Dem-Aging: autophagy-related pathologies and the "two faces of dementia".

Neuronal ceroid lipofuscinosis (NCL) is an umbrella term referring to the most frequent childhood-onset neurodegenerative diseases, which are also the main cause of childhood dementia. Although the molecular mechanisms underlying the NCLs remain elusive, evidence is increasingly pointing to shared disease pathways and common clinical features across the disease forms. The characterization of pathological mechanisms, disease modifiers, and biomarkers might facilitate the development of treatment strategies.The DEM-AGING project aims to define molecular signatures in NCL and expedite biomarker discovery with a view to identifying novel targets for monitoring disease status and progression and accelerating clinical trial readiness in this field. In this study, we fused multiomic assessments in established NCL models with similar data on the more common late-onset neurodegenerative conditions in order to test the hypothesis of shared molecular fingerprints critical to the underlying pathological mechanisms. Our aim, ultimately, is to combine data analysis, cell models, and omic strategies in an effort to trace new routes to therapies that might readily be applied in the most common forms of dementia.

Integrative human and murine multi-omics: Highlighting shared biomarkers in the neuronal ceroid lipofuscinoses.

Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative disorders whose molecular mechanisms remain largely unknown. Omics approaches are among the methods that generate new information on modifying factors and molecular signatures. Moreover, omics data integration can address the need to progressively expand knowledge around the disease and pinpoint specific proteins to promote as candidate biomarkers. In this work, we integrated a total of 62 proteomic and transcriptomic datasets originating from humans and mice, employing a new approach able to define dysregulated processes across species, stages and NCL forms. Moreover, we selected a pool of differentially expressed proteins and genes as species- and form-related biomarkers of disease status/progression and evaluated local and spatial differences in most affected brain regions. Our results offer promising targets for potential new therapeutic strategies and reinforce the hypothesis of a connection between NCLs and other forms of dementia, particularly Alzheimer's disease.

Neuronal Ceroid Lipofuscinosis: The Increasing Spectrum of an Old Disease.

Neuronal Ceroid Lipofuscinoses (NCL) are genetically heterogeneous heritable neurodegenerative disorders with worldwide distribution. They are considered as childhood diseases; however rare adult onset forms are known. NCL have a progressive course, affecting visual, motor and cognitive functions, and are associated with myoclonic epilepsy; behavioural problems can be observed at the onset. The outcome is invariably fatal, mostly during the second or third decade. The denomination is based on pathological criteria, i.e. the presence of intralysosomal storage of autofluorescent lipopigment of glycoprotein origin with characteristic ultrastructural features. The NCL are autosomal recessive diseases (but a rare autosomal dominant form of adult onset). Thirteen NCL associated genes have been identified so far, which allow a definite diagnosis to be reached and provide genetic counselling to the families. Still unidentified NCL genes are foreseen. Allelic heterogeneity is observed in some mutated genes; likewise phenotypic heterogeneity is seen in several NCL. The gene products are either soluble proteins (such as lysosomal enzymes) or membrane proteins related to lysosomes, endoplasmic reticulum, synaptic vesicles. Little is known about pathogenetic mechanisms, leading to storage formation and cell death. Current research is focusing on intracellular trafficking, neurotransmission and storage removal. No cure is available for any form. Innovative treatments led to some results in mouse models related to lysosome hydrolase defects. Evidences that autophagy, oxidative stress, excitotoxicity play roles in NCL cell pathology raise the possibility that selected steps of these processes might become target of treatments, and therefore modify the disease course.

Human herpesvirus-6B active infection associated with relapsing bilateral anterior optic neuritis.

BACKGROUND AND OBJECTIVES: Human herpesvirus-6 (HHV-6) is the causative agent of exanthem subitum. Both HHV-6 variants, A and B, have been associated with central nervous system (CNS) diseases, suggesting a wide neuropathogenic potential. We describe a case of recurrent bilateral anterior optic neuritis with HHV-6 active infection associated with clinical relapses. CASE REPORT: A 23-year old woman presented with progressive visual impairment, bilateral papillitis and painful ocular movements. Nested polymerase chain reaction (PCR) for DNA viruses, HHV-6 variant specific real time quantitative PCR, serological analysis and retrotranscription PCR (RT-PCR) for HHV-6 mRNA transcripts were performed. Nested PCR in PBMC and CSF samples was negative for all viruses but positive for HHV-6 DNA, subtyped as HHV-6B. The disease had a relapsing/remitting course. During relapses PBMC samples remained positive for HHV-6 DNA, and HHV-6 active infection was confirmed by the presence of anti-HHV-6 IgM and of HHV-6 U27 mRNA transcript. High viremia levels and relapses were overlapping. After the last relapse, the patient was successfully treated with gancyclovir. CONCLUSIONS: The case reported here suggests a possible association of HHV-6 in bilateral optic neuritis. HHV-6 could be monitored when bilateral optic neuritis is identified, in order to establish an appropriate antiviral therapy.

The image of self and of the environment in drug abusers: a comparative study using the TAT.

This study attempted to add to our understanding of the heroin abusers' identity problems, using images of the self and the environment. Murray's Thematic Apperception Test (TAT) was applied to a group of male drug users undergoing withdrawal treatment with methadone and also to a group of male, non-drug using controls. The needs of the subjects and the demands of the environment, plus interaction between the two, were compared between the two groups to obtain information about the self and lifestyle. Among the data which emerged, is an increased need for destructive aggression and an environment experienced as coercive and emarginating. Among the interactions we observed coerced imagination, difficulties in identification, personal relationships based on abandonment with persecutory projection of the female figure and a tendency toward immature defences such as avoidance, denial and acting out. This information is discussed in relation to possible means of treatment.

[The elderly and their existence model. A study with projective technics]. / L'anziano ed il suo modello di esistenza. Studio con tecniche proiettive.

Elderly subjects free from psychiatric diseases and hospitalised at centres run in accordance with different models have been examined. The T.A.T. was carried out. Certain common elements emerge that would appear to be related to the senile age. Others appear to be psychological superstructures related to the different conditions of existence.

[Jaundice caused by estro-progestinic agents. Description of a case]. / Ittero da estro-progestinici. Descrizione di un caso.

A case of oestroprogestinic icterus is reported. The potential toxicity of these drugs, which have now been in use for twenty years in medical and non-medical practice, on liver parenchyma is discussed. Such treatment should be carried out only under the attentive, constant control of a physician who should not neglect liver function in his examination.

PIP: A 31 year old woman was administered estroprogestinic drugs to cure menorrhagia. After 7 days of treatment jaundice was apparent; it receded spontaneously after stopping the treatment. It is not known whether it is the estrogen component or the progesterone one which is responsible for hepatic side effects. It is known, however, that most such cases occur in North Europe and in South America much more frequently than in South Europe or in North America. It is possible that either familiar predisposition, or racial factors play a role in the occurrence of liver dysfunctions after administration of combined oral contraceptives. Such drugs should be used only under strict medical control.