CHF5074 Reduces Biomarkers of Neuroinflammation in Patients with Mild Cognitive Impairment: A 12-Week, Double-Blind, Placebo-Controlled Study.

As neuroinflammation is an early event in the pathogenesis of Alzheimer's disease, new selective anti-inflammatory drugs could lead to promising preventive strategies. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of CHF5074, a new microglial modulator, in a 12-week, double-blind, placebo-controlled, parallel groups, ascending dose study involving 96 MCI patients. Subjects were allocated into three successive study cohorts to receive ascending, titrated doses of CHF5074 (200, 400 or 600 mg/day) or placebo. Vital signs, cardiac safety, neuropsychological performance and safety clinical laboratory parameters were assessed on all subjects. Plasma samples were collected throughout the study for measuring drug concentrations, soluble CD40 ligand (sCD40L) and TNF-α. At the end of treatment, cerebrospinal fluid (CSF) samples were optionally collected after the last dose to measure drug levels, ß-amyloid1-42 (Aß42), tau, phospho-tau181, sCD40L and TNF-α. Ten patients did not complete the study: one in the placebo group (consent withdrawn), two in the 200-mg/day treatment group (consent withdrawn and unable to comply) and seven in the 400-mg/day treatment group (five AEs, one consent withdrawn and one unable to comply). The most frequent treatment-emergent adverse events were diarrhea, dizziness and back pain. There were no clinically significant treatment-related clinical laboratory, vital sign or ECG abnormalities. CHF5074 total body clearance depended by gender, age and glomerular filtration rate. CHF5074 CSF concentrations increased in a dose-dependent manner. At the end of treatment, mean sCD40L and TNF-α levels in CSF were found to be inversely related to the CHF5074 dose (p=0.037 and p=0.001, respectively). Plasma levels of sCD40L in the 600-mg/day group were significantly lower than those measured in the placebo group (p=0.010). No significant differences between treatment groups were found in neuropsychological tests but a positive dose-response trend was found on executive function in APOE4 carriers. This study shows that CHF5074 is well tolerated in MCI patients after a 12-week titrated treatment up to 600 mg/day and dose-dependently affects central nervous system biomarkers of neuroinflammation.

Associations of the correlates of protection and implication on the statistical power for demonstrating non-inferiority: application of a re-sampling method on a large phase III influenza vaccine clinical trial.

BACKGROUND: In the later stage of the clinical development of new vaccines it is required to demonstrate their efficacy with the immunogenicity measures established as correlates for disease protection. Evaluation of interpandemic trivalent influenza vaccines is commonly assessed by three immunogenicity measures for each strain in different age groups: Seroprotection, Seroconversion and Geometric Mean Titers. US and European guidelines with respect to this topic have been issued for the licensure of new influenza vaccines. The statistical power of comparative trials, which consider these endpoint variables, could be affected to the extent that these measures are correlated. Results from a large non-inferiority trial in the clinical development of a novel cell-derived influenza vaccine have been analyzed with the aim of evaluating how statistical dependency between the above-mentioned three immunogenicity measures might affect the power to demonstrate non-inferiority. METHODS: The statistical non-inferiority criteria, which were met in the trial, were applied to different subsets (n=250, n=370 and n=500) using a re-sampling method from the original dataset (re-samples=10,000). RESULTS: The measures of immunogenicity were highly correlated, and the fulfillment or failure of any of the non-inferiority criteria for a specific measure partially predicted the same outcome for the other measures. Due to this dependency within each strain, the levels of power obtained by re-sampling methods were always higher than those obtained by theoretical calculations, which were based on the assumptions of independency between the three measures of immunogenicity. Seroconversion and Geometric Mean Ratio (GMR) showed a higher correlation. A failure in the fulfillment of the non-inferiority criteria for GMR predicted the failure for Seroconversion in >76% of cases. CONCLUSIONS: The correlation between different measures of immunogenicity should be taken into account when evaluating statistical power for non-inferiority in influenza vaccine trials and in establishing sample sizes. Statistical approaches that include either all three measures of immunogenicity or both Seroconversion and the ratio of GMTs as co-primary non-inferiority endpoints might create redundancy and could increase the probability of not meeting at least one non-inferiority criterion by chance, due to multiplicity.

Impact of prior or concomitant seasonal influenza vaccination on MF59-adjuvanted H1N1v vaccine (Focetria) in adult and elderly subjects.

BACKGROUND: When H1N1v vaccines become widely available, most elderly subjects will have already received their seasonal influenza vaccination. Adults seeking H1N1v vaccination may be offered seasonal vaccine as well. We investigated prior seasonal vaccination in adult and elderly subjects, and concomitant vaccination with seasonal vaccine in adults, on the tolerability and immunogenicity of the Novartis MF59-adjuvanted H1N1v vaccine, Focetria. METHODS: A total of 264 adult (four groups) and 154 elderly (three groups) subjects were enrolled. The licensure study cohorts for plain (Agrippal) and MF59-adjuvanted (Fluad) 2009-2010 seasonal vaccines were invited to receive Focetria 3 months later, with seasonal vaccine-naïve controls, and adults who received Focteria and seasonal vaccine concomitantly. Immunogenicity of all vaccines was assessed by haemagglutination inhibition on Days 1 and 22, safety and reactogenicity were monitored using patient diaries. RESULTS: All adult and elderly groups met all the European CHMP licensing criteria for H1N1v, as did adults receiving concomitant seasonal vaccine for the three seasonal strains. Vaccines were generally well tolerated, causing no SAEs, and profiles typical of MF59-adjuvanted vaccines. Reactions were mainly mild or moderate and transient, and unaffected by prior or concomitant seasonal vaccination except for elderly subjects previously given MF59-adjuvanted seasonal vaccine, whose reaction rates to Focetria were about half those seen in groups receiving their first MF59 vaccine. CONCLUSION: One dose of MF59-adjuvanted H1N1v vaccine met the licensure criteria for adult and elderly subjects 3 months after seasonal vaccination, or concomitantly with seasonal vaccine in adults, without impacting the tolerability or immunogenicity of either vaccine, thus facilitating mass influenza immunisation campaigns.

Dust exposure, respiratory symptoms, and longitudinal decline of lung function in young coal miners.

OBJECTIVES: To study the role of dust exposure on incidence of respiratory symptoms and decline of lung function in young coal miners. METHODS: The loss of lung function (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced expiratory flow (MEF), carbon monoxide transfer factor (TLCO)) with time and the incidence of respiratory symptoms in 909 Sardinian coal miners (followed up between 1983 and 1993 with seven separate surveys) has been compared with the past and current individual exposures to respirable mixed coal dust. Multiple linear and logistic regression models were used simultaneously controlling for age, smoking, past occupational exposures, and other relevant covariates. RESULTS: According to the relatively low dust exposures experienced during the follow up few abnormal chest x ray films were detected. In the cross sectional analysis of initial data, significant associations between individual cumulative exposure to dust, decrements in FEV1 and MEFs, and increasing prevalence of respiratory symptoms were detected after allowing for the covariates included in the model. The yearly decline of FVC, FEV1, and single breath carbon monoxide transfer factor (TLCO/VA) was still significantly related to the individual exposure to dust experienced during the follow up, even after allowing for age, smoking, initial cumulative exposure to dust, and initial level of each functional variable. In logistic models, dust exposure was a significant predictor of the onset of respiratory symptoms besides age and smoking. CONCLUSIONS: The results show that even moderate exposures to mixed coal dust, as in our study, significantly affect lung function and incidence of symptoms of underground miners. Although the frequency of chest x ray examination might be fixed at every three or four years, yearly measurements of lung function (spirometry, MEFs, and TLCO) are recommended for evaluation of the respiratory risk from the coal mine environment to assess the need for further preventive interventions.

Mortality from lung cancer among Sardinian patients with silicosis.

The mortality of 724 subjects with silicosis, first diagnosed in 1964-70 in the Sardinia region of Italy, was followed up through to 31 December 1987. Smoking, occupational history, chest x ray films, and data on lung function were available from clinical records for each member of the cohort. The overall cohort accounted for 10,956.5 person-years. The standardised mortality ratios (SMRs) for selected causes of death (International Classification of Diseases (ICD) eighth revision) were based on the age specific regional death rates for each calendar year. An excess of deaths for all causes (SMR = 1.40) was found, mainly due to chronic obstructive lung disease, silicosis, and tuberculosis with an upward trend of the SMR with increasing severity of the International Labour Office (ILO) radiological categories. Twenty two subjects died from lung cancer (SMR = 1.29, 95% confidence interval (95% CI) = 0.8-2.0). The risk increased after a 10 and 15 year latency but the SMR never reached statistical significance. No correlation was found between lung cancer and severity of the radiological category, the type of silica (coal or metalliferous mines, quarries etc), or the degree of exposure to silica dust. A significant excess of deaths from lung cancer was found among heavy smokers (SMR = 4.11) and subjects with airflow obstruction (SMR = 2.83). A nested case-control study was planned to investigate whether the association between lung cancer and airway obstruction was due to confounding by smoking. No association was found with the ILO categories of silicosis or the estimated cumulative exposure to silica. The risk estimate for lung cancer by airflow obstruction after adjusting by cigarette consumption was 2.86 for a mild impairment and 7.23 for a severe obstruction. The results do not show any clear association between exposure to silica, severity of silicosis, and mortality from lung cancer. Other environmental or individual factors may act as confounders in the association between silicosis and lung cancer. Among them, attention should be given to chronic airways obstruction as an independent risk factor for lung cancer in patients with silicosis.

Mechanisms of PCBs mixture toxicity on isolated rat hepatocytes.

Exposure of isolated hepatocytes to a polychlorinated biphenyl mixture induced a rapid loss of cell viability. The effect was not dose-dependent. The biochemical effects in the cellular toxicity did not involve glutathione content, protein sulfhydryl groups and lipid peroxidation. A transient increase in cytosolic Ca2+ was observed after exposing the hepatocytes to the polychlorinated biphenyl mixture. Our findings indicate that polychlorinated biphenyls are able to kill hepatocytes and suggest that elevation of cytosolic Ca2+ concentration could be responsable of the toxicity.

[Effects of the body in personal sampling of noise]. / Effetto del corpo nel campionamento personale di rumore.

In acoustic free fields the human body changes the energy distribution surrounding it, mainly under narrow band or pure tone noise conditions. Hence, sound levels measured close to the body should be intrinsically incorrect if performed via personal sampling. An experiment was carried out to verify whether this statement is still valid in a diffuse field, such as occurs in industrial workplaces. Noise measurements were made in diffuse field laboratory conditions without the presence of a person (steady state) and were repeated close to the ear of a person (perturbed state). The measurements were carried out with integrating precision sound level meters and also with personal noise dose meters. The trials were repeated in an industrial environment. The states 1/3 octave band levels were matched, as also were the equivalent continuous levels. These findings show that in diffuse fields the human body does not significantly affect equivalent continuous level measurements performed near the body. The mean differences between equivalent continuous levels measured by sound level meter were less than 0.3 dBA, and ranged from -0.6 to 0 dBA between levels measured by sound level meter and by personal noise dose meter. The results of the trial performed in the plant showed closer differences between steady and perturbed states and between sound level meter and personal noise dose meter measurements.

Blood lead levels in children of S.W. Sardinia.

The purpose of the present study was to make a preliminary evaluation of blood lead levels in school-aged children from three towns of southwestern Sardinia, Portoscuso, S. Antioco and Calasetta, the first of which is very close to a large industrial complex. Blood lead concentration was determined in venous blood samples by graphite furnace atomic absorption spectrophotometry. The survey revealed that children residing in the town of Portoscuso had higher mean blood lead levels (12.7 micrograms/dl) than children of the same age residing in S. Antioco and Calasetta (8.3 and 8.4 micrograms/dl respectively) and that levels were slightly higher in males than in females. This difference is suggested to be a result of the greater fallout of industrial pollutants in the area of Portoscuso.

[Polychlorobiphenyl content in adipose tissue of subjects not exposed professionally]. / Contenuto di PCB nel tessuto adiposo di soggetti non esposti professionalmente.

Polychlorinated biphenyl (PCB) levels were determined in 52 samples of adipose tissue removed during surgery from patients residing in a central region of Sardinia who had no previous occupational exposure. The average PCB value of the whole group was 0.72 microgram/g (range 0.11-2.81 micrograms/g); in males the average value (means = 0.97 microgram/g) was significantly higher than in females (means = 0.60 microgram/g). A positive correlation was observed between age and PCB levels in adipose tissue. This analysis could be usefully performed in occupationally exposed subjects so as to better assess the exposure level.

[Isoflurane pollution in operating rooms]. / Inquinamento da isoflurano nelle sale operatorie.

In three operating rooms of a Sardinian hospital, the Authors have measured the air levels of isoflurane using static samplers. Anaesthetic mean daily concentrations ranged from 3.5 to 41.5 ppm in room A, from 4.1 to 24.4 ppm in room B, from 9.5 to 30.4 ppm in room C above all depending on the length and the number of surgical operations. The Authors emphasize the need of suitable prevention measures.

[An episode of extraoccupational lead poisoning]. / Su un episodio di intossicazione extraprofessionale da piombo.

An episode of non occupational lead intoxication observed in the four members of family is described. While three of them had only biochemical signs of abnormal lead absorption, the remaining subject presented the serious clinical features of plumbism. The source of intoxication was contaminated wine. The importance, for diagnostical and medico-preventive purposes, of a possible non occupational absorption of lead is stressed.

[Peripheral vascular manifestations and osteoarticular changes in mine drillers and lumber workers]. / Manifestazioni vascolari periferiche e alterazioni osteoarticolari in perforatori di miniera e operai forestali.

In order to find, inside the same vibration syndrome, likely differences of the pathology due to the different technological features of the vibrating tools, 42 forestry workers have been compared with 168 mine workers. No significant differences have been noticed, as concerns both osteoarticular lesions and photopletismography study of peripheral blood circulation; in mine workers a prevalence of lesions of the nail-folds capillaries has been noticed, according to the authors dependent on the higher energy of the vibrations brought out boring-machines.

[Normal values of methemoglobinemia in a sample of Sardinian workers]. / Valori normali di metaemoglobinemia in un campione di lavoratori sardi.

The susceptibility of hemoglobinic iron to oxidation in the ferric form by action of numerous industrial substances, suggested the use of metHbemia dosage in biological monitoring of professional exposure to such substances. In order to have useful reference values, the metHbemia of 975 male workers, from various parts of Sardinia, was measured at least 12 hours after last work shift. 95% of the examined population had metHbemia values lower than 0,86% of total Hb; such result has been compared with other normal values, found in literature and likely causes of the differences between such values have been discussed. On the basis of our results and on the examination of literature an intervention prospectus is suggested for biological monitoring of exposure to methemoglobinising substances.