Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson’s Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice

Parkinson’s disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating αSyn/Syn III interaction and having the ability to reduce αSyn aggregation in vitro and to restore the motility of αSyn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of αSyn clearing agents for PD therapy

Lung microbiome in idiopathic pulmonary fibrosis and other interstitial lung diseases

Interstitial lung diseases represent a heterogeneous and wide group of diseases in which factors leading to disease initiation and progression are not fully understood. Recent evidence suggests that the lung microbiome might influence the pathogenesis and progression of interstitial lung diseases. In recent years, the utilization of culture-independent methodologies has allowed the identification of complex and dynamic communities of microbes, in patients with interstitial lung diseases. However, the potential mechanisms by which these changes may drive disease pathogenesis and progression are largely unknown. The aim of this review is to discuss the role of the altered lung microbiome in several interstitial lung diseases. Untangling the host–microbiome interaction in the lung and airway of interstitial lung disease patients is a research priority. Thus, lung dysbiosis is a potentially treatable trait across several interstitial lung diseases, and its proper characterization and treatment might be crucial to change the natural history of these diseases and improve outcomes

"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 \ub1 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys

Quando ospedalizzare un paziente con polmonite acquisita in comunità

Il sito di cura \ue8 probabilmente la decisione clinica pi\uf9 importante nella gestione di un paziente con polmonite acquisita in comunit\ue0 (CAP), alla luce del suo impatto sia sull'esito del paziente che sui costi sanitari. Diversi fattori possono contribuire in questa decisione, compresi l'esperienza e il giudizio clinico del medico, score di gravit\ue0 che predicono il rischio di morte e problematiche sociali ed assistenziali. Il riconoscimento, sia sul territorio che in Pronto Soccorso, della presenza di una polmonite grave, di insufficienza respiratoria acuta e della coesistenza di altre comorbilit\ue0 scompensate \ue8 fondamentale per l'indicazione alla ospedalizzazione. In tutti gli altri casi, la decisione del medico di ricoverare un paziente con CAP deve essere presa valutando anche uno score oggettivo di analisi del rischio di morte, avendo ben chiare le limitazioni proprie di ogni score.Where to treat a patient is probably the single most important decision in the management of communityacquired pneumonia (CAP), with a substantial impact on both patients' outcomes and healthcare costs. Several factors can contribute to the decision of the site of care of CAP patients, including physicians' experience and clinical judgment, severity scores developed to predict mortality, as well as social and healthcare-related issues. The recognition both in the community and in the emergency department of the presence of severe sepsis and acute respiratory failure, and the coexistence with unstable comorbidities other than CAP are indications for hospital admission. In all the other cases, physician's choice to admit a CAP patient should be validated against at least one objective tool of risk assessment, with a clear understanding of each score's limitations

The management of community-acquired pneumonia in the elderly

Pneumonia is one of the main causes of morbidity and mortality in the elderly. The elderly population has exponentially increased in the last decades and the current epidemiological trends indicate that it is expected to further increase. Therefore, recognizing the special needs of older people is of paramount importance. In this review we address the main differences between elderly and adult patients with pneumonia. We focus on several aspects, including the atypical clinical presentation of pneumonia in the elderly, the methods to assess severity of illness, the appropriate setting of care, and the management of comorbidities. We also discuss how to approach the common complications of severe pneumonia, including acute respiratory failure and severe sepsis. Moreover, we debate whether or not elderly patients are at higher risk of infection due to multi-drug resistant pathogens and which risk factors should be considered when choosing the antibiotic therapy. We highlight the differences in the definition of clinical stability and treatment failure between adults and elderly patients. Finally, we review the main outcomes, preventive and supportive measures to be considered in elderly patients with pneumoni