Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies

The exact mechanisms leading to Alzheimer's disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of Aβ. The most innovative of the pharmacological approaches was the stimulation of Aβ clearance from the brain of AD patients via the administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive vaccination). Several active and passive anti-Aβ vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate Aβ and an immune adjuvant, QS-21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4 carriers), has raised concerns on the safety of these antibodies directed against the N-terminus of the Aβ peptide. Solanezumab, a humanized anti-Aβ monoclonal antibody directed against the midregion of the Aβ peptide, was shown to neutralize soluble Aβ species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III trials with bapineuzumab and solanezumab will tell us if monoclonal anti-Aβ antibodies may slow down the rate of deterioration of AD. Based on the new diagnostic criteria of AD and on recent major failures of anti-Aβ drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of AD.     

Evaluation of tropical water sources and mollusks in southern Brazil using microbiological, biochemical, and chemical parameters

Florianópolis, a city located in the Santa Catarina State in southern Brazil, is the national leading producer of bivalve mollusks. The quality of bivalve mollusks is closely related to the sanitary conditions of surrounding waters where they are cultivated. Presently, cultivation areas receive large amounts of effluents derived mainly from treated and non-treated domestic, rural, and urban sewage. This contributes to the contamination of mollusks with trace metals, pesticides, other organic compounds, and human pathogens such as viruses, bacteria, and protozoan. The aim of this study was to perform a thorough diagnosis of the shellfish growing areas in Florianópolis, on the coast of Santa Catarina. The contamination levels of seawater, sediments, and oysters were evaluated for their microbiological, biochemical, and chemical parameters at five sea sites in Florianópolis, namely three regular oyster cultivation areas (Sites 1, 2, and oyster supplier), a polluted site (Site 3), and a heavily polluted site (Site 4). Samples were evaluated at day zero and after 14 days. Seawater and sediment samples were collected just once, at the end of the experiment. Antioxidant defenses, which may occur in contaminated environments in response to the increased production of reactive oxygen species (ROS) by organisms, were analyzed in oysters, as well as organic compounds (in oysters and sediment samples) and microbiological contamination (in oysters and seawater samples). The results showed the presence of the following contaminants: fecal coliforms in seawater samples (four sites), human adenovirus (all sites), human noroviruses GI and GII (two sites), Hepatitis A viruses (one site), JC Polyomavirus in an oyster sample from the oyster supplier, Giardia duodenalis cysts, and Cryptosporidium sp oocysts (one site). Among organochlorine pesticides, only DDT (dichlorodiphenyltrichloroethane) and HCH (hexachlorocyclohexane) were detected in some sediment and oysters samples in very low levels; site 4 had the highest concentrations of total aliphatic hydrocarbons, PAHs, and linear alkylbenzenes (LABs) found either in oysters or in sediment samples. The major concentration of fecal sterol coprostanol was found at site 4, followed by site 3. After 14 days of allocation in the four selected sites, there was a significant difference in the enzymes analyzed at the monitored spots. The detection of different contaminants in oysters, seawater, and sediment samples in the present study shows the impact untreated or inadequately treated effluents have on coastal areas. These results highlight the need for public investment in adequate wastewater treatment and adequate treatment of oysters, ensuring safe areas for shellfish production as well as healthier bivalve mollusks for consumption.     

The global cardiovascular risk chart]

BACKGROUND: Risk charts, built through risk functions deriving from longitudinal studies, are used in order to identify individuals at high risk for cardiovascular disease. For this reason the function has been identified and the global cardiovascular risk chart of the CUORE Project has been prepared, using Italian data coming from different cohorts enrolled between the '80s and the '90s, whose risk factors had been collected by standardized procedures. METHODS: The following risk factors have been used: age (10-year period, 40-49, 50-59, 60-69 years), gender (men and women), systolic blood pressure (< or = 129, 130-149, 150-169, > or = 170 mmHg), serum cholesterol (< or = 173, 174-212, 213-251, 252-290, > or = 291 mg/dl), smoking habit (yes, no) and presence of diabetes (yes, no); the first coronary or cerebrovascular event in people aged 40-69 years with no other previous cardiovascular events was considered as endpoint; survival has been assessed up to December 1998. RESULTS: Out of 18,028 people aged 40-69 years with no previous cardiovascular events, 647 first major cardiovascular events have been identified and validated, 449 coronary and 198 cerebrovascular. Charts are divided according to men and women and to diabetics and non-diabetics respectively; the different colors represent the percent level of risk and go from light green (< 5% in 10 years for men, < 1% in 5 years for women), dark green (between 5 and 10% for men, between 1 and 3% for women), yellow (between 10 and 15% for men, between 3 and 5% for women), orange (between 15 and 20% for men, between 5 and 7% for women), red (between 20 and 30% for men, between 7 and 10% for women), violet (> 30% for men, > 10% for women). CONCLUSIONS: The risk charts were built with data collected in recent years on men and women with a median follow-up of 10 years for men and 5 years for women, considering the first major fatal or non-fatal cardiovascular event as endpoint. Such a tool is easy to be applied by general practitioners and cardiologists in order to achieve a fast and objective evaluation of global cardiovascular risk.     

Development and validation of a multidimensional prognostic index for one-year mortality from comprehensive geriatric assessment in hospitalized older patients

Our objective was to construct and validate a Multidimensional Prognostic Index (MPI) for 1-year mortality from a Comprehensive Geriatric Assessment (CGA) routinely carried out in elderly patients in a geriatric acute ward. The CGA included clinical, cognitive, functional, nutritional, and social parameters and was carried out using six standardized scales and information on medications and social support network, for a total of 63 items in eight domains. A MPI was developed from CGA data by aggregating the total scores of the eight domains and expressing it as a score from 0 to 1. Three grades of MPI were identified: low risk, 0.0-0.33; moderate risk, 0.34-0.66; and severe risk, 0.67-1.0. Using the proportional hazard models, we studied the predictive value of the MPI for all causes of mortality over a 12-month follow-up period. MPI was then validated in a different cohort of consecutively hospitalized patients. The development cohort included 838 and the validation cohort 857 elderly hospitalized patients. Of the patients in the two cohorts, 53.3 and 54.9% were classified in the low-risk group, respectively (MPI mean value, 0.18 +/- 0.09 and 0.18 +/- 0.09); 31.2 and 30.6% in the moderate-risk group (0.48 +/- 0.09 and 0.49 +/- 0.09); 15.4 and 14.2% in the severe-risk group (0.77 +/- 0.08 and 0.75 +/- 0.07). In both cohorts, higher MPI scores were significantly associated with older age (p = 0.0001), female sex (p = 0.0001), lower educational level (p = 0.0001), and higher mortality (p = 0.0001). In both cohorts, a close agreement was found between the estimated mortality and the observed mortality after both 6 months and 1 year of follow-up. The discrimination of the MPI was also good, with a ROC area of 0.751 (95%CI, 0.70-0.80) at 6 months and 0.751 (95%CI, 0.71-0.80) at 1 year of follow-up. We conclude that this MPI, calculated from information collected in a standardized CGA, accurately stratifies hospitalized elderly patients into groups at varying risk of mortality.     

Natural Course of Functional Dyspepsia After <Emphasis Type="Italic">Helicobacter pylori</Emphasis>Eradication: A Seven-Year Survey

The role of Helicobacter pylori(Hp) in functional dyspepsia (FD) is controversial and previously published data do not help to clarify whether Hp eradication affects the natural course of FD. The aim of this study was to assess the clinical course of FD during a long follow-up period of 7 years in a homogeneous sample of Hp-eradicated patients. Among patients referred between 1991 and 1996, patients with FD and infected with Hp were enrolled. Patients were administered a structured symptom questionnaire and evaluated after Hp eradication at each 12-month time points. Patients were divided into three FD subgroups: predominantly ulcer-like, dismotility-like, and reflux-like symptom clusters. A composite symptom score ranging from 0 (no symptom) to 3 (severe symptoms) was assigned to each FD cluster. Of the 1685 screened patients, 405 had FD and 211 of them (52.1%) were also Hp-positive. During the follow-up, the amount of missing information varied from 10% to 17.5% within the first 6 years and was 30.8% at 7 years. The rates of improved patients ranged from 33% (reflux-like) to 34.9% (dismotility-like) to 47.3% (ulcer-like). However, only a proportion of 10%–50% of them was symptom-free after eradication and also at each 12-month evaluation, whereas the other patients became symptomatic at different times. FD symptoms slightly improve after Hp eradication over a long period of time but a large percentage of these improved patients may experience FD symptoms again, even after some years of well-being after Hp eradication. This study was not supported by any pharmaceutical company, government agency, or other grants: under the auspices of Roberto Farini Foundation for Gastroenterological Research. The data were analyzed by G. Leandro, MD. Preliminary versions of this paper were presented in abstract form at the 16th International Workshop of Gastrointestinal Pathology and Helicobacter, September 3–6, 2003, Stockholm Sweden; the 11th United European Gastroenterology Week, November 1–5, 2003, Madrid, Spain; the 10th National Congress on Digestive Diseases, March 27–31, 2004, Torino, Italy; and Digestive Disease Week, May 15–20, 2004, New Orleans, Louisiana, USA.     

Diabetes in Italy: a public health problem]

BACKGROUND: Type 2 diabetes is the most frequent form of diabetes in the adult population and is associated with an increasing risk of cardiovascular diseases. The objective of this study was to describe the prevalence and the state of control in an Italian population sample examined within the Osservatorio Epidemiologico Cardiovascolare study. METHODS: The sample of this study consisted in 8972 subjects, men and women aged 35-74 years. A fasting capillary blood glucose > or = 126 mg/dl or being on antidiabetic treatment were the criteria used to define diabetes, while a fasting capillary blood glucose < 140 mg/dl was considered to represent effective treatment (controlled diabetes) in treated patients. RESULTS: Diabetes was present in 8.4% of men and 6% in women. The prevalence of glucose intolerance was 8.2% in men and 4.3% in women. Only 50.7% of diabetic men and 56.5% of diabetic women knew about their disease; among these people, 21% was on treatment with oral antidiabetics and/or insulin. Such a therapy was effective in 39.5% of the treated cases. CONCLUSIONS: The prevalence of diabetes as well as glucose intolerance was greater in men and in the regions of the Center and South of Italy. The state of control of diabetes cannot be considered satisfactory; women and older age groups, when prevention strategies are less important, appear to be under better care.     

Enteroviral infection causing fatal myocarditis and subclinical myopathy

Enteroviral RNA detection in myocarditis and dilated cardiomyopathy is rare. Enteroviral particles and RNA have recently been identified in patient's skeletal muscle, suggesting that skeletal more than heart muscle hosts the virus in chronic infection. Enteroviral RNA and virus-like particles were found in the myocardium and in the skeletal muscle of two patients with fatal myocarditis: a 39 year old man who died five days after the onset of febrile flu; and a 49 year old woman, assisted for 50 days with a left ventricular assist device, who then died from cerebral haemorrhage. Automated sequencing, alignment, and sequence comparison confirmed the enteroviral origin of polymerase chain reaction products and excluded contamination. These findings agree with prior observations of enteroviral localisation in the skeletal muscle of patients with dilated cardiomyopathy, and further support the hypothesis that skeletal rather than heart muscle may host the virus and serve as a reservoir in cardiomyopathies related to chronic infection.


Keywords: enterovirus; myocarditis; viral particles; skeletal muscle