Effect of an Intracerebroventricular Injection of Aggregated Beta-amyloid (1-42) on Daily Rhythms of Oxidative Stress Parameters in the Prefrontal Cortex.

Accumulation of amyloid peptides in the brain plays a key role in the pathogenesis of Alzheimer's disease (AD). Aggregated beta-amyloid (Aß) peptide increases intracellular reactive oxygen species associated to a deficient antioxidant defense system. Prefrontal cortex plays a key role in memory and learning and is especially susceptible to oxidative stress. The objective of this work was to investigate the effects of an intracerebroventricular (i.c.v.) injection of Aß (1-42) on 24 h patterns of oxidative stress parameters and antioxidant defenses in the rat prefrontal cortex. Four-month-old male Holtzman rats were divided into two groups defined as: control (CO) and Aß-injected (Aß). Rats were maintained under12 h-light:12 h-dark conditions and received water and food ad libitum. Tissues samples were isolated every 6 h during a 24 h period. Interestingly, we found that an i.c.v. injection of Aß(1-42) increased lipid peroxidation, reduced total antioxidant capacity level, phase-shifted the daily peak of reduced glutathione, and had a differential effect on the oscillating catalase and glutathione peroxidase specific activity. Thus, elevated levels of Aß aggregates-a pathogenic hallmark of AD, caused altered temporal patterns of the cellular redox state in prefrontal cortex rat. These findings might contribute, at least in part, to the understanding of the molecular and biochemical basis of redox changes caused by circadian rhythms alterations observed in AD patients.

Increased levels of serum IL-18 are associated with the long-term outcome of severe traumatic brain injury.

OBJECTIVE: A long-lasting neuroinflammatory cascade may lead to the progression of brain damage, favoring neurodegeneration and cognitive impairment in patients with traumatic brain injury (TBI), but the potential mechanisms underlying this sequence of events remain elusive. Here we aimed to evaluate the impact of interleukin (IL)-18, a proinflammatory cytokine elevated in post-acute head injury and associated with neurodegeneration, on the long-term outcome of patients with chronic TBI. METHODS: The serum content of IL-18 was evaluated in 16 patients with severe TBI, during their rehabilitation phase, and in a matched group of 16 healthy controls. The disability of the enrolled patients was evaluated by means of the Glasgow Outcome Scale, Levels of Cognitive Functioning, and the Disability Rating Scale. RESULTS: The circulating levels of IL-18 were significantly increased in chronic TBI patients, as compared to healthy subjects, and correlated with the patients' cognitive impairment and disability severity. CONCLUSIONS: IL-18 may contribute to the long-term outcome and neurodegeneration in TBI patients. Even though further studies are needed to understand the molecular mechanisms underlying the effects of IL-18 on TBI progression and its associated drop in cognitive function, a possible role of this cytokine as a therapeutic target in TBI can be envisaged.

Adverse drug reactions as cause of hospital admissions: results from the Italian Group of Pharmacoepidemiology in the Elderly (GIFA).

OBJECTIVES: To determine the prevalence of adverse drug reaction (ADR)-related hospital admissions in an older population, to describe the most common clinical manifestations and drugs most frequently responsible for ADR-related hospital admissions, and to identify independent factors predictive of these ADRs. DESIGN: Multicenter pharmacoepidemiology survey conducted between 1988 and 1997. SETTING: Eighty-one academic hospitals throughout Italy. PARTICIPANTS: Twenty-eight thousand four hundred eleven patients consecutively admitted to participating centers during the survey periods. MEASUREMENTS: For each suspected ADR at admission, a physician, who coded description, severity, and potentially responsible drugs, completed a questionnaire. RESULTS: Mean age +/- standard deviation of the patients was 70 +/- 16. One thousand seven hundred four ADRs were identified upon hospital admission. In 964 cases (3.4% of all admissions), ADRs were considered to be the cause of these hospital admissions. Of these, 187 ADRs were coded as severe. Gastrointestinal complaints (19%) represented the most common events, followed by metabolic and hemorrhagic complications (9%). The drugs most frequently responsible for these ADRs were diuretics, calcium channel blockers, nonsteroidal antiinflammatory drugs, and digoxin. Female sex (odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.10-1.54), alcohol use (OR = 1.39, 95% CI = 1.20-1.60), and number of drugs (OR = 1.24, 95% CI = 1.20-1.27 for each drug increase) were independent predictors of ADR-related hospital admissions. For severe ADRs, age (OR = 1.50, 95% CI = 1.01-2.23 for age 65-79 and OR = 1.53, 95% CI = 1.00-2.33 for age > or =80, respectively), comorbidity (OR = 1.12, 95% CI = 1.05-1.20 for each point in the Charlson Comorbidity Index), and number of drugs (OR = 1.18, 95% CI = 1.11-1.25 for each drug increase) were the only predisposing factors. CONCLUSIONS: The most important determinant of risk for ADR-related hospital admissions in older patients is number of drugs being taken. When considering only severe ADRs, risk is also related to age and frailty.

Moderate alcohol consumption and adverse drug reactions among older adults.

PURPOSE: To assess the effect of moderate alcohol consumption on Adverse Drug Reactions (ADRs) among older adults admitted to acute care hospitals and to examine the consistency of this effect across gender and age groups. METHODS: We used the GIFA (Italian Group of Pharmacoepidemiology in the Elderly) database, which includes information on patients admitted to 81 medical centers in Italy. For this study we examined exclusively the ADRs detected at hospital admission that were classified as definite or probable based on the Naranjo algorithm. RESULTS: Among 22,778 participants, 894 were found to have one or more ADRs (3.9%). Gastrointestinal complications (n = 210; 0.9% of the population) were the most frequent ADRs, followed by metabolic/endocrine (n = 156; 0.7%), dermatological/allergic (n = 102; 0.4%) and arrhythmic (n = 78; 0.3%) complications. Diuretics were the most frequent culprit drugs, followed by NSAIDs and digoxin. An ADR was recorded in 383/10,427 (3.7%) non-drinkers and in 511/12,351 (4.1%) moderate drinkers. After adjusting for potential confounders, moderate alcohol consumption was associated with a 24% increased risk of ADRs (OR 1.24; 95%CI: 1.08-1.43). This effect seemed more evident among women (OR 1.30; 95%CI: 1.09-1.55), than men (OR 1.14; 95%CI: 0.90-1.43), while it was similar across different age groups (< 65 years OR 1.28; 95%CI: 0.99-1.66; 65-79 years OR 1.22; 95%CI: 0.98-1.52; > or = 80 years OR 1.20; 95%CI: 0.93-1.56). Considering the most common ADRs, moderate alcohol users presented a significantly higher risk of drug-related headache (OR 3.89; 95%CI: 1.43-10.61) and metabolic/endocrine complications (OR 1.67; 95%CI: 1.19-2.33). CONCLUSIONS: Moderate alcohol intake is associated with an increased risk of ADRs; this effect seems more evident among women than men, and it does not differ across age groups.