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The discovery that mammalian target of rapamycin (mTOR) inhibition increases lifespan in mice and restores/delays many aging phenotypes has led to the identification of a novel potential therapeutic target for the treatment of Alzheimer's disease (AD). Among mTOR inhibitors, everolimus, which has been developed to improve the pharmacokinetic characteristics of rapamycin, has been extensively profiled in preclinical and clinical studies as anticancer and immunosuppressive agent, but no information is available about its potential effects on neurodegenerative disorders. Using a reliable mouse model of AD (3 × Tg-AD mice), we explored whether short-term treatment with everolimus injected directly into the brain by osmotic pumps was able to modify AD-like pathology with low impact on peripheral organs. We first established in non-transgenic mice the stability of everolimus at 37 °C in comparison with rapamycin and, then, evaluated its pharmacokinetics and pharmacodynamics profiles through either a single peripheral (i.p.) or central (i.c.v.) route of administration. Finally, 6-month-old (symptomatic phase) 3 × Tg-AD mice were treated with continuous infusion of either vehicle or everolimus (0.167 μg/μl/day, i.c.v.) using the osmotic pumps. Four weeks after the beginning of infusion, we tested our hypothesis following an integrated approach, including behavioral (tests for cognitive and depressive-like alterations), biochemical and immunohistochemical analyses. Everolimus (i) showed higher stability than rapamycin at 37 °C, (ii) poorly crossed the blood-brain barrier after i.p. injection, (iii) was slowly metabolized in the brain due to a longer t 1/2 in the brain compared to blood, and (iv) was more effective in the CNS when administered centrally compared to a peripheral route. Moreover, the everolimus-induced mTOR inhibition reduced human APP/Aβ and human tau levels and improved cognitive function and depressive-like phenotype in the 3 × Tg-AD mice. The intrathecal infusion of everolimus may be effective to treat early stages of AD-pathology through a short and cyclic administration regimen, with short-term outcomes and a low impact on peripheral organs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Clinical studies suggest a link between peripheral insulin resistance and cognitive dysfunction. Interestingly, post-mortem analyses of Alzheimer disease (AD) subjects demonstrated insulin resistance in the brain proposing a role for cognitive deficits observed in AD. However, the mechanisms responsible for the onset of brain insulin resistance (BIR) need further elucidations. Biliverdin reductase-A (BVR-A) emerged as a unique Ser/Thr/Tyr kinase directly involved in the insulin signaling and represents an up-stream regulator of the insulin signaling cascade. Because we previously demonstrated the oxidative stress (OS)-induced impairment of BVR-A in human AD brain, we hypothesize that BVR-A dysregulation could be associated with the onset of BIR in AD. In the present work, we longitudinally analyze the age-dependent changes of (i) BVR-A protein levels and activation, (ii) total oxidative stress markers levels (PC, HNE, 3-NT) as well as (iii) IR/IRS1 levels and activation in the hippocampus of the triple transgenic model of AD (3xTg-AD) mice. Furthermore, ad hoc experiments have been performed in SH-SY5Y neuroblastoma cells to clarify the molecular mechanism(s) underlying changes observed in mice. Our results show that OS-induced impairment of BVR-A kinase activity is an early event, which starts prior the accumulation of Aβ and tau pathology or the elevation of TNF-α, and that greatly contribute to the onset of BIR along the progression of AD pathology in 3xTg-Ad mice. Based on these evidence we, therefore, propose a new paradigm for which: OS-induced impairment of BVR-A is firstly responsible for a sustained activation of IRS1, which then causes the stimulation of negative feedback mechanisms (i.e. mTOR) aimed to turn-off IRS1 hyper-activity and thus BIR. Similar alterations characterize also the normal aging process in mice, positing BVR-A impairment as a possible bridge in the transition from normal aging to AD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate chitosan (CS)-, glycol chitosan (GCS)- and corresponding thiomer-based nanoparticles (NPs) for delivering dopamine (DA) to the brain by nasal route. Thus, the polyanions tripolyphosphate and sulfobutylether-β-cyclodextrin (SBE-β-CD), respectively, were used as polycation crosslinking agents and SBE-β-CD also in order to enhance the DA stability. The most interesting formulation, containing GCS and SBE-β-CD, was denoted as DA GCS/DA-CD NPs. NMR spectroscopy demonstrated an inclusion complex formation between SBE-β-CD and DA. X-ray photoelectron spectroscopy analysis revealed the presence of DA on the external surface of NPs. DA GCS/DA-CD NPs showed cytotoxic effect toward Olfactory Ensheathing Cells only at higher dosage. Acute administration of DA GCS/DA-CD NPs into the right nostril of rats did not modify the levels of the neurotransmitter in both right and left striatum. Conversely, repeated intranasal administration of DA GCS/DA-CD NPs into the right nostril significantly increased DA in the ipsilateral striatum. Fluorescent microscopy of olfactory bulb after acute administration of DA fluorescent-labeled GCS/DA-CD NPs into the right nostril showed the presence of NPs only in the right olfactory bulb and no morphological tissue damage occurred. Thus, these GCS based NPs could be potentially used as carriers for nose-to-brain DA delivery for the Parkinson's disease treatment., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Limbic forebrain endocannabinoid (eCB) signaling is critically involved in stress integration by modulating neurotransmitters release. The purpose of this study was to examine, by brain microdialysis, the effects of fatty acid amide hydrolase (FAAH) inhibition on noradrenergic and γ-aminobutyric acid (GABA)-ergic neurotransmission in the prefrontal cortex (PFC) and basolateral amygdala (BLA) of rats subjected to a 20-min swim stress. Microdialysis started on stress- and drug-naïve rats that were treated with the FAAH inhibitor URB597 (0.1 or 0.3 mg/kg) 30 min before undergoing the stress procedure. Dialysate samples were collected every 20 min from the beginning of the experiment. Concentrations of noradrenaline (NA) and GABA were determined by HPLC coupled to electrochemical and fluorescence detection, respectively. We found that neither URB597 treatment nor 20 min of swim stress exposure per se altered NA and GABA extracellular levels in PFC or BLA. Interestingly, rats treated with 0.1 mg/kg of URB597 followed by 20 min of stress showed significantly higher NA and GABA levels in PFC and BLA. These effects were absent in rats treated with 0.3 mg/kg URB597, indicating a dose-specific effect. Moreover, we found that the pretreatment with the CB1 receptor antagonist rimonabant blocked the URB597 effects on NA and GABA release in PFC and BLA of animals subjected to forced swimming. The present study might provide an important first step toward understanding the mechanisms through which URB597 modulates stress-induced neuroendocrine secretion and behavioral coping strategies., (© 2015 Wiley Periodicals, Inc.)

Aim: 1) To identify the principal radiological signs of atypical pulmonary mycobacteriosis by means of X-rays and CT/HRCT; 2) to compare the two methods in order to evaluate their reliability with particular interest for the diagnostic role of HRCT in the identification of the disease; 3) to establish any significant differences in the pathology between AIDS and immunocompetent patients., Material and Methods: The chest X-rays and CT/HRCT of 28 atypical pulmonary mycobacteriosis patients (16 with AIDS and 12 immunocompetent) have been studied. The subjects were examined during the period of October 1993 to May 2000 and were found to be positive for atypical mycobacterium and consequently underwent a standard chest X-ray. Twenty cases were followed-up with a chest CT/HRCT; of these only 17 were performed within 30 days of the traditional chest X-ray which was considered to be the time limit in order to validate the comparison between the two methods., Results: The significant semeiotical findings were the parenchymal consolidations observed in 25 patients (89%) by standard chest X-rays; the CT/HRCT confirmed the findings in 4 cases while in 13 it enhanced the evaluation of their extensions. In 9 cases the standard chest X-ray established the presence of cavitations which were confirmed by the CT/HRCT in only 7 cases. Lymphadenopathy was observed in 3/28 patients (10.7%) through standard X-rays and in 15/17 cases (82%) through CT/HRCT. The latter method revealed to be extremely useful in the identification of this pathology. Nodules and micronodules were seen in 5 patients with traditional X-rays and in 9 cases with CT/HRCT. Bronchogenic spread signs of disease became visible only with CT and in particular with HRCT (11/17 patients = 65%). Comparing the two groups (AIDS and immunocompetent) taken into consideration, the most frequent lesion present in both was parenchymal consolidation resulting more bilateral in the AIDS subjects. Cavitation and pleural edema were seen more often in the AIDS group while bronchiectasia, bronchogenic spread and signs of previous pleuro-parenchymal suffering were more frequent in the immunocompetent patients. Lymphadenopathy was frequently found in the total study population but appeared slightly prevalent for the group not afflicted with AIDS., Conclusion: Radiological study of the chest permitted the identification of signs useful in the diagnosis of mycobacteriosis in all the patients studied. The application of CT/HRCT added helpful elements in almost all of the cases examined demonstrating to be more effective than the standard chest X-ray not only in terms of improved evaluation of known lesions but also in the identification of lesions which are difficult to determine by means of traditional radiology.

The main objective of this study was to examine the perception of the first symptom during methacholine bronchoconstriction as soon as it occurred, and in the second instance to quantify the intensity of the breathlessness by means of the Borg Scale performed at the end of challenge so to not determine any difficulties for identification of the first symptom. A methacholine challenge test was carried out in 139 symptom-free asthmatics with a normal pulmonary function. When the first symptom was reported by the subject, the forced expiratory volume in one second (FEV1) was measured immediately. FEV1 was expressed as a percentage of the best personal value (FEV1%BPV). The intensity of the breathlessness was rated using a modified Borg Scale at the end of the challenge test so as not to confuse the patient. Seven subjects felt nothing during challenge. The first symptoms varied: constriction behind the breastbone (49%), inspiratory shortness (16.5%), coughing (10%), wheezing, throat constriction, general chest tightness, pain behind the sternum, and a sensation of rheum behind the sternum. FEV1%BPV at the first symptom was 80.5 +/- 10 (range 41-99). No symptom was perceived by 42% of the subjects within the 80-100 range of FEV1%BPV. FEV1%BPV at the first symptom was related to the log of the provocative dose causing a 20% fall in FEV1 (r = 0.2, p < 0.05). An inverse correlation between Borg Score and final FEV1%BPV (r = -0.25, p < 0.01) was found at the end of challenge. A subgroup of 39 subjects with similar final FEV1%BPV values (68-72) showed a correlation between the Borg Score at end of challenge and FEV1%BPV at the first symptom (r = 0.59, p < 0.001). The first symptom of the methacholine-induced bronchoconstriction varies in asthmatics and may be atypical, the bronchoconstriction level at which it is felt also varies among individuals, highly methacholine-responsive subjects perceive the bronchoconstriction later, while late perceivers of the first symptom show less intense breathlessness at the end of challenge. The measurement of the patient's ability to perceive asthmatic symptoms during the methacholine challenge test could be used to single out poor perceivers.

Pneumoconiosis is not reported in food industry workers, and more specifically in the confectionery industry. We diagnosed diffuse pulmonary interstitial nodular fibrosis due to inhalation of powder containing quartz in a 54 year-old asymptomatic woman. Silicosis was due to a 5-year period of talc dust exposure 35 years earlier in the confectionery industry. The diagnosis was supported by a history of exposure, transbronchial lung biopsy specimen, 67Gallium scan, and CT scan. Our patient had an unusual history of exposure, which was not readily disclosed until the patient's memories, and after consultation with an expert in confectionery techniques, indicated she had been exposed to talc powder during her employment in the confectionery industry.

Sarcoidosis has a large variety of chest x-ray manifestations, but primary acute cavitation is very rare. We report a case of cavitary sarcoidosis occurring in an asymptomatic 25 year-old white patient. The diagnosis was established from chest x-ray, transbronchial biopsy specimen, bronchoalveolar lavage and gallium 67 scan. The peculiarities of this case are: 1) the presence of hilar adenopathy; 2) the cavitation occurred during the decreased activity of the disease; 3) the resolution of cavity without therapy. We suggest asymptomatic sarcoidosis should be considered in the differential diagnosis of pulmonary cavitation.