Cognitive functioning and survival in the elderly: the SSADH C538T polymorphism.

The variability of the Succinic Semialdehyde Dehydrogenase (SSADH, or ALDH5A1) gene affects both pathological and normal phenotypes correlated to cognitive function. We tested the association between the C538T polymorphism of the SSADH gene and preservation of cognitive function in the elderly, and its possible effects on survival. A sample from southern Italy (514 subjects; 18-107 years) was screened for C538T variability. We found that, within the 65-85 years age range, the T/T genotype is overrepresented in subjects with impaired cognitive function (MMSE < or = 23) compared to those with conserved cognitive function (MMSE > 23). Furthermore, we found that the T/T genotype affects survival after 65 years of age. In fact, after this age, the survival function of T/T homozygous subjects is lower than that of the others. Given that the enzymatic activity of the protein encoded by allele T is 82.5% of the activity of the protein encoded by allele C, our results suggest that the efficiency of the SSADH enzyme is important for the preservation of cognitive function and survival in the elderly.

A cluster analysis to define human aging phenotypes.

The definition of a precise and consistent aging phenotype that allows to measure the physical and cognitive decline, as well as the increase of mortality hazard late in life, is a major problem for studies aimed at finding the genetic factors modulating rate and quality of human aging. In this frame, it seems promising the concept of frailty which tends to figure out the subjects who are more vulnerable and more prone to negative outcomes, such as death or hospitalization. Cognitive, functional and psychological measures turned out to be the most effective measures to define frailty, as they condense most of the frailty cycle that occurs in the elderly and is probably responsible of the aging related physical decline. We used MMSE, Hand Grip strength, and GDS as variable parameters in a hierarchical Cluster Analysis (CA) in order to recognise aging phenotypes. By using a sample of 65-85 years old subjects we identified three frailty phenotypes that were consistent from both geriatric and genetic perspectives. Therefore, the method we propose may provide unbiased phenotypes suitable for the identification of genetic variants affecting the quality of aging in this age range. The CA method was less effective in ultranonagenarians, probably due to the high prevalence of frail subjects in this age group that makes difficult to distinguish discrete phenotypes.

Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly.

The human sirtuin 3 (SIRT3) gene encodes a putative mitochondrial NAD-dependent deacetylase (SIRT3) which belongs to the evolutionary conserved family of sirtuin 2 proteins. Studies in model organisms have demonstrated that SIR2 genes control lifespan, while no data are available regarding a possible role of SIRT3 in human longevity. By analysing the genotype-specific survival function relevant to the G477T marker of SIRT3, we found that in males the TT genotype increases (p=0.0272), while the GT genotype decreases (p=0.0391) survival in the elderly. Since SIRT3 lies in a chromosomal region (11p15.5) where four genes potentially associated with longevity are located (HRAS1, Insulin-like Growth Factor 2, Proinsulin, and Tyrosine Hydroxylase) we tested for linkage-disequilibrium between G477T alleles and alleles of the above genes. The disequilibrium was not significant in any case, thus suggesting that SIRT3 itself, or a gene strictly linked to SIRT3, may have a role in human longevity.

The allele (A)(-110) in the promoter region of the HSP70-1 gene is unfavorable to longevity in women.

Heat shock proteins (HSPs) are crucial for maintenance of cell homeostasis and survival both during and after various stresses. The capability to cope with stress is believed to affect the chance of health and survival at organismal level. We have investigated whether the gene pool relevant to the (A/C)(-110) polymorphism in the promoter region of the HSP70-1 gene changes as the population ages and survival selection occurs. A total of 591 southern Italian subjects were enrolled in the study (263 males and 328 females; age range 18-109 years), free of clinically manifest diseases and with normal haemato-chemical parameters. A significant age-related decrease of the frequency of allele (A)(-110) was observed in females. The probability ratio of 0.403 (95% confidence interval [0.163, 0.910]) computed by considering female centenarians as cases and young women (18-49 years old) as controls showed that the (A)(-110) allele is unfavorable to longevity in females.

The study of APOA1, APOC3 and APOA4 variability in healthy ageing people reveals another paradox in the oldest old subjects.

The genes coding for apolipoprotein A1 (APOA1), apolipoprotein C3 (APOC3) and apolipoprotein A4 (APOA4) are tandemly organised within a short region on chromosome 11q23-q24. Polymorphisms of these genes have been extensively investigated in lipoprotein disorders and cardiovascular diseases, but poorly investigated in healthy ageing. The aim of this study was to describe possible modifications of the APOA1, APOC3, and APOA4 gene pool by cross-sectional studies carried out in a healthy ageing population whose ages ranged from 18 to 109 years (800 subjects, 327 males and 473 females, free of clinically manifested disease, and with emato-chemical parameters in the norm). APOA1-MspI-RFLP (-75 nt from the transcription starting site), APOC3-SstI-RFLP (3'UTR, 3238 nt), and APOA4-HincII-RFLP (Asp127/Ser127) were analysed according to age and sex. A significant age-related variation of the APOA1 gene pool was observed in males. An analysis of the allele average effect exerted by APOA1-MspI-RFLP A/P alleles (Absence/Presence of the restriction site) on lipidemic parameters in 46-80 year old males showed that allele A decreased, while allele P significantly increased, serum LDL-cholesterol. Unexpectedly, the P allele was over-represented in the group of the oldest old subjects, thus giving evidence of another "genetic paradox of centenarians".

Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease.

Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction between APOE polymorphism and mtDNA inherited variability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplogroups is different between epsilon4 carriers and non-carriers (P=0.018), thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 allele, lowering the epsilon4 odds ratio from statistically significant to non-significant values.

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.

Indications and limits of the exercise test in chronic heart failure.

Assessment of exercise capacity has been widely used in the evaluation of chronic heart failure (CHF), both to define the severity of the syndrome and to assess the changes induced by therapy. Various exercise tests and protocols can be used. The simple stress test using the exercise bicycle or the treadmill can give useful indications only in patients with severe or lower functional reductions. Maximum exercise duration usually depends on the patient's and the physician's motivation. The addition of respiratory gas exchange measurements, maximum oxygen consumption (VO(2)) or anaerobic threshold, increases the exactness of the assessment of the exercise limitation in CHF. VO(2) maximum provides an objective marker of aerobic capacity and it is biased by neither the patient nor the physician. This technique, however, requires the patient to exercise to exhaustion, and it is somewhat subjective and not indicative of normal daily exercise routine. The anaerobic threshold is a useful way of evaluating adaptability to submaximal efforts and the impact of the therapy on the daily performance. Nevertheless, it is significantly influenced by the fitness level and it has a reduced prognostic capability compared to VO(2) maximum. Submaximal exercise tests discriminate particularly between patients with severe CHF. The major limits are the influence of the patient's motivation and its limited validation in terms of reproducibility and prediction in controlled surveys.

The cardiogenic syncope in the elderly: a review on the epidemiology and social costs.

Although syncope is a common clinical problem in the elderly, little is known of its epidemiology and social costs. According to some epidemiological enquiries, syncope is responsible for 3% of emergency room visits and for 6% of the medical admissions in general hospitals. Although some types of syncope are benign and self-limited, those of traumatic origin with abrupt loss of consciousness represent a considerable morbidity, particularly in elderly patients. The prevalence in 10 years was of 23%, with an annual occurrence of 6-7% and a recurrence rate of 30%. Despite accurate investigations, syncope remains unexplained in about 50% of the patients. The first year mortality for cardiac syncope is 20-30%, against 5% for non-cardiac causes and 10% for syncope of unknown origin. Sudden death occurred in 17% of cardiac syncope cases. An approximate cost analysis can be obtained through the survey of costs relative to the length of the hospitalization and to the number of the main diagnostic tests applied. It must be underlined, however, that the clinical history and physical examination supply the most important contribution to the diagnosis in old patients, and these often are more than sufficient to suggest the suitable choice among the instrumental tests to be applied; this approach helps considerably to reduce the hospital costs.

Middle term evaluation of amlodipine vs nitrendipine: efficacy, safety and metabolic effects in elderly hypertensive patients.

The aim of the study was to evaluate, in a population of elderly hypertensives, the efficacy for 24 hours, the safety and the effects on carbohydrates and lipids metabolism of amlodipine (A) and nitrendipine (N). After a 3-week placebo wash-out, 50 patients with mild to moderate essential hypertension (HBP) or isolated systolic hypertension (ISH), were randomized in 4 groups treated with once-daily A 5,10mg or N 10,20mg increasing until patients responded to treatment. All subjects were submitted to a 24-hour non invasive ambulatory blood pressure monitoring (ABPM) at the start of the study (t0) and after four weeks of therapy (t4). It was registered a mean daily reduction in the pressure load of 15.0% in group A, 14.1% in group B, 13.9% in group C and 15.6% in group D; (p < 0.001). 82% of the patients treated with A and 85% treated with N resulted "responder". The metabolic parameters considered showed no significant changes. The overall incidence of adverse effects were temporary and extremely limited (2%). As monotherapies, amlodipine and nitrendipine are both suitable for the management of mild to moderate hypertension in elderly.

[Spontaneous development and prognostic factors in patients needing heart transplantation. Multivariate analysis of 171 patients]. / Evolution spontanée et facteurs pronostiques chez les candidats à la transplantation cardiaque. Analyse multivariée chez 171 patients.

In an attempt to determine predictive factors of spontaneous death in patients needing heart transplantation, we studied 27 clinical and paraclinical variables in 171 patients aged from 14 to 61 years. Sixty-one of these patients died before transplantation could be performed, 59 were still alive awaiting transplantation and 51 received a heart transplant. The actuarial survival rate with or without transplantation was 65 percent at 1 year and 51 percent at 2 years. Univariate analysis showed that the following factors were associated with a higher mortality rate: age, history or symptoms of right heart failure, poor general condition, end-diastolic left ventricular diameter and ejection fraction. There was no correlation between high mortality rate and type of heart disease, sex, duration of symptoms, NYHA functional class, cardiothoracic ratio and data obtained from electrocardiography and right heart catheterization. At multivariate analysis (Cox's model), no variable could be selected as predictive factor of mortality. The natural outcome of patients needing heart transplantation therefore is globally unfavourable. This means that once has been decided to perform heart transplantation the operation should not be delayed.

[Effects of diltiazem in supraventricular paroxysmal tachyarrhythmias]. / Effetti del diltiazem nelle tachiaritmie parossistiche sopraventricolari.

Diltiazem (0.3 mg/kg body weight intravenous in 2 minutes) was administered to 40 patients (24 males, 16 females, mean age 51.55 years) with paroxysmal supraventricular tachyarrhythmias: 7 patients with atrial fibrillation, 6 patients with atrial flutter, 25 patients with paroxysmal supraventricular tachycardia, 2 patients with uncommon atrioventricular reciprocating tachycardia. In patients with atrial fibrillation intravenous diltiazem produced a significant decrease of ventricular response (from 160 +/- 11 to 113.57 +/- 10.34--p less than 0.01). In patients with atrial flutter intravenous diltiazem produced variable effects: an increase in atrio-ventricular block (from 2:1 to 3:1 atrio-ventricular conduction (2 patients); conversion to sinus rhythm (1 patient); change to atrial fibrillation (1 patient); no appreciable change of the basic rhythm (2 patients). In paroxysmal supraventricular tachycardia patients conversion to sinus rhythm occurred in 20/22 patients (91%) treated with intravenous diltiazem (mean conversion time 4.69 minutes). In the 2 patients with uncommon atrioventricular nodal reciprocating tachycardia diltiazem increased P'-R and R-P' intervals without appreciable change of the basic rhythm. No serious side effects from drug administration were noted. Intravenous diltiazem appears to be as a highly effective medication in conversion or control of paroxysmal supraventricular tachyarrhythmias.

[An experience with a mobile coronary care unit: from a study project to a permanent community service (author's transl)]. / L'unità coronarica mobile dell'Ospedale Regionale di Udine. Da progetto di studio a servizio permanente.

Mobile coronary care units and stratified systems for coronary care have received rather poor attention in Italy up until now. To evaluate advantages and disadvantages, organizational problems, costs, etc. of a mobile unit in an Italian community provided with a reference centre for acute coronary artery disease, a study project was started in 1977. The organization of such unit was based on that of the hospital in Belfast. The covered area (200,000 inhatitants) was carefully limited to keep delays at a minimum. A program of public education, stressing the necessity for early calls for medical intervention was developed. All calls were evaluated by a physician on duty in the CCU before intervention. The results of this experience, extended to four years, are reported showing that a Mobile Coronary Care Unit is valuable from a medical point of view, is economically sound and practical in a medium size Italian city such as Udine. According to this, the Mobile Coronary Care Unit was changed from a study project to a permanent community service.

[Usefulness of multicenter evaluation of the reliability of a program for automatic analysis in clinical electrocardiography]. / Utilità della valutazione policentrica dell'affidabilità di un programma per l'analisi automatica in elettrocardiografia clinica.

The HP-5 program for computer analysis of the ECG has been evaluated as far as sensibility and specificity in a multicenter study. A consistent number of tracings were sampled according to a statistical formula and all measurements and statements given by the computer were checked in a standardized manner. The collected data were classified and computerized. The HP-5 program has shown a very high specificity for tracings classified as normal (0.7% of false negatives) and for those classified abnormal (no false positive), while the level of agreement between manual and computer readings of the tracings classified atypical or borderline, was fair (75%). It is concluded that the new program represents a significant step forward in the practical use of computerized ECG.