Stefania Spila-Alegiani

Incidence of Coronary Heart Disease in Type 2 Diabetic Men and Women Impact of microvascular complications, treatment, and geographic location

OBJECTIVE—Cardiovascular disease (CVD) is the main cause of morbidity/mortality in diabetes. We set forth to determine incidence and identify predictors (including microvascular complications and treatment) of first coronary heart disease (CHD) event in CVD-free type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A cohort of 6,032 women and 5,612 men, sampled from a nationwide network of hospital-based diabetes clinics, was followed up for 4 years. Baseline assessment included retinopathy, nephropathy, and foot ulcers. First CHD events (myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, and electrocardiogram-proven angina) were analyzed for 29,069 person-years. RESULTS—The age-standardized incidence rate (per 1,000 person-years) of first CHD event (n = 881) was 28.8 (95% CI 5.4–32.2) in men and 23.3 (20.2–26.4) in women. Major CHD (myocardial infarction, coronary artery bypass grafting, and percutaneous transluminal coronary angioplasty) was less frequent in women (5.8 [4.3–7.2]) than in men (13.1 [10.9–15.4]; a sex ratio of 0.5 [0.4–0.6]). Incidence rates of all outcomes were higher in patients with microvascular complications (for major CHD, age-adjusted rate ratios were 1.6 [1.2–2.21] in men and 1.5 [1.0–2.2] in women). By multivariate Cox analysis, age and diabetes duration were risk predictors common in both sexes. In men, glycemic control and treated hypertension were additional independent risk factors, but residing in the south was associated with a significant 29% risk reduction. In women, higher triglycerides/lower HDL cholesterol and microvascular complications were independent risk factors. CONCLUSIONS—In CVD-free patients with type 2 diabetes, risk of first CHD event depends on sex, geographic location, and presence of microvascular disease. Hyperglycemia and hypertension, particularly in men, and diabetic dyslipidemia, especially in women, are risk factors amenable to more aggressive treatment.

Mortality cancer risk in parkinsonian patients: A population-based study

To the Editor: The recent study by Gorell et al.1 proposes a risk-reducing effect of tobacco smoking on PD because they found, as in a number of prior investigations, an inverse relationship between smoking and PD. Although the authors consider several possible explanations for the rarity of smoking in PD, they do not consider the most likely explanation for this well-known inverse association. Rather than interpret the findings as indicative of a “protective” effect of smoking on development of PD, the correct interpretation may be that PD is “protective” against being a smoker (e.g., see reference 2, which was not cited by the authors but has an almost identical title to that of their work). Thus, despite the pathoetiologic attractiveness of a protective effect of smoking, a likely explanation for the under-representation of smoking among PD patients is that the patients-to-be lose interest in smoking as a very early presymptomatic feature of their neurodegenerative condition.2 It is generally agreed that PD, like many other neurodegenerative conditions, develops over years, and only becomes noticeably symptomatic to afflicted persons and their families somewhere between 3 and 30 years into the neurodegenerative process.3,4 Because of the subtle subcortical mental and motor manifestations, the former of which may best be classified as decreased initiative or a type of bradyphrenia, some have proposed a “personality” predisposing to PD. However, back-extrapolations from clinical and pathologic data, as well as PET neuroimaging data, indicate that pathologic PD must precede symptomatic PD (with classic motor signs of tremor, shuffling gait, and bradykinesia) by some years.3,4 Gorell et al. report useful data regarding the temporal association of smoking cessation and development of PD. These data support an explanation in which early (preclinical) parkinsonism is marked by, inter alia, decreased desire to smoke. Namely, “distant quitters”—those who stopped smoking .20 years before “symptomatic PD”—show little difference in PD prevalence from those who never smoked. But the closer the examined interval to the onset of evident PD, the stronger the correlation with decreased smoking. As can be seen from the data in the authors’ table 1, the relative risk of PD was 1.0 (by definition) for nonsmokers, nearly the same (0.86) for distant quitting, 0.37 for recent quitting, and very much less (0.08) for currently heavy smokers. Reformulated, with some statistical caveats, this shows that for this group of PD patients and matched controls, only 4% of current heavy smokers, 13% of recent quitters, 26% of distant quitters, and 29% of “never smoked” had PD compared with an overall 24% of individuals who had PD. As the authors argue, this gradient could be expected for a protective effect of smoking on PD: namely, longer periods of smoking cause reduced likelihood of PD (although such a large difference in effect between persons smoking ;35 versus ;55 years would be surprising). However, the data are exactly what would be expected for an inhibiting effect of PD on smoking: namely, among those patients with “presymptomatic” PD, closer time frames to the onset of evident motoric symptoms are associated with reduced interest in and likelihood of persistent smoking. Even without such analysis, the social dynamics of tobacco addiction in this cohort5 with median age ;70, who started smoking ;1940 and were studied 1988–1992, are such that it is more plausible that a disease process (namely earliest PD) caused them to stop smoking, rather than postulate that about 90% of the PD patients (unlike others) who smoked just happened to quit their 30to 50-year–long tobacco habits spontaneously in the 1970s and 1980s. Therefore, I believe this well-performed case-control study does not provide strong evidence that smoking is biologically protective of PD, but rather is more consistent with earliest (preclinical) PD decreasing tobacco-smoking behavior.

Estimate of parkinsonism prevalence through drug prescription histories in the Province of Rome, Italy.

Introduction– The objective of the study was to estimate the prevalence of parkinsonism in the Province of Rome using antiparkinsonian prescription histories from 1986 to 1991. Methods– A subject was defined as a case of parkinsonism if he/she had received “specific” and “consistent” antiparkinsonian therapy in the study period. Results– In November 1990, 6,572 patients were defined as prevalent cases of parkinsonism. The crude prevalence ratio, for the total population of the Province of Rome, is 173.5 per 100,000 inhabitants (165.9 per 100,000 in men and 180.5 per 100,000 in women). The method was validated by record‐linkage with clinical records of all patients visited during 1990 at the Department of Neurological Sciences of the University of Rome “La Sapienza”. The sensitivity of the prevalence study was 83.6%. Conclusions– The use of a computerized data base of all prescription data, routinely collected for administrative purposes, enabled us to obtain a prevalence estimate based on a very large population, with low costs and in a relatively short time.

Gangliosides and Guillain-Barré syndrome

Cases of Guillain-Barré syndrome (GBS) associated with parenteral use of gangliosides have been reported in several European countries. To evaluate the hypothesis of association between ganglioside exposure and occurrence of GBS, a case-control study was conducted. GBS cases discharged during 1989 from public and private hospitals in three Italian provinces were identified: 42 GBS cases and 420 controls matched on age and gender were enrolled. Data of onset of symptoms of GBS was taken from clinical records. Exposure status of subjects was ascertained through the regional computerized drug prescription monitoring system. The odds ratio of association between ganglioside use, in the 30 days prior to onset of symptoms, and GBS was 9.1 (95% confidence interval 2.8-29.4). Although there are formidable difficulties in distinguishing prodromal therapy of GBS from drug causation, the association with ganglioside therapy is strong and supportive of the hypothesis of a role of ganglioside preparations in the occurrence of GBS.

Reactogenicity in the elderly of nine commercial influenza vaccines : results from the Italian SVEVA study

A 10-fold increase of reported adverse events following influenza vaccination in the 1995-1996 campaign was reported. To evaluate the relative reactogenicity of different influenza vaccines a prospective observational study was conducted in 72 Italian local health units (LHU) in the period October-December 1996. Of the 16,637 enrolled individuals aged 65 or more, 27.4% reported the occurrence of at least one adverse event within 72 h of vaccination. The odds ratios, adjusted through a multivariate logistic model, were highest for whole vaccine recipients. Most of the observed events were of moderate clinical severity and were mainly represented by local symptoms. None of the products was found to show an unusual or concerning reactogenicity profile, and no severe events associated with immunization were reported.

Mortality in a population-based cohort of patients treated with antiparkinsonian drugs

Objectives ‐ A number of studies have been focused on the mortality of parkinsonian patients, as compared with the rest of the population. In these studies, a mortality greater than expected on the basis of mortality of the general population has been shown. Nevertheless, just a few of these studies have investigated in detail the specific causes of death, probably as a consequence of both small cohort sizes and a short time period of observation. The aim of this study was to estimate cause‐specific mortality in a cohort of patients treated with antiparkinsonian drugs. Methods ‐ The study was performed on a wide population‐based cohort of patients identified and followed‐up through the computerized health databases of the Italian province of Rome (about 3,800,000 inhabitants). The follow‐up lasted from January 1987 to December 1994. Standardized Mortality Ratios (SMR) were calculated for each specific cause of death, using the Rome province population as reference. Results ‐ A cohort of 10,322 subjects, receiving antiparkinsonian drugs, were identified. There were 4328 deaths on an average follow‐up of 5.7 years. This figure was 17% higher than was expected. A gradual decrease in SMR was observed in the oldest age groups. Statistically significant (95%) excesses of death were related to the nervous system (SMR=1037; 95% CI 964–1110), mental disorders (SMR=182; 95% CI 129–246), and endocrine and metabolic diseases (SMR=117; 95% CI 102–133). Lower than expected mortality was found to be caused by malignant neoplasms (SMR=56; 95% CI 51–61). Conclusions ‐ Apart from deaths specifically related to Parkinsons disease, the main differences between our cohort of patients and the general population were related to mortality due to malignant neoplasms and mental disorders. The gradual decrease in SMR for the oldest age groups, seems to indicate a greater reduction of life expectancy for patients with early onset of symptoms. This age‐related trend could explain the relatively small excess of mortality, as in our cohort the median age of patients at entry was 74 years.

Sudden unexpected deaths and vaccinations during the first two years of life in Italy: a case series study.

Background The signal of an association between vaccination in the second year of life with a hexavalent vaccine and sudden unexpected deaths (SUD) in the two days following vaccination was reported in Germany in 2003. A study to establish whether the immunisation with hexavalent vaccines increased the short term risk of SUD in infants was conducted in Italy. Methodology/Principal Findings The reference population comprises around 3 million infants vaccinated in Italy in the study period 1999–2004 (1.5 million received hexavalent vaccines). Events of SUD in infants aged 1–23 months were identified through the death certificates. Vaccination history was retrieved from immunisation registries. Association between immunisation and death was assessed adopting a case series design focusing on the risk periods 0–1, 0–7, and 0–14 days after immunisation. Among the 604 infants who died of SUD, 244 (40%) had received at least one vaccination. Four deaths occurred within two days from vaccination with the hexavalent vaccines (RR = 1.5; 95% CI 0.6 to 4.2). The RRs for the risk periods 0–7 and 0–14 were 2.0 (95% CI 1.2 to 3.5) and 1.5 (95% CI 0.9 to 2.4). The increased risk was limited to the first dose (RR = 2.2; 95% CI 1.1 to 4.4), whereas no increase was observed for the second and third doses combined. Conclusions The RRs of SUD for any vaccines and any risk periods, even when greater than 1, were almost an order of magnitude lower than the estimates in Germany. The limited increase in RRs found in Italy appears confined to the first dose and may be partly explained by a residual uncontrolled confounding effect of age.

The Unconventional Di Bella Cancer Treatment. A Reflection on the Italian Experience

Supported by a specific act of the Italian Parliament.The committees and members of the Italian StudyGroup for the Di Bella Multitherapy Trials are asfollows. Research Coordinating Center: D. Greco,R. Raschetti, B. Caffari, F. Chiarotti, R. Da Cas, B.De Mei, G. Di Giovambattista, M. Maggini, F. Men-niti-Ippolito, S. Modigliani, P. Popoli, P. Ruggeri, S.Spila-Alegiani, C. Tomino, G. Traversa, P. Bruzzi, T.Gamucci. Steering Committee: G. Benagiano, D.Amadori, P. Bruzzi, E. Buiatti, E. Ciranni, F. Cog-netti, G. Colucci, P.F. Conte, G. Di Bella*, D. Greco,S. Iacobelli, F. Mandelli, E. Marubini, M. Massotti,S. Monfardini, F. Oleari, R. Raschetti, G. L. San-nazzari, L. Tomatis, U. Veronesi. (*Dr. G. Di Bella,the son of Dr. L. Di Bella, only participated in thefirst two meetings of the Steering Committee. Onmany occasions, he strongly disagreed with theperformance and results of the trials. No part ofthe current article has been discussed with orendorsed by Dr. G. Di Bella.) International ReviewBoard: P. Calabresi (Rhode Island), F. Cavalli (Bell-inzona, Switzerland), P. Kleihues (Lyon Cedex,France), J.G. Mc Vie (London, UK), H. Pinedo (Am-sterdam, The Netherlands), K. Sikora (Lyon Cedex,France), T. Tursz (Villejuif Cedex, France). Indepen-dent Endpoint Evaluation Committee: A. R. Bianco,R. Labianca, P. L. Rossi Ferrini, G. Simonetti, A.Sobrero. Investigators: Ancona—R. Cellerino, S.Antognoli, R. Berardi, R. Bracci, P. Lippe, F. Pulita;Aosta—F. Di Vito, D. Martinod, M. Musi; Avi-ano—A. Veronesi, R. Lazzarini; Bari—G. Colucci(Principal Investigator [PI]), V. Attolico, F. Giotta, M.Longo, E. Maiello; Bologna—S. Tura, F. Gherlin-zoni, M. Tani; Bolzano—H. Amor, P. Borona, F.Girardi, C. Graiff; Cagliari—G. Broccia, M. G. Co-rona, A. Desogus, V. Mascia, S. Pasqualucci; Ca-tania—G. Failla, M. R. Aiello, S. Cordio, P. Finoc-chiaro. Chieti—S. Iacobelli (PI), E. Melena, M. DeTursi, M. T. Scognamiglio, N. Tinari; Forli`—D.Amadori (PI), M. Maltoni, O. Nanni, F. Scardovi, P.Serra; Genoa—R. Rosso, F. Boccardo, A. Barp, T.Coli, M. Grimaldi; Milan—N. Cascinelli, L. Ascani,E. Bajetta, P. Bidoli, A. Cassata, D. De Candis, W.Giannessi, G. Procopio; Milan—S. Di Donato, A.Boiardi, D. Cerri, M. Eoli, A. Silvani; Milan—U.Veronesi (PI), M. Colleoni, N. Rotmensz; Na-ples—S. Monfardini (PI), G. Comella, A. De Mat-teis, A. Gravina, C. Gridelli, F. Perrone, M. R.Salzano, C. Sandomenico; Naples—C. Battista, G.Iodice, R. Fico, A. Nicchia; Padua—M. Lise, G. L.De Salvo, E. Di Lenardo, G. Iadicicco; Palermo—B.Agostara, I. Cafarelli; Perugia—M. Tonato, F.Radicchi, S. Sorbolini, O. Taschini; Pisa—P. F.Conte (PI), A. Carmignani, L. Del Mastro, A. Gen-nari, C. Orlandini; Potenza—L. Manzione, A. Di-nota, G. Lombardi; Reggio Calabria—G. Gasparini,M. G. Arena, M. Fanelli, F. Modafferi, A. Morabito;Rome—F. Mandelli (PI), P. Fazi, F. Mauro, M.Martelli, C. Ricci, M. Vignetti; Rome—F. Cognetti(PI), A. D’Alessio, S. De Marco, V. Ferraresi, T.Gamucci, D. Giannarelli, E. Magnani, P. Rellecati,E. M. Ruggeri, M. Zeuli; Turin—G. L. Sannazzari(PI), M. Borgognone, R. Chio`, A. Gasco, R. Ragona,M. Sacco, R. Soffietti, R. Verna, M. Tessa;Turin—A. Pileri; Trento—E. Galligioni, A. Lucenti,F. Moltrer, F. Paolazzi.The authors thank the Stabilimento ChimicoFarmaceutico Militare, Florence, Italy (Colonel G.Muzzi, Director), for the production of the melato-nin tablets and retinoid solution and the Group forthe supervision and control of custom-made drugsof the Istituto Superiore di Sanita`, Roma (E. Cir-anni, Director; R. Alimenti, S. Alimonti, G. Cavaz-zutti, L. Gagliardi, B. Gallinella, G. Incarnato, F. LaTorre, A. Mosca, G. Multari, L. Turchetto, L. Valvo).Address for reprints: Giuseppe Traversa, M.D., De-partment of Epidemiology and Biostatistics, IstitutoSuperiore di Sanita`, Viale Regina Elena 299, 00161Rome, Italy.Received April 26, 1999; revision received July 22,1999; accepted July 29, 1999.

Anticholinergic antiparkinsonian therapy in outpatients treated with neuroleptic drugs: a prescription survey.

Extrapyramidal adverse effects (EPAs) due to neuroleptic treatment are routinely treated with anticholinergic antiparkinsonian drugs (APDs). We studied the use of these drugs in the general population exposed to neuroleptic drugs to improve our knowledge of the epidemiology of EPAs.We selected all the neuroleptic and antiparkinsonian drug prescriptions delivered in the province of Rome (ca. 3 750 000 inhabitants) from 1986 to 1989. During the study period, 10.6% of neuroleptic-treated subjects were concurrently prescribed anticholinergic antiparkinsonian drugs. The influence of different factors on APD prescriptions was evaluated through a logistic regression model. The highest probability of receiving APDs was associated with trifluperidol treatment (odds ratio=5.0, using chlorpromazine as baseline); among the commonly prescribed neuroleptics, sulpiride, levosulpiride and tiapride chlorydrate had the lowest probability of coprescription with APDs (odds ratios less than 0.1). The probability of being prescribed anticholinergic antiparkinsonian drugs decreased with age and increased with the amount of neuroleptics prescribed.This study surveys a very large sample using a population-based approach, whereas the same topics have previously only been studied in limited inpatient populations.

Cardiovascular safety of tiotropium Respimat vs HandiHaler in the routine clinical practice: A population-based cohort study

The cardiovascular safety of tiotropium Respimat formulation in the routine clinical practice is still an open issue. Our aim was to compare the risk of acute myocardial infarction and heart rhythm disorders in incident users of either tiotropium Respimat or HandiHaler. The study population comprises patients aged ≥45 years, resident in two Italian regions with a first prescription of tiotropium (HandiHaler or Respimat) between 01/07/2011-30/11/2013. The cohort was identified through the database of prescriptions reimbursed by the Italian National Health Service. Comorbidities and clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for acute myocardial infarction and/or for heart rhythm disorders during the exposure period. Hazard ratios were estimated in the propensity score-matched groups through Cox regression. After matching, 31,334 patients with incident prescription of tiotropium were included. The two groups were balanced with regard to baseline characteristics. Similar incidence rates of the primary outcome between Respimat and HandiHaler users were identified (adjusted hazard ratio 1.02, 95% CI 0.82–1.28). No risk difference between Respimat and HandiHaler emerged when considering clinical events separately. This large cohort study showed a comparable acute cardiovascular safety profile of the two tiotropium formulations.