parallel group of 42 FH patients, L9/L9 homozygotes, matched for gender, age, type of LDLR gene mutation, as well as for type, dose and duration of statin treatment. In FH patients, no difference in the basal plasma TC and LDL-C levels was observed between carriers of L10 variant (L9/L10+L10/L10) and L9/L9 homozygotes. The same was true in FH patients carrying the p.Q474HfsX63 LDLR mutation. In the subgroups of statin-treated patients, the reduction of TC and LDL-C was greater in carriers of L10 (-34.0% and -42.5%, respectively) than in L9/L9 homozygotes (-27.5% and -34.3%, respectively) (P<0.001). CONCLUSION: The variant L10 of the leucine repeats in PCSK9 signal peptide is to be considered as a factor capable of modulating the lipid-lowering effects of statins in FH.

Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down's syndrome.

Abnormal and excessive accumulation of the amyloid beta-peptide (A beta) in the brain is a major and common characteristic of all Alzheimer's disease (AD) forms irrespective of their genetic background. Insoluble aggregates of A beta are identified as amyloid plaques. These deposits are thought to form when the amount of A beta is increased in the brain parenchyma as a result of either overexpression or altered processing of the amyloid precursor protein (APP). Soluble A beta ending at carboxyl-terminal residue 40 (A beta 40) and, in lesser amount, the form ending at residue 42 (A beta 42), are normal products of the APP metabolism in cell cultures. Increased secretion of soluble A beta 42 has been observed in cells transfected with constructs modeling APP gene mutations of familial forms of AD (refs 4, 5). On the basis of these in vitro data it has been hypothesized that the presence of soluble A beta 42 plays a role in the formation of amyloid plaques. Subjects affected by Down's syndrome (DS) have an increased APP gene dosage and overexpress APP. Apparently because of this overexpression, they almost invariably develop amyloid deposits after the age of 30 years, although they are free of them at earlier ages. Moreover, it has been observed that A beta 42 precedes A beta 40 in the course of amyloid deposition in DS brain. Thus, DS subjects provide the opportunity to investigate in the human brain the metabolic conditions that precede the formation of the amyloid deposits. Here we report that soluble A beta 42 is present in the brains of DS-affected subjects aged from 21 gestational weeks to 61 years but it is undetectable in age-matched controls. It is argued that overexpression of APP leads specifically to A beta 42 increase and that the presence of the soluble A beta 42 is causally related to plaque formation in DS and, likely, in AD brains.

Severe HDL deficiency due to novel defects in the ABCA1 transporter.

OBJECTIVES: The objective was the identification and functional characterization of mutations in the ABCA1 gene in four patients with severe HDL deficiency. SUBJECTS: Patients were referred to the clinic because of almost complete HDL deficiency. METHODS: The ABCA1 gene was sequenced directly. The analysis of the ABCA1 protein, ABCA1 mRNA and ABCA1-mediated cholesterol efflux was performed in cultured fibroblasts. Intracellular localization of ABCA1 mutants was investigated in transfected HEK293 cells. RESULTS: Two patients were homozygous for mutations in the coding region of the ABCA1 gene, resulting in an amino acid substitution (p.A1046D) and a truncated protein (p.I74YFsX76). The third patient was homozygous for a splice site mutation in intron 35 (c.4773 + 1g>a), resulting in an in-frame deletion of 25 amino acids (del p.D1567_K1591) in ABCA1. These patients had clinical manifestations of accumulation of cholesterol in the reticulo-endothelial system. The fourth patient, with preclinical atherosclerosis, was a compound heterozygote for two missense mutations (p.R587W/p.W1699C). ABCA1-mediated cholesterol efflux was abolished in fibroblasts from patients with p.A1046D and del p.D1567_K1591 mutants and in fibroblasts homozygous for p.R587W. A reduced ABCA1 protein content was observed in these cells, suggesting an increased intracellular degradation. The mutant p.W1699C was largely retained in the endoplasmic reticulum, when expressed in HEK293 cells. CONCLUSIONS: The homozygotes for mutations which abolish ABCA1 function showed overt signs of involvement of the reticulo-endothelial system. This was not the case in the compound heterozygote for missense mutations, suggesting that this patient retains some residual ABCA1 function that reduces cholesterol accumulation in the reticulo-endothelial system.

Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.

Atherogenic low density lipoproteins are cleared from the circulation by hepatic low density lipoprotein receptors (LDLR). Two inherited forms of hypercholesterolemia result from loss of LDLR activity: autosomal dominant familial hypercholesterolemia (FH), caused by mutations in the LDLR gene, and autosomal recessive hypercholesterolemia (ARH), of unknown etiology. Here we map the ARH locus to an approximately 1-centimorgan interval on chromosome 1p35 and identify six mutations in a gene encoding a putative adaptor protein (ARH). ARH contains a phosphotyrosine binding (PTB) domain, which in other proteins binds NPXY motifs in the cytoplasmic tails of cell-surface receptors, including the LDLR. ARH appears to have a tissue-specific role in LDLR function, as it is required in liver but not in fibroblasts.

Effects of a phytosterol-enriched dairy product on lipids, sterols and 8-isoprostane in hypercholesterolemic patients: a multicenter Italian study.

BACKGROUND AND AIMS: Plant sterols, added to several food sources, lower serum cholesterol concentrations. Plant sterol-induced cholesterol lowering is paralleled by a mild decrease in plasma levels of the antioxidant beta-carotene, the amount of this decrease being considered clinically non-significant. Whether the effect on lipid profile of daily consumption of plant sterol-enriched low-fat fermented milk (FM) is paralleled by a concomitant variation in a reliable marker of the oxidative burden like plasma isoprostane levels is unresolved. METHODS AND RESULTS: The effect of plant sterol consumption on plasma lipid and isoprostane levels of hypercholesterolemic patients was evaluated in a multicenter, randomized double blind study. Hypercholesterolemic patients consumed a FM daily for 6 weeks. Subjects were randomized to receive either 1.6g of plant sterol-enriched FM (n=60) or control FM product (n=56). After 6 weeks of plant sterol-enriched FM consumption, LDL cholesterol was reduced from 166.2+/-2.0 to 147.4+/-2.8 mg/dL (p=0.01). A significant reduction was observed for total cholesterol (from 263.5+/-2.6 to 231.0+/-3.2mg/dL, p=0.01). There was greater LDL cholesterol lowering among hypercholesterolemic patients with higher LDL cholesterol at baseline. We found a reduction of plasma 8-isoprostane in patients taking plant sterol-enriched FM (from 43.07+/-1.78 to 38.04+/-1.14 pg/ml, p=0.018) but not in patients taking the control product (from 42.56+/-2.12 to 43.19+/-2.0 pg/ml, p=NS). Campesterol and beta-sitosterol levels were not influenced by phytosterol consumption. CONCLUSIONS: Daily consumption of low-fat plant sterol dairy product favourably changes lipid profile by reducing LDL-cholesterol, and may also have an anti-oxidative effect through a reduction of plasma isoprostanes.

Hypertriglyceridaemia and low plasma HDL in a patient with apolipoprotein A-V deficiency due to a novel mutation in the APOA5 gene.

APOA5 encodes a novel apolipoprotein (apo A-V) which appears to be a modulator of plasma triglyceride (TG). In apoA5 knock out mice plasma TG level increases almost fourfold, whereas in human APOA5 transgenic mice it decreases by 70%. Some SNPs in the APOA5 gene have been associated with variations in plasma TG in humans. In addition, hypertriglyceridaemic (HTG) patients have been identified who carried rare nonsense mutations in the APOA5 gene (Q139X and Q148X), predicted to result in apo A-V deficiency. In this study we report a 17-year-old male with high TG and low high density lipoprotein cholesterol (HDL-C), who at the age of two had been found to have severe HTG and eruptive xanthomas suggesting a chylomicronaemia syndrome. Plasma postheparin LPL activity, however, was normal and no mutations were found in LPL and APOC2 genes. The sequence of APOA5 gene revealed that the patient was homozygous for a point mutation (c.289 C>T) in exon 4, converting glutamine codon at position 97 into a termination codon (Q97X). Apo A-V was not detected in patient's plasma, indicating that he had complete apo A-V deficiency. The administration of a low-fat and low-oligosaccharide diet, either alone or supplemented with omega-3 fatty acids, started early in life, reduced plasma TG to a great extent but had a negligible effect on plasma HDL-C. Loss of function mutations of APOA5 gene may be the cause of severe HTG in patients without mutations in LPL and APOC2 genes.

Therapeutic management of a new case of LCAT deficiency with a multifactorial long-term approach based on high doses of angiotensin II receptor blockers (ARBs).

Familial lecithin cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by the appearance of corneal opacity, anemia, proteinuria progressing to chronic renal failure and abnormalities in the composition of plasma lipoproteins. No established therapy currently exists for this condition. We report here a new case of FLD caused by two novel mutations in the LCAT gene in which, for the first time, aggressive therapy with angiotensin II receptor blockers and lipid-lowering drugs showed benefit in blood pressure, lipid abnormalities, proteinuria and also kidney function, probably delaying progression to renal failure.

Effect of statins on fibroblasts from human nasal polyps and turbinates.

BACKGROUND: Statins are serum cholesterol-lowering agents used for the prevention and treatment of atherosclerotic vascular disease. There is, however, growing evidence that statins have immunomodulatory and anti-inflammatory activities and may prove invaluable in the treatment of immunological and inflammatory disorders. OBJECTIVE: On these basis we evaluated the effect of statins on the proliferation of fibroblasts derived from human nasal polyps and turbinates and determined their ability to modulate airway remodelling. METHODS: Fluvastatin (0.01-0.1-1 microM), Atorvastatin (0.1-1-10 microM) and Simvastatin (0.1-1-10 microM) were tested on cultured fibroblasts derived from human nasal polyps and turbinates stimulated or not with Fibroblast Growth Factor beta (10 ng/ml). All cultures were treated with 3H-Thymidine (1 microCi/ml) to test cell proliferation. RESULTS: Our results show that proliferation of turbinate-derived fibroblasts is significantly inhibited by the three statins. Fluvastatin is already effective at the lowest dose (0.01 microM), whereas Atorvastatin and Simvastatin act at the plasmatic peak concentration (1 microM). No significant effect was found on fibroblasts derived from nasal polyps, except for Simvastatin which was effective after 144 hours of stimulation. CONCLUSIONS: These drugs show a remarkable antiprolhferative effect and their different outcome depending on the different kind of fibroblasts in vitro is prompting news in the studies about statin use for the treatment of chronic inflammatory diseases.

Using multi-criteria risk ranking methodology to select case studies for a generic risk assessment framework for exotic disease incursion and spread through Europe.

We present a novel approach of using the multi-criteria pathogen prioritisation methodology as a basis for selecting the most appropriate case studies for a generic risk assessment framework. The approach uses selective criteria to rank exotic animal health pathogens according to the likelihood of introduction and the impact of an outbreak if it occurred in the European Union (EU). Pathogens were evaluated based on their impact on production at the EU level and international trade. A subsequent analysis included criteria of relevance to quantitative risk assessment case study selection, such as the availability of data for parameterisation, the need for further research and the desire for the case studies to cover different routes of transmission. The framework demonstrated is flexible with the ability to adjust both the criteria and their weightings to the user's requirements. A web based tool has been developed using the RStudio shiny apps software, to facilitate this.

Transmission parameters of highly pathogenic avian influenza (H7N1) among industrial poultry farms in northern Italy in 1999-2000.

We estimated between-farm transmission parameters of the highly pathogenic avian-influenza (HPAI) epidemic that struck the poultry industry of northern Italy (including turkeys, layer hens, broilers, gamebirds, and waterfowl) from December 1999 through April 2000. We estimated the average number of susceptible farms that were infected with HPAI virus by each infectious farm during a day (beta) with a generalised linear model (GLM). The HPAI's reproductive ratios (R(h); the average number of new infected farms (IFs) that were caused by an infectious farm) were calculated separately for the regions of Lombardy and Veneto, where 382 out of 413 (92.5%) of IFs were located. In both regions, R(h) decreased to approximately 1 during the second month of the epidemic (showing that its containment had been initiated). Subsequently, during the last two months of the epidemic, beta and R(h) were reduced to 0.04/day and 0.6, respectively, in Veneto and to 0.07/day and 0.8 in Lombardy. The reduction of the susceptible population through strict control measures, including pre-emptive slaughter of at-risk poultry flocks, was implemented to a greatest extent in Veneto and this might have been associated with a more rapid control of the epidemic in this region than in Lombardy.

[Treatment of colorectal cancer liver metastases]. / Il trattamento delle metastasi epatiche da cancro del colon-retto.

Liver is the main target for colorectal cancer (CRC) metastases. About 50% of all patients affected by CRC develop liver metastases. Surgery remains the only potentially curative strategy and indications to surgery and resectability criteria are now less restrictive than before so that a more aggressive attitude in the treatment of metastatic lesions is the rule. However surgery is not possible in the majority of patients. For non resectable patients two options are available: local treatment strategies (Radio-frequency ablation and Cryosurgery: alone or in combination with surgery) and chemotherapy. High rates of objective response achieved with Fluoropyrimidines, Oxaliplatin (OHP) and Irinotecan (CPT-11) based chemo-therapy, enable initially unresectable patients to undergo surgery, with a 5-year survival rate comparable to that observed for primary resectable patients. Therefore chemotherapy has not only a palliative aim, but becomes a fundamental moment of a combined medical and surgical treatment with curative purpose. After surgery two-thirds of patients will relapse in first two years, so that adjuvant therapy has been investigated to reduce recurrence rates, mainly testing hepatic arterial infusion (HAI) schedules. So far no randomized trials have been published on the role of systemic intravenous adjuvant chemo-therapy. Finally we report the results of our monoinstitutional experience, suggesting a possible role of systemic adjuvant chemotherapy in reducing recurrence rates after liver metastasectomy. Probably in the next years new targeted drugs and locoregional therapies will contribute to further improve prognosis of such patients, in a neoadjuvant, adjuvant and palliative setting.

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Seventy-one mutations of the low density lipoprotein (LDL) receptor gene were identified in 282 unrelated Italian familial hypercholesterolemia (FH) heterozygotes. By extending genotype analysis to families of the index cases, we identified 12 mutation clusters and localized them in specific areas of Italy. To evaluate the impact of these mutations on the clinical expression of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mutation. These 2 groups were comparable in terms of the patients' age, sex distribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (+18%) and high density lipoprotein cholesterol lower (-5%) than the values found in receptor-defective subjects. The prevalence of tendon xanthomas and coronary artery disease (CAD) was 2-fold higher in receptor-negative subjects. In patients >30 years of age in both groups, the presence of CAD was related to age, arterial hypertension, previous smoking, and LDL cholesterol level. Independent contributors to CAD in the receptor-defective subjects were male sex, arterial hypertension, and LDL cholesterol level; in the receptor-negative subjects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that of receptor-defective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the epsilon2 allele and a raising effect of the epsilon4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol. Haplotype analysis showed that all families of the major clusters shared the same intragenic haplotype cosegregating with the mutation, thus suggesting the presence of common ancestors.

Clinical usefulness of serum pepsinogens I and II, gastrin-17 and anti-Helicobacterpylori antibodies in the management of dyspeptic patients in primary care.

BACKGROUND: Several tests have been proposed for evaluating dyspeptic symptoms and their relationship to the underlying gastric disease. Serum pepsinogens and gastrin-17 are known to be useful biomarkers for the detection of gastric pathologies. AIM: To evaluate the capability of screening dyspeptic patients in the primary care by analyses of serum pepsinogens I (sPGI) and II (sPGII), gastrin-17 (sG-17) and the IgG anti-Helicobacter pylori antibodies (IgG-Hp). PATIENTS AND METHODS: Three hundred and sixty-two consecutive patients with dyspeptic symptoms (208 females, mean age 50.6 +/- 16 years, range 18-88 years) referred by general practitioners for upper gastrointestinal endoscopy were enrolled. A blood sample was taken from each subject for IgG-Hp, sPGI, sPGII and sG-17 analyses. RESULTS: Two hundred and eighty-seven patients had a complete screening; of these, 132 resulted positive for Hp infection. Patients with atrophic chronic gastritis showed significantly lower serum pepsinogen I levels and sPGI/sPGII ratio than patients with non-atrophic chronic gastritis. Moreover, by calculating the values of sPGI by sG-17 and sG-17 by sPGII/sPGI, subjects with atrophic chronic gastritis could be distinguished from those with non-atrophic chronic gastritis and from those with normal mucosa, respectively. sG-17 levels were found to be a useful biomarker for the detection of antral atrophic gastritis, while the combination of sPGI, the sPGI/sPGII ratio and sG-17 was found effective in identifying corpus atrophy. CONCLUSION: A panel composed of PGI, PGII, G-17 and IgG-Hp could be used as a first approach in the 'test and scope' and/or 'test and treat' strategy in the primary care management of dyspeptic patients.

Vascular risk factors, vascular disease, lipids and lipid targets in patients with familial dysbetalipoproteinemia: a European cross-sectional study.

BACKGROUND: Familial dysbetalipoproteinemia (FD), also known as type III hyperlipoproteinemia, is a genetic dyslipidemia characterized by elevated very low density lipoprotein (VLDL) and chylomicron remnant particles that confers increased risk of cardiovascular disease (CVD). The objective of this study was to evaluate the prevalence of vascular risk factors, CVD, lipid values, treatment and lipid targets in patients with FD across Europe. METHODS: This cross-sectional study was performed in 305 patients with FD from seven academic hospitals in four European countries. Information was collected from clinical records. RESULTS: Patients mean (±standard deviation) age was 60.9±14.4 years, 201 (66%) were male, 69 (23%) had diabetes mellitus (DM) and 87 (29%) had a prior history of CVD. Mean body mass index was 28.5±5.0 kg/m2. Lipid-lowering medication was used by 227 (74%) patients (27% usual dose (theoretical low-density lipoprotein cholesterol (LDL-C) reduction≤40%) and 46% intensive dose (theoretical LDL-C reduction>40%)). Non high-density lipoprotein cholesterol (non-HDL-C) levels below treatment target (<3.3 mmol/L) were present in 123 (40%) patients and 163 patients (53%) had LDL-C levels below target (<2.5 mmol/L). No significant determinants were found for having non-HDL-C levels below target, while a prior history of CVD (OR 1.90, 95%CI 1.05-3.47) and presence of DM (OR 2.00, 95%CI 1.08-3.70) were associated with having LDL-C levels below treatment target. CONCLUSION: The majority of FD patients had non-HDL-C levels above the treatment target of 3.3 mmol/L. Intensive dose lipid-lowering medication was used by only half of the patients, leaving them at increased cardiovascular risk.

Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians.

Previous studies have shown that mitochondrial DNA (mtDNA) haplogroup J is significantly over-represented in healthy centenarians with respect to younger controls, thus suggesting that this haplogroup predisposes to successful aging and longevity. On the other hand, the same haplogroup is reported to have elevated frequency in some complex diseases. To verify if centenarians clustered in a particular lineage within J we have sequenced the D-loop region from 18 centenarians and 18 younger controls, previously characterized to be J. Then the entire mtDNA molecule was sequenced in a sub-sample of nine centenarians to find possible functional mutations associated with haplogroup J in successful aging. No clustering of the J haplogroup mtDNA from centenarians was observed. In addition, most of the mutations found are known as disease-associated mutations. The general picture that emerges from the study is that the J haplogroup of centenarians is surprisingly similar to that found in complex diseases, as well as in Leber Hereditary Optic Neuropathy. This finding implies that the same mutations could predispose to disease or longevity, probably according to individual-specific genetic backgrounds and stochastic events. This data reveals another paradox of centenarians and confirms the complexity of the longevity trait.

Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2).

The possibility that four loci (REN, THO, PARP, SOD2) are associated with longevity was explored by comparing the genotypic pools of subjects older than 100 years with those of younger subjects matched for sex and geographic area (northern and southern Italy). The markers (all located within the respective gene) were HUMREN4; HUMTHO1; HUMPARP (gt)845nt; SOD2(C/T)401nt. In order to reduce the number of genotypes, multiallelic polymorphisms were recoded as diallelic according to allele size and frequency patterns (small: S, and large: L, alleles). A significant loss of LL homozygous genotypes was found at the THO locus in male but not in female centenarians with respect to matched controls. On the other hand no significant difference was found between case/control genotypic frequencies at REN, PARP, SOD2 loci. The latter loci therefore do not affect inter-individual variability in life expectancy (at least in terms of qualitative variants associated with the tested markers). However, the data is consistent with an association between the THO locus and longevity.

Serum lipid levels during interferon therapy in patients with chronic hepatitis C.

Interferon-alpha (IFN-alpha) may affect lipid metabolism by stimulating hepatic fatty acid synthesis. The aim of this study was to evaluate serum lipid levels during IFN-alpha therapy in patients with biopsy-proven chronic active hepatitis C. A total of 22 patients (18 males and 4 females; age 25-55 years) received 3 MU of recombinant IFN-alpha 2b 3 times a week for 6 months. Serum lipids were determined at baseline and then every month until the end of therapy. All patients had normal serum lipid levels at baseline. No significant level of modification occurred in patients during the therapy. An increase in serum lipid levels during low-dose IFN-alpha therapy seems to be uncommon in hepatitis C virus-infected patients with baseline normal levels.