rubrica

Cause ed epidemiologia analitica

  • Lorenzo Richiardi1

  1. Università di Torino

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Ricerca bibliografica periodo dal 16 giugno – 31 agosto 2013

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Stringa: ("italy"[MeSH Terms] OR "italy"[All Fields]) AND ("2013/06/16"[PDat] : "2013/08/31” [PDat]) AND (“Case-Control” [All fields] OR “Cohort”[all fileds] OR “Cross-sectional”[All fields]) AND ("risk"[All Fields] OR "association"[all fields] OR "epidemiologic factors"[MeSH Terms]) and (“odds ratios”[all fields] OR “odds ratio”[all fields] OR “ORs”[all fields] OR “rate ratio”[all fileds] OR “rate ratios”[all fileds] OR “RR”[all fileds] OR “RRs” [all fileds] OR “risk ratio”[all fields] OR “risk ratios”[all fields] OR “prevalence ratio*” [all fields] OR “prevalence ratios” [all fields] OR “hazard ratio” [all fields] OR “hazard ratios” [all fields] OR “HR”[all fields] OR “HRs”[all fields]) NOT "Clinical Trials as Topic"[Mesh] NOT "Sensitivity and Specificity"[Mesh] NOT "Comorbidity"[Mesh] NOT "Predictive Value of Tests"[Mesh] NOT "Prognosis"[Mesh] NOT "Review"[publication type] NOT "Population Surveillance"[Mesh]

FOCUS: Generici, non tumori o malattie cardiovascolari NOT (("neoplasms"[Mesh] OR (neoplasm*[ti/ab]) OR tumor*[ti/ab] OR cancer*[ti/ab]) OR ("cardiovascular diseases"[MeSH Terms] OR (cardiovascular*[title/abstract] AND diseas*[title/abstract])))

1. Rattazzi M, Villalta S, Galliazzo S, Del Pup L, Sponchiado A, Faggin E, Bertacco E, Buso R, Seganfreddo E, Pagliara V, Callegari E, Puato M, Caberlotto L, Scannapieco G, Fadini GP, Pauletto P. Low CD34(+) cells, high neutrophils and the metabolic syndrome are associated with an increased risk of venous thromboembolism. Clin Sci (Lond). 2013 Aug;125(4):211-8. doi: 10.1042/CS20120698.
Department of Medicine, University of Padova, Padova, Italy. marcello.rattazzi@unipd.it

Abstract
The relationship between MetS (metabolic syndrome), levels of circulating progenitor/immune cells and the risk of VTE (venous thromboembolism) has not yet been investigated. We studied 240 patients with previous VTE and 240 controls. The presence of MetS was identified according to NCEP ATP III guidelines and flow cytometry was used to quantify circulating CD34(+) cells. VTE patients showed higher BMI (body mass index), waist circumference, triacylglycerol (triglyceride) levels, blood glucose, hs-CRP (high-sensitivity C-reactive protein) and lower HDL-C (high-density lipoprotein cholesterol) levels. The prevalence of MetS was significantly higher in VTE (38.3%) than in control individuals (21.3%) with an adjusted OR (odds ratio) for VTE of 1.96 (P=0.002). VTE patients had higher circulating neutrophils (P<0.0001), while the CD34(+) cell count was significantly lower among patients with unprovoked VTE compared with both provoked VTE (P=0.004) and controls (P=0.003). Subjects were also grouped according to the presence/absence of MetS (MetS(+) or MetS(-)) and the level (high/low) of both CD34(+) cells and neutrophils. Very high adjusted ORs for VTE were observed among neutrophils_high/MetS(+) (OR, 3.58; P<0.0001) and CD34(+)_low/MetS(+) (OR, 3.98; P<0.0001) subjects as compared with the neutrophils_low/MetS(-) and CD34(+)_high/MetS(-) groups respectively. In conclusion, low CD34(+) blood cell count and high circulating neutrophils interplay with MetS in raising the risk for venous thromboembolic events.

2. Sgolastra F, Petrucci A, Severino M, Gatto R, Monaco A. Relationship between Periodontitis and Pre-Eclampsia: A Meta-Analysis. PLoS One. 2013 Aug 19;8(8):e71387. doi: 10.1371/journal.pone.0071387.
Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.

Abstract
BACKGROUND: Studies have suggested controversial results regarding a possible association between pre-eclampsia (PE) and periodontal disease (PD) and no meta-analysis has been performed to clarify this issue. METHODS: A literature search of electronic databases was performed for articles published through March 24, 2013, followed by a manual search of several dental and medical journals. The meta-analysis was conducted according to the recommendations of the Cochrane Collaboration and PRISMA. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Heterogeneity was assessed with the χ(2)-based Cochran Q test and I(2) statistic. The level of significance was set at P <0.05. RESULTS: Fifteen studies were included, including three cohort and 12 case-control studies. A positive association was found between PE and PD (OR 2.17, 95% CI 1.38-3.41, P = 0.0008). However, a high and significant heterogeneity was found (χ(2) = 62.42, P<0.00001, I(2) = 75%). In most cases, subgroup analysis had low power to detect significant differences between PE and non-PE groups. CONCLUSION: Based on the findings of the meta-analysis, PD appears to be a possible risk factor for PE. However, given the important differences in the definitions and diagnoses of PD and PE among the studies, as well as their lack of good methodological quality, future trials are needed to confirm the results of the present meta-analysis.

3. Vierucci F, Del Pistoia M, Fanos M, Gori M, Carlone G, Erba P, Massimetti G, Federico G, Saggese G. Vitamin D status and predictors of hypovitaminosis D in Italian children and adolescents: a cross-sectional study. Eur J Pediatr. 2013 Aug 20. [Epub ahead of print]
Pediatric Unit, Department of Pediatrics, Santa Chiara University Hospital, Via Roma 67, 56126, Pisa, Italy, vieruf@hotmail.it.

Abstract
Hypovitaminosis D affects children and adolescents all around the world. Italian data on vitamin D status and risk factors for hypovitaminosis D during pediatric age are lacking. Six hundred fifty-two children and adolescents (range 2.0-21.0 years) living in the northwestern area of Tuscany were recruited at the Department of Pediatrics, University Hospital Pisa. None of them had received vitamin D supplementation in the previous 12 months. 25-hydroxyvitamin D (25-OH-D) and parathyroid hormone (PTH) levels were analyzed in all subjects. Severe vitamin D deficiency was defined as serum levels of 25-OH-D < 25.0 nmol/L (10.0 ng/mL) and vitamin D deficiency as < 50.0 nmol/L (20.0 ng/mL). Serum 25-OH-D levels of 50.0-74.9 nmol/L (20.0-29.9 ng/mL) indicated vitamin D insufficiency, whereas 25-OH-D levels ≥ 75.0 nmol/L (30.0 ng/mL) were considered sufficient. Hypovitaminosis D was defined as 25-OH-D levels < 75.0 nmol/L (30.0 ng/mL). The median serum 25-OH-D level was 51.8 nmol/L, range 6.7-174.7 (20.7 ng/mL, range 2.7-70.0), with a prevalence of vitamin D deficiency, insufficiency, and sufficiency of 45.9, 33.6, and 20.5 %, respectively. The prevalence of severe vitamin D deficiency was 9.5 %. Adolescents had lower median 25-OH-D levels (49.8 nmol/L, range 8.1-174.7; 20.0 ng/mL, range 3.2-70.0) than children (55.6 nmol/L, range 6.8-154.6; 22.3 ng/mL, range 2.7-61.9, p = 0.006). Non-white individuals (n = 37) had median serum 25-OH-D levels in the range of deficiency (28.2 nmol/L, range 8.1-86.2; 11.3 ng/mL, range 3.2-34.5), with 36/37 having hypovitaminosis D. Logistic regression showed significant increased risk of hypovitaminosis D in the following: blood samples taken in winter (odds ratio (OR) 27.20), spring (OR 26.44), and fall (OR 8.27) compared to summer; overweight (OR 5.02) and obese (OR 5.36) subjects compared to individuals with normal BMI; low sun exposure (OR 8.64) compared to good exposure, and regular use of sunscreens (OR 7.06) compared to non-regular use. Gender and place of residence were not associated with vitamin D status. The 25-OH-D levels were inversely related to the PTH levels (r = -0.395, p < 0.0001). Sixty-three out of the 652 (9.7 %) subjects showed secondary hyperparathyroidism. Conclusion Italian children and adolescents who were not receiving vitamin D supplementation had high prevalence of hypovitaminosis D. Careful identification of factors affecting vitamin D status is advisable to promptly start vitamin D supplementation in children and adolescents.

4. Pala V, Lissner L, Hebestreit A, Lanfer A, Sieri S, Siani A, Huybrechts I, Kambek L, Molnar D, Tornaritis M, Moreno L, Ahrens W, Krogh V. Dietary patterns and longitudinal change in body mass in European children: a follow-up study on the IDEFICS multicenter cohort. Eur J Clin Nutr. 2013 Aug 14. doi: 10.1038/ejcn.2013.145. [Epub ahead of print]
Epidemiology and Prevention Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Abstract
BACKGROUND/OBJECTIVES:Longitudinal studies investigating dietary patterns (DPs) and their association with childhood overweight/obesity are lacking in Europe. We identified DPs and investigated their association with overweight/obesity and changes in body mass index (BMI) in a cohort of European children.SUBJECTS/METHODS:Children aged 2-10 from eight European countries were recruited in 2007-2008. Food frequency questionnaires were collected from 14 989 children. BMI and BMI z-scores were derived from height and weight and were used to identify overweight/obese children. After 2 years (mean), anthropometric measurements were repeated in 9427 children. Principal component analysis was used to identify DPs. Simplified DPs (SDPs) were derived from DPs. Adjusted odds ratios (ORs) for overweight/obesity with increasing DP intake were estimated using multilevel logistic regression. Associations of BMI change with DP and SDP were assessed by multilevel mixed regression. Models were adjusted for baseline BMI, age, sex, physical activity and family income.RESULTS:Four DPs were identified that explained 25% of food intake variance: snacking, sweet and fat, vegetables and wholemeal, and protein and water. After 2 years, 849(9%) children became overweight/obese. Children in the highest vegetables and wholemeal tertile had lower risk of becoming overweight/obese (OR: 0.69, 95% confidence intervals (CIs): 0.54-0.88). Children in the highest SDP tertile of vegetables and wholemeal had similarly lower risk of becoming overweight/obese (OR: 0.64, 95% CIs: 0.51-0.82), and their BMI increased by 0.7 kg/m(2) over the study period-significantly less than the increase in the lowest tertile (0.84 kg/m(2)).CONCLUSIONS:Our findings suggest that promoting a diet rich in vegetables and wholemeal cereals may counteract overweight/obesity in children.European Journal of Clinical Nutrition advance online publication, 14 August 2013; doi:10.1038/ejcn.2013.145.

Commento a cura di Lorenzo Richiardi: Lo studio IDEFICS è uno studio multicentrico che coinvolge circa 15,000 bambini di età compresa tra 2 e 9 anni arruolati in diversi paesi in Europa, tra cui l’Italia. Si focalizza sui determinanti dell’obesità nei bambini. Questo articolo mette in associazione i dati sulla dieta raccolti al questinario di baseline in circa 10,000 bambini con il rischio di obesità e sovrappeso ed il cambio nel valore di indice di massa corporeo dopo un follow-up di 2 anni. Usando l’analisi delle componenti proncipali sono stati identificati 4 pattern alimentari che spiegavano complessivamente il 25% della varianza. Ad ogni pattern è stato dato un nome sulla base dell’alimento che più lo rappresentava. A distanza di due anni dall’arruolamento, il 7% dei bambini è diventato sovrappeso ed il 2% è diventato obeso. Il patern alimentare caratterizzato da un alto consumo di verdure era associato ad una diminuzione di rischio, mentre gli altri pattern (ad esempio, quello denominato “zuccheri e grasssi”) non erano associati all’obesità/sovrappeso o al cambimanto di indice di massa corporea. Studi sugli effetti della dieta sull’obesità del bambino sono estremamente rilevanti, anche se permangono le difficoltà di rilevazione dell’esposizione (misclassificazione, incompletezza dell’informazione), riproducibilità dei risultati e confondimento che rendono difficile l’identificazione di effetti causali.

5. Bucciarelli P, De Stefano V, Passamonti SM, Tormene D, Legnani C, Rossi E, Castaman G, Simioni P, Cini M, Martinelli I. Influence of proband's characteristics on the risk of venous thromboembolism in relatives with factor V Leiden or prothrombin G20210A polymorphisms. Blood. 2013 Aug 2. [Epub ahead of print]
A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy;

Abstract
In family studies, the risk of venous thromboembolism (VTE) in relatives with factor V Leiden (FVL) or G20210A prothrombin (PT20210A) gene polymorphisms may differ according to genotype and clinical presentation of the proband. To address this hypothesis, a retrospective cohort family study was carried out on 192 kindreds with at least one member with homozygous FVL or PT20210A, for a total of 886 relatives. The proband of the family was heterozygous in 68 and homozygous or with both polymorphisms in 124 kindreds. Twenty-three probands were asymptomatic, 11 had had arterial thrombosis, 7 obstetrical complications, and 151 venous thrombosis (122 VTE and 29 superficial vein thrombosis). The incidence of VTE (per 1000 patient-years) in relatives was higher when the proband had heterozygous than homozygous polymorphism [1.25 (95%CI:0.73-1.91) vs 0.44 (0.19-0.78)], and when the proband had had VTE instead of other or no clinical manifestations [0.95 (0.57-1.42) vs 0.50 (0.19-0.96)]. Compared to relatives belonging to kindreds with homozygous probands without VTE, the adjusted hazard ratio of VTE for relatives selected from kindreds with heterozygous probands with VTE was 4.14 (95%CI:1.17-14.71). The genotype and clinical presentation of the proband influence the risk of VTE in relatives with FVL or PT20210A.

6. Simone B, De Stefano V, Leoncini E, Zacho J, Martinelli I, Emmerich J, Rossi E, Folsom AR, Almawi WY, Scarabin PY, den Heijer M, Cushman M, Penco S, Vaya A, Angchaisuksiri P, Okumus G, Gemmati D, Cima S, Akar N, Oguzulgen KI, Ducros V, Lichy C, Fernandez-Miranda C, Szczeklik A, Nieto JA, Torres JD, Le Cam-Duchez V, Ivanov P, Cantu-Brito C, Shmeleva VM, Stegnar M, Ogunyemi D, Eid SS, Nicolotti N, De Feo E, Ricciardi W, Boccia S. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol. 2013 Jul 31. [Epub ahead of print]
Institute of Public Health - Section of Hygiene, Department of Public Health, Università Cattolica del Sacro Cuore, L.go F.Vito 1, 00168, Rome, Italy.

Abstract
Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

7. Coppedè F, Lorenzoni V, Migliore L. The reduced folate carrier (RFC-1) 80A>G polymorphism and maternal risk of having a child with Down syndrome: a meta-analysis. Nutrients. 2013 Jul 5;5(7):2551-63. doi: 10.3390/nu5072551.
Department of Translational Research and New Technologies in Medicine and Surgery, Division of Medical Genetics, University of Pisa, Via S. Giuseppe 22, Pisa 56126, Italy. f.coppede@geog.unipi.it

Abstract
A common polymorphism (c.80A>G) in the gene coding for the reduced folate carrier (SLC19A1, commonly known as RFC-1) has been associated with maternal risk of the birth of a child with Down Syndrome (DS), but results are controversial. We searched major online databases to identify available case-control studies, and performed a meta-analysis to summarize the data concerning this association. Nine independent case-control studies were identified for a total of 930 DS mothers (MDS) and 1240 control mothers. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using both fixed and random effects models. An increase in the risk of having a birth with DS was observed for carriers of the homozygous GG genotype (OR 1.27, 95% CI 1.04-1.57; p = 0.02, fixed effects model), even after removal from the meta-analysis of published data with deviations from Hardy-Weinberg equilibrium (HWE) in controls (OR 1.26, 95% CI 1.02-1.55; p = 0.03, fixed effects model). Moreover, the pooled OR under the fixed effects model showed an increase in the maternal risk for the G allele (OR 1.14, 95% CI 1.01-1.30; p = 0.03). Present results suggest that the maternal RFC-1 80A>G polymorphism might be associated with an increased risk of having a birth with DS, particularly among carriers of the GG genotype.

8. Ricci F, Staurenghi G, Lepre T, Missiroli F, Zampatti S, Cascella R, Borgiani P, Marsella LT, Eandi CM, Cusumano A, Novelli G, Giardina E. Haplotypes in IL-8 Gene Are Associated to Age-Related Macular Degeneration: A Case-Control Study. PLoS One. 2013 Jun 19;8(6):e66978. Print 2013.
UOSD Patologia retinica Fondazione PTV "Policlinico Tor Vergata", Rome, Italy.

Abstract
BACKGROUND: Age-related macular degeneration (AMD) is the main cause of blindness in the developed world. The etiology of AMD is multifactorial due to the interaction between genetic and environmental factors. IL-8 has a role in inflammation and angiogenesis; we report the genetic characterization of IL-8 allele architecture and evaluate the role of SNPs or haplotypes in the susceptibility to wet AMD, case-control study. METHODS: Case-control study including 721 AMD patients and 660 controls becoming from Italian population. Genotyping was carried out by Real Time-PCR. Differences in the frequencies were estimated by the chi-square test. Direct sequencing was carried out by capillary electrophoresis trough ABI3130xl. RESULTS: rs2227306 showed a p-value of 4.15*10(-5) and an Odds Ratio (OR) for T allele of 1.39 [1.19-1.62]. After these positive results, we sequenced the entire IL-8 regulatory and coding regions of 60 patients and 30 controls stratified for their genotype at rs2227306. We defined two different haplotypes involving rs4073 (A/T), rs2227306 (C/T), rs2227346 (C/T) and rs1126647 (A/T): A-T-T-T (p-value: 2.08*10(-9); OR: 1.68 [1.43-1.97]) and T-C-C-A (p-value: 7.07*10(-11); OR: 0.60 [0.51-0.70]). To further investigate a potential functional role of associated haplotypes, we performed an expression study on RNA extracted from whole blood of 75 donors to verify a possible direct correlation between haplotype and gene expression, failing to reveal significant differences. CONCLUSIONS: These results suggest a possible secondary role of IL-8 gene in the development of the disease. This paper outlines the importance of association between inflammation and AMD. Moreover IL-8 is a new susceptibility genomic biomarker of AMD.

9. Zamora-Ros R, Rabassa M, Cherubini A, Urpí-Sardà M, Bandinelli S, Ferrucci L, Andres-Lacueva C. High concentrations of a urinary biomarker of polyphenol intake are associated with decreased mortality in older adults. J Nutr. 2013 Sep;143(9):1445-50. doi: 10.3945/jn.113.177121. Epub 2013 Jun 26.
Nutrition and Food Science Department, XaRTA INSA, INGENIO-CONSOLIDER Program, Fun-C-food CSD2007-063, Pharmacy School, University of Barcelona, Barcelona, Spain.

Abstract
Polyphenols might have a role in the prevention of several chronic diseases, but evaluating total dietary polyphenol (TDP) intake from self-reported questionnaires is inaccurate and unreliable. A promising alternative is to use total urinary polyphenol (TUP) concentration as a proxy measure of intake. The current study evaluated the relationship between TUPs and TDPs and all-cause mortality during a 12-y period among older adult participants. The study population included 807 men and women aged 65 y and older from the Invecchiare in Chianti study, a population-based cohort study of older adults living in the Chianti region of Tuscany, Italy. TUP concentrations were measured at enrolment (1998-2000) using the Folin-Ciocalteau assay after a solid-phase extraction. TDPs were also estimated at baseline throughout a validated food frequency questionnaire and using our database based on USDA and Phenol-Explorer databases. We modeled associations using Kaplan-Meier survival and Cox proportional hazards models, with adjustment for potential confounders. During the 12-y follow-up, 274 participants (34%) died. At enrollment, TUP excretion adjusted for age and sex tended to be greater in participants who survived [163 ± 62 mg gallic acid equivalents (GAE)/d)] than in those who died (143 ± 63 mg GAE/d) (P = 0.07). However, no significant differences were observed for TDPs. In the multivariable Cox model, participants in the highest tertile of TUP at enrolment had a lower mortality rate than those in the lowest tertile [HR = 0.70 (95% CI: 0.49-0.99); P-trend = 0.045], whereas no significant associations were found between TDP and overall mortality. TUP is an independent risk factor for mortality among community-dwelling older adults, suggesting that high dietary intake of polyphenols may be associated with longevity.

10. Meloni M, Setzu D, Del Rio A, Campagna M, Cocco P. QTc interval and electrocardiographic changes by type of shift work. Am J Ind Med. 2013 Oct;56(10):1174-9. doi: 10.1002/ajim.22207. Epub 2013 Jun 21.
Department of Public Health, Clinical and Molecular Medicine, Occupational Health Section, University of Cagliari, Monserrato (Cagliari), Italy.

Abstract
BACKGROUND: We conducted a cross sectional survey of electrocardiographic changes among shift-workers. METHODS: We classified the electrocardiogram morphology, and measured the QTc interval in 91 male workers engaged in regular daily work-shifts, 32 in 24 hr work-shift (h24), and 93 in irregular 6 hr work-shift (h6). RESULTS: With reference to daily workers, the QTc interval was prolonged among h6 workers (P < 0.001) and h24 workers (P < 0.005). The age- and obesity-adjusted standardized prevalence ratio (SPR) of a borderline/prolonged QTc was 2.2-fold among h6 workers (95% CI 1.2, 4.2); conduction disorders (SPR = 2.6; 95% CI 1.3, 5.2) and repolarization disorders (SPR = 1.9; 95% CI 1.0, 3.5) were also more frequently observed among h6 workers. Excluding 19 subjects with risk factors for prolonged QTc did not change the results. CONCLUSIONS: Our study reveals significant changes in the ECG morphology in relation to shift-work, especially in unpredictable and non-standard working hours. Am. J. Ind. Med. 56:1174-1179, 2013.

11. Ciccacci C, Di Fusco D, Marazzi MC, Zimba I, Erba F, Novelli G, Palombi L, Borgiani P, Liotta G. Association between CYP2B6 polymorphisms and Nevirapine-induced SJS/TEN: a pharmacogenetics study. Eur J Clin Pharmacol. 2013 Jun 18. [Epub ahead of print]
Department of Biomedicine and Prevention, Genetics Section, School of Medicine, University of Rome "Tor Vergata", 00133, Rome, Italy.

Abstract
PURPOSE: Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor, widely prescribed for type 1 human immunodeficiency virus infection. A small proportion of individuals treated with NVP experience severe cutaneous adverse events, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Our aim was to verify whether genetic variability in NVP-metabolizing cytochromes or in transporter genes could be involved in susceptibility to SJS/TEN. METHODS: Twenty-seven patients with NVP-induced SJS/TEN and 78 controls, all from Mozambique, were genotyped for the ABCB1 and ABCC10 transporter genes and for CYP2B6, CYP3A4 and CYP3A5 cytochrome gene variants. A case-control and a genotype-phenotype analysis were performed. RESULTS: CYP2B6 G516T and T983C single nucleotide polymorphisms (SNPs) were found to be associated with SJS/TEN susceptibility. The 983C allele in particular was found to be highly associated with a higher risk to develop SJS/TEN [odds ratio (OR) 4.2, P = 0.0047]. The GT haplotype (wildtype for both SNPs) showed a protective effect, with an OR = 0.33 (P = 0.0016). CONCLUSIONS: This is the first study showing that genetic variability in a metabolizing enzyme can also contribute to NVP-induced SJS/TEN susceptibility.

12. Franchi C, Sequi M, Tettamanti M, Bonometti F, Nobili A, Fortino I, Bortolotti A, Merlino L, Pasina L, Djade CD, Marengoni A. Antipsychotics prescription and cerebrovascular events in Italian older persons.
J Clin Psychopharmacol. 2013 Aug;33(4):542-5. doi: 10.1097/JCP.0b013e3182968fda. Laboratory for Quality Assessment of Geriatric Therapies and Services, IRCCS-Istituto di Riceerche Farmacologiche Mario Negri, Milan, Italy. carlotta.franchi@marionegri.it

Abstract
Meta-analyses have found conflicting evidence on the link between antipsychotics and cerebrovascular events (CVEs). The primary aim of this study was to evaluate the association between any antipsychotic prescription and CVEs in Italian elderly; second, to compare the effect of typical and atypical antipsychotics on CVEs; and third, to investigate the effect of antipsychotics on CVEs in the subgroup of persons coprescribed with acetylcholinesterase inhibitors (AChEIs). Administrative claims from community-dwelling people aged 65 to 94 years living in Northern Italy were analyzed using a retrospective case-control design, from 2003 to 2005. The primary outcome measure was a hospital discharge diagnosis of CVEs during 2005. Four age-, sex-, and local health unit-matched control subjects were identified for each case. Antihypertensive drugs, anticoagulants, platelet inhibitors, antidiabetic drugs, lipid-lowering drugs, and AChEI were used as covariates in conditional logistic regression models testing the odds ratio (OR) for CVEs due to antipsychotics use. Three thousand eight hundred fifty-five cases of CVEs were identified and matched with 15,420 control subjects. In multiadjusted models, the association of any antipsychotics, typical or atypical with CVEs, was not significant. When antipsychotics were categorized according to the number of boxes prescribed during the observational period, being prescribed with at least 19 boxes of typical antipsychotics was significantly associated with CVEs (OR, 2.4; 95% confidence interval, 1.08-5.5). An interaction was found between any antipsychotic and AChEI coprescription on CVEs (OR, 0.46; 95% confidence interval, 0.23-0.92). In conclusion, only typical antipsychotics were associated with an increased odd of CVEs, but the association was duration dependent. Persons prescribed simultaneously with AChEI and antipsychotics may be at a lower risk of CVEs.

13. Parazzini F, Cipriani S, Bravi F, Pelucchi C, Chiaffarino F, Ricci E, Viganò P. A metaanalysis on alcohol consumption and risk of endometriosis. Am J Obstet Gynecol. 2013 Aug;209(2):106.e1-106.e10. doi: 10.1016/j.ajog.2013.05.039. Epub 2013 May 23.
Department of Obstetrics, Gynecology, and Neonatology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy. Electronic address: fabio.parazzini@marionegri.it.

Abstract
OBJECTIVE: To offer a general figure of the available data on the relation between alcohol intake and risk of endometriosis, we conducted a systematic review and a metaanalysis of studies published up to May 2012. STUDY DESIGN: We carried out a literature search of all case-control and cohort studies published as original articles in English up to May 2012. Only those papers that were published as full-length articles were considered. Pooled estimates of the relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were calculated using fixed or, when significant heterogeneity among estimates emerged, random effects models. A total of 15 studies were identified for the review. RESULTS: The summary estimate was 1.24 (95% CI, 1.12-1.36) for any alcohol intake vs no alcohol intake. Considering the results of the analyses of infrequent, moderate/regular, and heavy alcohol intake vs no alcohol intake, the summary RR estimates were, respectively, 1.14 (95% CI, 0.86-1.52), 1.23 (95% CI, 1.08-1.40), and 1.19 (95% CI, 0.99-1.43). Three studies reported separate results for current and former drinkers, and the summary RR were 1.42 (95% CI, 1.14-1.76) and 1.09 (95% CI, 0.83-1.43), respectively. CONCLUSION: The present metaanalysis provides evidence for an association between alcohol consumption and endometriosis risk. Further studies are needed to clarify whether alcohol consumption may exacerbate an existing disease or could be related to the severity of the disease.

14. Warner M, Mocarelli P, Brambilla P, Wesselink A, Samuels S, Signorini S, Eskenazi B. Diabetes, Metabolic Syndrome, and Obesity in Relation to Serum Dioxin Concentrations: The Seveso Women's Health Study. Environ Health Perspect. 2013 Aug;121(8):906-11. doi: 10.1289/ehp.1206113. Epub 2013 May 13.
Center for Environmental Research and Children's Health, School of Public Health, University of California, Berkeley, Berkeley, California, USA.

Abstract
Background: In animal studies, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters glucose transport and increases serum lipid levels and blood pressure. Epidemiologic evidence suggests an association between TCDD and metabolic disease.Objectives: On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in the highest known residential exposure to TCDD. Using data from the Seveso Women's Health Study (SWHS), a cohort study of the health of the women, we examined the relation of serum TCDD to diabetes, metabolic syndrome, and obesity > 30 years later.Methods: In 1996, we enrolled 981 women who were newborn to 40 years of age in 1976 and resided in the most contaminated areas. Individual TCDD concentration was measured in archived serum that had been collected soon after the explosion. In 2008, 833 women participated in a follow-up study. Diabetes was classified based on self-report or fasting serum glucose and glycated hemoglobin levels. Metabolic syndrome was defined by International Diabetes Federation criteria. Obesity was defined as body mass index ≥ 30 kg/m2.Results: A 10-fold increase in serum TCDD (log10TCDD) was not associated with diabetes (adjusted hazard ratio = 0.76; 95% CI: 0.45, 1.28) or obesity [adjusted odds ratio (OR) = 0.80; 95% CI: 0.58, 1.10]. Log10TCDD was associated with metabolic syndrome, but only among women who were ≤ 12 years of age at the time of the explosion (adjusted OR = 2.03; 95% CI: 1.25, 3.29; pinteraction = 0.01).Conclusions: We found an increased prevalence of metabolic syndrome associated with TCDD, but only among women who were the youngest at the time of the explosion. Continued follow-up of the SWHS cohort will be informative.

15. Montenegro L, De Michina A, Misciagna G, Guerra V, Di Leo A. Virus C hepatitis and type 2 diabetes: a cohort study in southern Italy. Am J Gastroenterol. 2013 Jul;108(7):1108-11. doi: 10.1038/ajg.2013.90. Epub 2013 Apr 9.
Department of Emergency and Organ Transplantation, University of Bari, Hospital Policlinico, Bari, Italy.

Abstract
OBJECTIVES: The relationship between hepatitis C virus (HCV) infection and type 2 diabetes mellitus (DM 2) is still uncertain. The objective of this study was to evaluate the association between HCV infection, measured as positivity to anti-HCV antibodies, and the incidence of DM 2 in a cohort of subjects sampled from the general population and followed up for 20 years. METHODS: At baseline, the cohort consisted of a random sample of 2,472 subjects (72% response rate, age range 30-69 years) from the electoral register of a town in Southern Italy. The cohort subjects were examined three times: in 1985 (M1), in 1992 (M2), and in 2005 (M3). At M1, M2, and M3, each participant filled in a questionnaire and had a blood sample taken to measure blood glucose and other serum variables including glutamic pyruvic alanine aminotransferase (ALT). Anti-HCV antibodies were analyzed with standard techniques at M1 and M2. Diabetes type 2 diagnosis was a history of diabetes and/or serum glucose ≥126 mg/dl and/or treatment with insulin or hypoglycemic drugs. Logistic regression was used for multivariable data analysis. RESULTS: Diabetes prevalence was higher in subjects with positive anti-HCV antibodies at M1 and M2, and diabetes incidence was higher in subjects with baseline positive anti-HCV antibodies at M1-M2 and lower at M2-M3. In multivariable models, controlling for gender, age, and body mass index (BMI), there was no association between incident cases of diabetes and positive anti-HCV antibodies at baseline, either at M1-M2 (odds ratio (OR) 0.73, 95% confidence interval (CI) 0.43-1.22) or at M2-M3 (0.65, 0.41-1.04). HCV was associated with DM 2 only in subjects with elevated ALT (OR 0.58, 95% CI 0.31-1.08, if ALT normal; OR 1.47, 95% CI 1-2.16, if ALT elevated, controlling for age, gender, and BMI). CONCLUSIONS: Our findings, in a cohort study at population level, support an association between the presence of anti-HCV antibodies at baseline and a higher incidence of type 2 diabetes in the following 20 years only in subjects with elevated ALT.

16. Polito L, Kehoe PG, Davin A, Benussi L, Ghidoni R, Binetti G, Quadri P, Lucca U, Tettamanti M, Clerici F, Bagnoli S, Galimberti D, Nacmias B, Sorbi S, Guaita A, Scarpini E, Mariani C, Forloni G, Albani D. The SIRT2 polymorphism rs10410544 and risk of Alzheimer's disease in two Caucasian case-control cohorts. Alzheimers Dement. 2013 Jul;9(4):392-9. doi: 10.1016/j.jalz.2012.02.003. Epub 2012 May 30.
Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy; Golgi Cenci Foundation, Abbiategrasso, Italy.

Abstract
BACKGROUND: Human sirtuins are a current hotspot for research in neurodegenerative disorders, including Alzheimer's disease (AD). This study investigated whether genetic variants in two members of the sirtuin family, SIRT2 and SIRT3, affected AD susceptibility. METHODS: A genetic case-control study was performed, comprising 534 probable AD cases and 638 nondemented control subjects from the north of Italy and Canton Ticino, Switzerland (discovery population). The study was focused on SIRT2 rs10410544, SIRT3 rs4980329, and SIRT3 rs536715 single nucleotide polymorphisms (SNPs). These SNPs were genotyped by real-time polymerase chain reaction allelic discrimination assay or restriction fragment length polymorphism. The SNPs rs7412 and rs429358, mapping within the apolipoprotein E (APOE) gene, were genotyped by real-time polymerase chain reaction allelic discrimination assay too. In a replication population comprising 756 AD cases and 847 nondemented control subjects, SIRT2 rs10410544, APOE rs7412, and APOE rs429358 were genotyped as mentioned previously. RESULTS: In the discovery population, we observed an association between SIRT2 rs10410544 T allele and AD (adjusted odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.02-1.50, P = .02, after correction for sex, age, and APOE ɛ4 genotype). The association between AD and SIRT2 rs10410544 T allele was only present in APOE ɛ4 noncarriers (adjusted OR = 1.29, 95% CI: 1.03-1.61, P = .03). The replication study did not confirm this evidence. However, the combined analysis on the two cohorts detected the association (adjusted OR = 1.17, 95% CI: 1.02-1.35, P = .02), and only APOE ɛ4 noncarriers were at risk (adjusted OR = 1.2, 95% CI: 1.02-1.43, P = .03). CONCLUSIONS: The SIRT2 rs10410544 T allele deserves further investigation as a novel minor genetic risk factor for AD in the APOE ɛ4-negative Caucasian population.

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