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Importance: The association between age-related hearing loss (ARHL) and physical or cognitive frailty has been poorly explored. These associations could define new perspectives for delaying frailty-related processes in older age., Objective: To examine whether peripheral ARHL and age-related central auditory processing disorder (CAPD) are independently associated with physical or cognitive frailty., Design, Setting, and Participants: This cross-sectional study analyzed registry data from December 31, 2014, on 1929 older (≥65 years) participants of the Salus in Apulia Study (Southern Italy) who underwent audiologic, physical, and neuropsychological assessment. Data analysis was performed from December 12, 2019, to January 4, 2020., Main Outcomes and Measures: Prevalence of peripheral ARHL in older individuals with physical and/or cognitive frailty and those without frailty assessed using the Fried criteria (physical) and the Mini-Mental State Examination (cognitive). Multivariable logistic regression models were used to assess associations of audiologic variables with frailty phenotype., Results: Data from 1929 participants (mean [SD] age, 73.6 [6.3] years; 974 male [50.5%]) were eligible for the analyses. The prevalence of peripheral ARHL was higher in the physical frailty group (96 [26.6%]) than in the nonfrail group (329 [21.0%]) (difference, 5.61 percentage points; 95% CI, 0.63-10.59 percentage points) and in the cognitive frailty group (40 [38.8%]) than in the nonfrail group (385 [21.1%]) (difference, 17.75 percentage points; 95% CI, 8.2-27.3 percentage points). Age-related CAPD was more prevalent in the physical frailty group (62 [17.2%]) than in the nonfrail group (219 [14.0%]) (difference, 3.21 percentage points; 95% CI, -1.04 to 7.46 percentage points) and in the cognitive frailty group (28 [27.2%]) than in the nonfrail group (253 [13.9%]) (difference, 13.33 percentage points; 95% CI, 4.10-22.21 percentage points). In the multivariable models, age-related CAPD was associated with cognitive frailty in the fully adjusted model (odds ratio [OR], 1.889; 95% CI, 1.094-3.311). There was also an inverse association between the unitary increase in Synthetic Sentence Identification With the Ipsilateral Competitive Message scores, indicating a lower likelihood of this disorder, and cognitive frailty (OR, 0.989; 95% CI, 0.988-0.999). Peripheral ARHL was associated with cognitive frailty only in the partially adjusted model (OR, 1.725; 95% CI, 1.008-2.937)., Conclusions and Relevance: In this cross-sectional study of 1929 participants, age-related CAPD was independently associated with cognitive frailty. Whether the management of ARHL may help prevent the development of different frailty phenotypes or improve their clinical consequences should be addressed in longitudinal studies and, eventually, well-designed randomized clinical trials.

The association between late-life depression (LLD) and age-related hearing loss (ARHL) was suggested by preliminary studies, but reliance on LLD subtypes may introduce significant bias. We examined the association between ARHL and LLD according to the age of onset (early-onset depression (EOD) and late-onset depression (LOD)). We investigated the association between ARHL and LLD diagnosed according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR in 1749 Italian community-dwelling older subjects from the population-based GreatAGE Study, Southern Italy. Peripheral ARHL was assessed as a pure tone average (PTA) threshold > 40 dB hearing level in the better ear- and age-related CAPD as a score of < 50% to the Synthetic Sentences Identification with Ipsilateral Competitive Message (SSI-ICM) test. LLD amounted at 10.29% of the sample, subdivided in LOD (6.21%) and EOD (4.08%). Age-related CAPD tended to be higher in LOD (28.91%) than in EOD (19.05%). After accounting for covariates, LOD was tendentially associated to age-related CAPD, but not to peripheral ARHL. This trend was confirmed by the linear models in which LOD was significantly associated to worsen SSI-ICM percentages (odds ratio 2.38, 95% confidence interval 1.32-4.30, p = 0.004), but not to PTA values. In a fully adjusted model of LOD, the effect of the association between CAPD and LOD was explained by social dysfunction. LLD was not associated to peripheral ARHL. Age-related CAPD was associated to LOD, a form of depression with cognitive dysfunction hallmark. The ARHL assessment may be an important opportunity to prevent depressive disorders in later life, particularly for LOD.

Objective: We explored the associations of age-related central auditory processing disorder (CAPD) with mild cognitive impairment (MCI) and dementia in an older population-based cohort in Apulia, Southern Italy (GreatAGE Study)., Study Design: Cross-sectional data from a population-based study., Setting: Castellana Grotte, Bari, Italy., Subjects and Methods: Between 2013 and 2018, MCI, dementia, age-related CAPD (no disabling hearing loss and <50% score on the SSI-ICM test [Synthetic Sentence Identification-Ipsilateral Competing Message]), neurologic and neuropsychological examinations, and serum metabolic biomarkers assays were investigated on 1647 healthy volunteers aged >65 years., Results: The prevalences of age-related CAPD, MCI, and dementia were 14.15%, 15.79%, and 3.58%, respectively. Among the subjects with MCI and dementia, 19.61% and 42.37% had age-related CAPD. In the regressive models, age-related CAPD was associated with MCI (odds ratio, 1.50; 95% CI, 1.01-2.21) and dementia (odds ratio, 2.23; 95% CI, 1.12-4.42). Global cognition scores were positively associated with increasing SSI-ICM scores in linear models. All models were adjusted for demographics and metabolic serum biomarkers., Conclusion: The tight association of age-related CAPD with MCI and dementia suggests the involvement of central auditory pathways in neurodegeneration, but it is not clear which is the real direction of this association. However, CAPD is a possible diagnostic marker of cognitive dysfunction in older patients.

Age related hearing loss (ARHL) affects about one third of the elderly population. It is suggested that the senescence of the hair cells could be modulated by inflammation. Thus, intake of anti- and pro-inflammatory foods is of high interest., Methods: From the MICOL study population, 734 participants were selected that participated in the 2013 to 2018 examination including hearing ability and from which past data collected in 2005/2008 was available. ARHL status was determined and compared cross-sectionally and retrospectively according to clinical and lifestyle data including food and micronutrient intake., Results: ARHL status was associated with higher age but not with education, smoking, relative weight (BMI), and clinical-chemical blood markers in the crossectional and retrospective analyses. Higher intake of fruit juices among ARHL-participants was seen cross-sectionally, and of sugary foods, high-caloric drinks, beer, and spirits retrospectively. No difference was found for the other 26 food groups and for dietary micronutrients with the exception of past vitamin A, which was higher among normal hearing subjects., Conclusions: Pro-inflammatory foods with a high-sugar content and also beer and spirits were found to be assocated with positive ARHL-status, but not anti-inflammatory foods. Diet could be a candidate for lifestyle advice for the prevention of ARHL.

Introduction: Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial domains/phenotypes. We operationalized a new biopsychosocial frailty (BF) construct, estimating its impact on the risk of incident dementia and its subtypes., Methods: In 2171 older individuals from the population-based Italian Longitudinal Study on Aging (ILSA), we identified by latent class procedures the BF construct as the physical frail status plus at least one of the two items of the 30-item Geriatric Depression Scale impaired (items 3/10)., Results: Over a 3.5-year follow-up, participants with BF showed an increased risk of overall dementia (hazard ratio [HR]: 2.16, 95% confidence interval [CI]:1.07-4.37), particularly vascular dementia (VaD) (HR: 3.21, 95% CI: 1.05-9.75). Similarly, over a 7-year follow-up, an increased risk of overall dementia (HR: 1.84, 95% CI: 1.06-3.20), particularly VaD (HR: 2.53, 95% CI: 1.08-5.91), was also observed., Discussion: In a large cohort of Italian older individuals without cognitive impairment at baseline, a BF model was a short- and long-term predictor of overall dementia, particularly VaD., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Most studies focused on only one measure of social dysfunction in older age, without proper validation and distinction across different dimensions including subjectivity, structural, and functional aspects., Objective: We sought to validate the Social Dysfunction Rating Scale (SDRS) and its factorial structure, also determining the association of SDRS with cognitive functions, global psychopathology, and social deprivation., Methods: The SDRS was administered to 484 Italian community-dwelling elderly, recruited in the GreatAGE study, a population-based study on aging conducted in Castellana Grotte, Bari, Southern Italy. We determined objective and subjective psychometric properties of SDRS against the gold standard evaluation of social dysfunction according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID-I) criterion., Results: The SDRS showed a moderate accuracy with an optimal cut-off of 26 maximized with higher sensitivity (0.74,95% CI:0.63-0.84) than specificity (0.57,95% CI:0.50-0.64). A five-factor structure was carried out and five dimensions of SDRS were identified (loneliness; social isolation; feeling of contribution/uselessness; lack of leisure activities; anxiety for the health). Education and global cognitive functions were inversely correlated to SDRS, while a direct association with global psychopathology, depression, and apathy was found. The prevalence of higher SDRS scores was major in subjects with current psychiatric disorders versus other subjects.∥Conclusion: The SDRS could be a valid instrument to capture both size and quality of social dysfunction, both in subjects with psychiatric disorders and in normal subjects. Several categories of social dysfunction differed only in the degree of health deprivation, not in social or material deprivation.

Background/aim: The aim of the study was to evaluate the prognostic power of late-life depression (LLD) compared with amnestic mild cognitive impairment (aMCI) for the onset of Alzheimer's disease (AD) within 4 years of follow-up., Methods: We estimated the incidence of AD in 60 patients presenting with aMCI, 115 patients suffering of LLD treated with antidepressants with good compliance, and 66 healthy control (HC) patients, followed for 4 years., Results: The risk to develop AD, within 4 years, was 68.33% for aMCI and 49.57% for LLD. In AD patients 5.60% deteriorated without depression, and 72.20% deteriorated with depression after 4 years of follow-up (p < 0.0001). No HC patients deteriorated to AD or any other dementia type., Conclusion: In our results, aMCI was the first predictive condition that increased the risk to develop AD. Depression is a potentially preventable medical condition across the lifespan and may be a modifiable risk factor., (© 2018 S. Karger AG, Basel.)

Introduction: We investigated the clinical differences between familial and sporadic frontotemporal dementia (FTD), screening for mutations in known FTD genes., Methods: We diagnosed 22 affected individuals belonging to eight families and 43 sporadic cases with FTD in Apulia, Southern Italy, in 2 years. Mutations in common causative FTD genes (GRN, MAPT, VCP, and TARDBP) and C9ORF72 expansions were screened., Results: Behavioral variant of FTD was the most common clinical subtype (50% and 69% in familial and sporadic cases, respectively). Social conduct impairment/disinhibition, loss of insight, and inflexibility were the most frequent clinical features observed at onset. One new mutation was identified in GRN in family A., Discussion: Disease onset in sporadic FTD was more frequently characterized by a clustering of behavioral symptoms with apathy and loss of personal hygiene. Mutations in common causative FTD genes are not a major cause of familial and sporadic FTD in the Southern Italian population., (Copyright © 2017. Published by Elsevier Inc.)

Objective: To investigate the role of CYP2D6 phenotype in the outcome of postoperative (PO) pain (POP) treatment., Design: Longitudinal cohort study. Open-label trial with post hoc analysis., Setting: General Hospital Surgery and Recovery Units., Patients: Ninety unrelated Caucasians submitted to abdominal/thoracic surgery., Interventions: Standard multimodal POP treatment including opioids (tramadol) and nonsteroidal anti-inflammatory drugs (ketoprofen) at different dosages and infusion rates according to the predicted mild, moderate, or severe POP., Outcome Measures: Pain (Numeric Rating Scale-NRS) and sedation (Ramsay Sedation Scale-RSS) up to 24 hours after surgery. By genotyping 16 CYP2D6 alleles, the four CYP2D6 phenotypes poor metabolizer (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM) were predicted., Results: As compared with the CYP2D6-EM phenotype, in the early PO time (30 min) a higher RSS mean score in IM was observed (P = 0.035). A suggestion towards higher mean score in PM (P = 0.091) and a minor mean score in UM (P = 0.091) was also detected. No difference in the outcome of pain across the CYP2D6 phenotypes was observed., Conclusions: In respect to the normal CYP2D6 phenotype, our results suggested that slowly metabolizers (IMs and PMs) might have a major sedation, whereas more rapid metabolizers (UM) a minor sedation, in the early time after surgery. A minor role of CYP2D6 phenotype in PO analgesia may be suggested., (Wiley Periodicals, Inc.)

Background: Frailty is a clinical syndrome generally associated with a greater risk for adverse outcomes such as falls, disability, institutionalization, and death. Cognition and dementia have already been considered as components of frailty, but the role of frailty as a possible determinant of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) has been poorly investigated. We estimated the predictive role of frailty syndrome on incident dementia and its subtypes in a nondemented, Italian, older population., Methods: We evaluated 2581 individuals recruited from the Italian Longitudinal Study on Aging sample population consisting of 5632 subjects aged 65 to 84 years and with a 3.9-year median follow-up. A phenotype of frailty according to a modified measurement of Cardiovascular Health Study criteria was operationalized. Dementia, AD, and VaD were classified using current published criteria., Results: Over a 3.5-year follow-up, 65 of 2581 (2.5%) older subjects, 16 among 252 frail individuals (6.3%), of which 9 were affected by VaD (3.6%), developed overall dementia. In a proportional hazards model, frailty syndrome was associated with a significantly increased risk of overall dementia (adjusted hazard ratio: 1.85; 95% confidence interval: 1.01-3.40) and, in particular, VaD (adjusted hazard ratio: 2.68; 95% confidence interval: 1.16-7.17). The risk of AD or other types of dementia did not significantly change in frail individuals in comparison with subjects without frailty syndrome., Conclusion: In our large population-based sample, frailty syndrome was a short-term predictor of overall dementia and VaD., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Cognition has already been considered as a component of frailty, and it has been demonstrated that it is associated with adverse health outcomes. We estimated the prevalence of frailty syndrome in an Italian older population and its predictive role on all-cause mortality and disability in nondemented subjects and in demented patients. We evaluated 2,581 individuals recruited from the Italian Longitudinal Study on Aging, a population-based sample of 5,632 subjects, aged 65-84 years old. Participants received identical baseline evaluation at the 1st survey (1992-1993) and were followed at 2nd (1995-1996) and 3rd survey (2000-2001). A phenotype of frailty according to partially modified measurement of Cardiovascular Health Study criteria was operationalized. The overall prevalence of frailty syndrome in this population-based study was 7.6% (95% confidence interval (CI) 6.55-8.57). Frail individuals noncomorbid or nondisable were 9.1% and 39.3%, respectively, confirming an overlap but not concordance in the co-occurrence among these conditions. Frailty was associated with a significantly increased risk of all-cause mortality over a 3-year follow-up (hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.52-2.60) and over a 7-year follow-up (HR 1.74, 95% CI 1.44-2.16), but with significant increased risk of disability only over a 3-year follow-up (HR 1.32, 95% CI 1.06-1.86 over a 3-year follow-up and HR 1.16, 95% CI 0.88-1.56 over a 7-year follow-up). Frail demented patients were at higher risk of all-cause mortality over 3- (HR 3.33, 95% CI 1.28-8.29) and 7-year follow-up periods (HR 1.89, 95% CI 1.10-3.44), but not of disability. Frailty syndrome was a short-term predictor of disability in nondemented older subjects and short- and long-term predictor of all-cause mortality in nondemented and demented patients.

Objective: To investigate the role of the apolipoprotein E (APOE) locus in frontotemporal dementia (FTD) and primary progressive aphasia (PPA)., Design: Case-control study., Setting: Neurology clinic, Rome, Italy., Patients: Eighty-six patients with a clinical diagnosis of sporadic FTD, including 32 patients with a clinical diagnosis of PPA, and 99 nondemented cognitively intact control subjects., Main Outcome Measures: Genotype analysis of the 3 single-nucleotide polymorphisms rs449647, rs769446, and rs405509 in the promoter region of the APOE gene and of the 2 single-nucleotide polymorphisms rs429358 and rs7412 forming the common apoE polymorphism., Results: Significant associations with FTD were observed for genotypes rs449647 A/T (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0-4.5), rs769446 T/C (OR, 4.4; 95% CI, 1.9-10.2), and APOE ε3/ε4 (OR, 4.1; 95% CI, 1.6-10.9). Significant associations with PPA were also observed for genotypes APOE ε3/ε4 (OR, 22.5; 95% CI, 1.2-229.4) and ε4/ε4 (OR, 7.5; 95% CI, 2.6-21.6). Significant associations with FTD were observed for haplotypes A-C-G-C-C (OR, 5.6; 95% CI, 1.4-21.5) and T-T-T-C-C (OR, 5.2; 95% CI, 1.1-24.0). Significant associations with PPA were also observed for haplotypes A-T-T-T-C (OR, 0.4; 95% CI, 0.2-0.9) and A-T-T-C-C (OR, 5.2; 95% CI, 1.4-19.3)., Conclusion: Although the physiological role of apoE in FTD and PPA needs further investigations, our results suggest an involvement of the APOE gene locus in the genetics of FTD and PPA.

Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimer's disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Previous studies examining the association between the interleukin 6 (IL-6)-174 C/G polymorphism and Alzheimer's disease (AD) have yielded conflicting results. Furthermore, the C allele of the IL-6 variable number of tandem repeats (VNTR) polymorphism was associated with a delayed onset and a decreased risk of AD., Methods: A total sample of 149 AD patients, and 298 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotyped for the apolipoprotein E (APOE) polymorphism, the VNTR polymorphism in the 3' flanking region, and the -174G/C single-nucleotide polymorphism (SNP) in the promoter region of IL-6 gene on chromosome 7. Furthermore, we performed a haplotype analysis on these two polymorphisms on IL-6 locus., Results: IL-6 VNTR and -174G/C allele and genotype frequencies were similar between AD patients and controls, also after stratification for late-onset (> or =65 years) and early-onset (<65 years) or APOE epsilon4 status. Furthermore, there was no evidence of linkage disequilibrium between the VNTR and -174G/C polymorphisms, not supporting a previous reported additive effect of both IL-6 polymorphisms on AD risk., Conclusions: Our findings did not support a role of IL-6-174 G/C and IL-6 VNTR polymorphisms in the risk of sporadic AD in southern Italy, suggesting that these polymorphisms of IL-6 gene were at most weak genetic determinants of AD., (Copyright 2009 Elsevier Inc. All rights reserved.)

The single nucleotide polymorphisms (SNPs) rs449647, rs769446 and rs405509 in the promoter region of the APOE gene have been variously suggested to be epsilon 4-independent risk factors for Alzheimer's disease (AD). A previous Italian study found that the rs449647 was significantly associated with late-onset AD. The aim of this study was to verify whether these APOE promoter SNPs are genetic risk factors for AD and to investigate their interaction with the common APOE polymorphism. A total of 169 clinically diagnosed AD patients and 99 cognitively intact age-matched controls were included in the study. Significant associations with AD independent from sex, age and APOE/epsilon 4 status were found for rs449647 A/A and rs405509 G/G genotypes (positive), and rs449647 A/T and rs405509 T/T genotypes (negative). Haplotype frequency estimation at the APOE locus showed significant associations for the ATG4, ATT4 and ACG3 (positive) and ATT2, ATT3 and TCG3 (negative) haplotypes. Therefore this study confirms the role of the rs449647 A/A genotype as risk factor for AD in Italy and suggests that promoter genotypes and APOE haplotypes might have a complex function in AD-associated genetic risk factors.

The occurrence of psychotic symptoms is common in Alzheimer's disease (AD), configuring a possibly distinguished clinical entity defined "Psychosis in Alzheimer's Disease" (AD-P). In order to investigate demographic clinical and biological variables potentially associated to the occurrence of AD-P, 148 AD patients were selected. Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) scores, socio-economic status and 5-HTTLPR and APOE gene polymorphisms were determined for each subject. AD-P patients were significantly more frequent carriers of the long (L) allele of 5-HTTLPR. The percentage of AD-P increased with the number of copies of the L-allele: 13% among S homozygote; 36% among heterozygotes; 51% among L-homozygotes. No difference resulted between AD-P and non-psychotic AD (AD-NP) in the distribution of the epsilon4 allele of APOE. The risk of AD-P was increased in L/L homozygous (OR = 7.25, p = 0.003) and, to a lesser extent, in heterozygous (OR = 3.91; p = 0.018). Backward logistic regression analysis showed that the risk for AD-P was increased in older subjects (OR = 1.07; p = 0.018) while an increase of MMSE score was protective (OR = 0.90; p = 0.004). The occurrence of AD-P resulted significantly related to age at examination, cognitive status, and to the presence of the 5-HTTLPR L-allele.

Currently available epidemiological evidence suggested that an increase of saturated fatty acids (SFA) could have negative effects on cognitive functions, while increased polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) may be protective against cognitive decline. In a Southern Italian elderly population from the Italian Longitudinal Study on Aging (ILSA), a clear reduction of risk of age-related cognitive decline (ARCD) has been found with elevated intake of PUFA and MUFA. Furthermore, in the ILSA, while dietary fatty acids intakes were not associated with incident mild cognitive impairment (MCI), high PUFA intake appeared to have borderline non-significant trend for a protective effect against the development of MCI. These epidemiological findings on predementia syndromes, i.e. MCI or ARCD, together with a recent randomised controlled trial on a possible effect on cognitive and depressive symptoms of omega-3 PUFA supplementation in patients with very mild AD, suggested a possible role of fatty acids intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia.

Catalase (CAT) -262 C/T promoter (rs1001179), cathepsin D (CTSD) exon 2 (rs17571), and apolipoprotein E (APOE) gene polymorphisms were studied in 242 patients with sporadic Alzheimer's disease (AD) and 421 unrelated age-, sex-, and ethnically matched control subjects from Apulia (Southern Italy). No statistically significant differences in CAT rs1001179 and CTSD rs17571 genotype and allele distribution between AD cases and healthy controls were observed for the whole AD sample, and when AD group was categorized by age at onset in early- and late-onset AD subsets. Furthermore, we did not find any statistically significant differences in rates between CAT rs1001179 and CTSD rs17571 genotypes and AD controlling for APOE e4 allele status. Our data, at present, do not support a role of two gene polymorphisms of the short arm of the chromosome 11, the CAT rs1001179 and CTSD rs17571, as a possible susceptibility factors for sporadic AD.

Background: Drug use increases with advancing age, and in older patients it is associated with an increase in adverse drug reactions (ADRs). ADRs are a primary cause of morbidity and mortality worldwide., Objectives: To evaluate the prevalence, clinical characteristics and avoidability of ADR-related hospital admissions in elderly patients., Methods: From November 2004 to December 2005, all patients aged >or=65 years consecutively admitted to the Geriatric Unit of the Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo in Italy, were evaluated for enrolment in the study. ADRs were defined according to the WHO Adverse Reaction Terminology system. Drugs were classified according to Anatomical Therapeutic Chemical classification system. The Naranjo algorithm was used to evaluate the relationship between drug use and the ADR (definite, probable, possible or doubtful) and Hallas criteria were used to evaluate the avoidability of the ADR (definitely avoidable, possibly avoidable or unavoidable). All cases of a suspected ADR were discussed by a team trained in drug safety, including three geriatricians, one clinical pharmacologist and one pharmacist. Only cases of an ADR with an agreement >or=80% were included., Results: Of the 1756 patients observed, 102 (5.8%, 42 males, 60 females, mean age 76.5 +/- 7.4 years, range 65-93 years) showed certain (6.8%) or probable (91.2%) ADR-related hospitalization. Gastrointestinal disorders (48 patients, 47.1%); platelet, bleeding and clotting disorders (20 patients, 19.6%); and cardiovascular disorders (13 patients, 12.7%) were the most frequent ADRs. NSAIDs (23.5%), oral anticoagulants (20.6%), low-dose aspirin (acetylsalicylic acid) [13.7%] and digoxin (12.7%) were the drugs most frequently involved in ADRs. Of the ADRs, 45.1% were defined as definitely avoidable, 31.4% as possibly avoidable, 18.6% as unavoidable and 4.9% as unclassifiable. Of 78 patients with definitely or possibly avoidable ADRs, 17 patients (21.8%) had received an inappropriate prescription, 29 patients (37.2%) had not received a prescription for an effective gastroprotective drug concomitantly with NSAID or low-dose aspirin treatment and 32 patients (41%) were not monitored during drug treatment., Conclusion: In the elderly, almost 6% of hospitalizations are ADR related. Most of these ADRs are potentially avoidable. Strategies that reduce inappropriate prescriptions and monitoring errors, as well as improving active prevention of ADRs, are needed in elderly subjects.

Multiple osteochondromas (MO), also known as hereditary multiple exostoses (HME), is one of the most common hereditary musculoskeletal diseases in Caucasians (1/50,000) with wide clinical variability and genetic heterogeneity. Two genes have thus far been identified as causing the disease, namely EXT1 and EXT2. Various methods to detect mutations in the EXT genes have been used. Here a cohort of 100 MO patients belonging to unrelated Italian families have been analyzed by single-strand conformation polymorphism (SSCP) analysis or by denaturing high performance liquid chromatography (DHPLC). However, neither of these techniques can detect deletions or duplications of entire exons. Families that were negative at SSCP/DHPLC analysis underwent two-color multiple ligation-dependent probe amplification (MLPA) analysis. By these complementary techniques mutation detection was significantly improved and 26 novel mutations have been revealed as well as 18 previously described mutations to give a total of 44 different mutations. Thus we can conclude that combining MLPA with DHPLC in point-mutations negative MO families, the detection of mutations in EXT genes can significantly improve the identification of both point-mutations and mid-size rearrangements. More important, we were able to characterize all those patients who were negative at the first PCR-based method screening., ((c) 2007 Wiley-Liss, Inc.)

We investigated the association of sex and age with the occurrence of apolipoprotein E (apoE) and angiotensin-converting enzyme (ACE) genotypes in healthy aging and longevity in 1344 healthy individuals and 64 centenarians. As compared to participants younger than 60 years, a significant higher frequency of the apoE/epsilon2 was observed in men aged 60-90 years (p <.001) and in centenarians (p <.001). Logistic regression analysis confirmed this outcome in both participants aged 60-90 years (odds ratio [OR] = 1.897; 95% confidence interval [CI], 1.227-2.931) and centenarians (OR = 3.263; 95% CI, 1.860-5.722). A further significant association of ACE/D allele and age was observed in centenarians (OR = 2.135; 95% CI, 1.253-3.636). Heterosis was also observed at the ACE locus. No relationship between apoE and ACE polymorphism was found. These findings suggest a role of sex in the association of apoE and ACE gene polymorphisms with healthy aging and longevity.

The prevalence of Alzheimer's disease (AD) and AD-related dementias (ADRD) in acute ward-hospitalized elderly patients is not well known, owing principally to misclassification and undercoding of AD and ADRD on hospital discharge abstract forms (DAFs). The aims of this study were to evaluate the prevalence of AD and ADRD, as evaluated by the DAF in elderly patients hospitalized in acute wards, and to compare clinical severity, length of stay, comorbidity, and number of diagnostic procedures in patients with AD versus ADRD to explain the different reimbursement costs of DRG12 (AD) versus DRG429 (ADRD). From the inpatient DAF database of the Casa Sollievo della Sofferenza Hospital, the DAFs of patients aged 65 years or over discharged from January 1, 2001, to March 31, 2003, with principal or secondary diagnoses of AD (ICD9-CM code 331) or ADRD (ICD9-CM codes from 290.0 to 290.43) were extracted and grouped by APR-grouper version 12. Age, gender, length of stay, principal and secondary diagnoses and procedures, and APR-DRG severity index (SI) and mortality risk (MR) were evaluated in these patients. Senile dementia was reported in 294 patients (0.58 percent, N = 50,253). In 123 patients (41.8 percent) dementia was the principal diagnosis, whereas in 171 patients (58.2 percent) dementia was reported on the DAF as a secondary diagnosis. Of the 123 patients with a principal diagnosis of dementia, 35 patients were included in the DRG-12 (AD) and 88 patients were included in the DRG-429 (ADRD). No differences were found in mean age, length of stay, comorbidity, or number of diagnostic procedures, as well as in the APR-DRG SI and APR-DRG MR between AD and ADRD patients. Conversely, reimbursement amounts were established as Euro4,033 for DRG-12 (AD) and Euro2,952 for DRG-429 (ADRD). AD and ADRD are undercoded in elderly hospitalized patients. The limits of the ICD9-CM classification system and the influence of reimbursement amounts may influence the coding reports by physicians.

Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene. The analysis was performed in two genetically and diagnostically distinct groups of sporadic AD from Italy and the USA. In the Italian group a significant association between the IL-1alpha-889 T/T genotype and AD (OR=3.022, 95% CI: 1.001-9.119) was found, whereas no difference was found in the group from the USA. Results were also compared with previously published studies that analyzed the same IL-1 polymorphisms in AD. In both groups, the analysis of the estimated haplotypes shows that AD patients and controls who carry the IL-1beta-511 C allele, were also more frequently carriers of the IL-1Ra 1 allele (haplotypes -C-1). The total frequency of the two -C-1 haplotypes (C-C-1 plus T-C-1) was about one half of the total frequency of the eight estimated haplotypes. This was confirmed by significant linkage disequilibrium between these two loci in both the Italian and USA groups. In the Italian group a weak association of the T-C-2 haplotype with the disease (OR=1.648, 95% CI: 1.519-1.788) was also found, whereas in the USA group no difference was found. Although ours and other published data on different samples of Caucasian and non-Caucasian AD show a great heterogeneity in the frequencies of the IL-1alpha-889, the IL-1beta-511 and the IL-1Ra VNTR gene polymorphisms, we confirm the role of the IL-1alpha-889 T/T genotype as a risk factor for sporadic AD, and show the presence of an allelic association between IL-1beta C and IL-1Ra 1 alleles in both the Italian and the USA groups, confirmed by the presence of significant levels of linkage disequilibrium between these two loci.

Background: The effects of cognitive impairment and comorbidity on the prevalence of disability in elderly patients who are hospitalized in acute wards are not well defined., Objectives: To evaluate the role of comorbidity and cognitive impairment on the prevalence of disability in a cohort of hospitalized older patients., Patients and Methods: This study included 179 patients aged 65 years and over admitted to the Geriatric Unit of the Casa Sollievo della Sofferenza Hospital, in Italy. Cognitive status was evaluated by means of the Mini Mental State Examination (MMSE) and Clinical Dementia Rating Scale (CDR); the functional status was evaluated according to the Activity of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) indices. Comorbidity was identified using the Cumulative Illness Rating Scale (CIRS index)., Results: Of the 179 patients enrolled 73 patients were diagnosed with dementia [Alzheimers' Disease (AD) = 49 patients, Vascular Dementia (VD) = 24 patients], 35 patients with Mild Cognitive Impairment (MCI) and 71 patients had no cognitive impairment. The severity of disability was significantly higher in patients with dementia (ADL = 3.1 +/- 2.1, IADL = 1.5 +/- 2.0) than patients with MCI (ADL = 5.1 +/- 1.4, IADL = 5.2 +/- 2.2) (p < 0.0001) and patients without cognitive impairment (ADL = 5.5 +/- 0.9, IADL = 6.4 +/- 1.9) (p < 0.0001). No significant differences in CIRS index were observed between patients with dementia and MCI and no cognitive impairment patients (Dementia = 2.4 +/- 1.4 vs MCI = 2.9 +/- 1.4 vs No cognitive impairment = 2.7 +/- 1.2; p = 0.1). Moreover, a significant correlation between cognitive impairment and functional status (MMSE/ADL: r = 0.45, p = 0.0001, MMSE/IADL: r = 0.54, p = 0.0001) but not between comorbidity and functional status (CIRS/ADL: r = 0.0007, CIRS/IADL: r = 0.040) was observed. Separating patients with dementia by diagnosis of AD or VD, no significant differences in MMSE (AD = 12.2 +/- 6.7 vs VD = 13.2 +/- 6.5, p = 0.6), CDR (AD = 2.2 +/- 0.8 vs VD = 2.1 +/- 0.7, p = 0.6), ADL (AD = 3.1 +/- 2.1 vs VD = 3.0 +/- 2.1, p = 0.8), IADL (AD = 1.3 +/- 1.9 vs VD = 2.0 +/- 2.2, p = 0.1) or CIRS (AD = 2.2 +/- 1.5 vs VD = 2.8 +/- 1.3, p = 0.06) scores were observed., Conclusions: Cognitive impairment and not comorbidity, was significantly associated with disability in hospitalized older patients.

The association of the STH gene polymorphism with Alzheimer disease (AD) is debated. In the analysis of two genetically and diagnostically distinct groups of Alzheimer patients from the USA and Italy, the authors did not find an association with the STH polymorphism. However, the APOE-4-associated risk of AD greatly increased if the STH-G allele was also present. The STH-G allele appears to be a risk modifier for AD.

The role of methylenetetrahydrofolate reductase (MTHFR) and angiotensin converting enzyme (ACE) gene polymorphisms as risk factors for the occurrence of Alzheimer's disease (AD) is still controversial. In this study, we investigated the common MTHFR C677-->T and ACE insertion/deletion (I/D) gene polymorphisms as risk factors for AD in two genetically and diagnostically distinct cohort of Alzheimer's patients. We analyzed a neuropathologically confirmed American cohort of 124 AD patients and 97 elderly controls, and a clinically diagnosed Italian cohort of 126 probable AD cases, 106 elderly controls, and a community-based sample of 1232 subjects aged under 65 years. No difference was found in polymorphism distribution between cases and controls in both study cohorts. We also tested a possible association between the polymorphisms investigated. No interaction was found between the MTHFR and ACE alleles. Moreover, no association was found for the ACE and MTHFR polymorphisms with age at onset, disease duration and MMSE score at observation. Thus, in our study, MTHFR C677-->T and ACE I/D polymorphisms do not appear to confer an added risk for AD.

Osteochondromas represent the largest group of benign tumors of bone. Multiple osteochondromatosis or hereditary multiple exostoses (EXT) is an autosomal dominant inherited disorder characterized by the presence of multiple benign cartilage-capped exostoses. EXT is genetically heterogeneous with at least 3 chromosomal loci: EXT1 (8q24.1), EXT2 (11p11-p13), and EXT3 (19p). In <5% of EXT patients, the inactivation of both copies of EXT alleles (LOH) is associated with malignant transformation. We have analyzed the EXT1 and EXT2 genes in 9 unrelated EXT families and in a patient with a sporadic osteochondroma, all originating from Italy. Four families show an EXT1 mutation, consisting of a small deletion in 3 of them and a small insertion in the 4th. All these mutations lead to premature termination of translation and thus a truncated EXT1 protein. Three families presented EXT2 mutations consisting of nucleotide substitutions leading to alterations of the third intron splice-site, to an amino acid substitution and to a nonsense mutation. All these mutations cosegregate with the disease phenotype. The sporadic osteochondroma patient carried a novel missense mutation in exon 11 of EXT2 gene, leading to an amino acid substitution. Seven of these mutations have never been described before. EXT2 missense mutations were also confirmed by amino acids conservation between human and mouse and by analysis of a healthy control population. In conclusion, our study provide further evidence that loss of function of the EXT1 or EXT2 gene is the main cause of EXT supporting the putative tumor-suppressor function of these genes., (Copyright 2001 Wiley-Liss, Inc.)

Background and Purpose: The epsilon4 allele of the apolipoprotein E (apoE) has been related to the occurrence of myocardial infarction, but its association with ischemic stroke is controversial. We have evaluated the relation between apoE alleles and the occurrence of cerebrovascular ischemia., Methods: The apoE epsilon genotypes of 100 patients with a documented history of ischemic stroke without clinically apparent dementia (stroke+) and 108 subjects without such history (stroke-) were determined. The relative frequency of the apoE alleles and genotypes was estimated in 398 healthy subjects aged < 40 years from the same ethnic background., Results: The frequency of the apoE epsilon4 allele in stroke+ (0.18 [95% CI, 0.12 to 0.25]) was higher than in stroke- (0.07 [95% CI, 0.03 to 0.12]; P<.001) or in healthy subjects (0.09 [95% CI, 0.07 to 0.12]; P<.001). Carriers of the epsilon4 allele differed between stroke+ (0.30 [95% CI, 0.19 to 0.42]) and stroke- (0.12 [95% CI, 0.5 to 0.22]; P=.004) or healthy subjects (0.16 [95% CI; 0.12 to 0.22]; P=.015). Accordingly, epsilon3/epsilon3 homozygotes were less frequent in stroke+ (0.59 [95% CI, 0.45 to 0.71]) than in stroke- (0.72 [95% CI, 0.59 to 0.82]; P=.063) or in healthy subjects (0.73 [95% CI, 0.67 to 0.78]; P=.01). In a multiple logistic regression analysis, age (P<.03), positive family history (P<.04) and apoE (P<.002) independently contributed to a stroke history, with epsilon4 carriers exhibiting a higher estimated risk (odds ratio, 5.05)., Conclusions: Our data show an association between apoE gene and a personal history of ischemic stroke and support the possibility that the apoE gene is a susceptibility locus for the risk of cerebrovascular ischemic disease.