Parkinson's Disease-Mild Cognitive Impairment (PD-MCI): A Useful Summary of Update Knowledge

Mild cognitive impairment (MCI) is a common feature in Parkinson's Disease (PD), even at the time of diagnosis. Some levels of heterogeneity in nature and severity of cognitive impairment and risk of conversion to Parkinson's Disease Dementia (PDD) exist. This brief overview summarized the current understanding of MCI in PD, by considering the following major points: historical development of the clinical entity, evaluation, epidemiology, predictors and outcomes, neuroimaging findings, pathophysiology, treatment, and pharmacological and non-pharmacological intervention. MCI in PD represents a concept in evolution and plays a pivotal role in advancing our understanding of the disease mechanisms, with the ultimate goal of building effective strategies to prevent conversion into PDD. Challenges for future research are also discussed

Pretreatment with Ibuprofen Augments Circulating Tumor Necrosis Factor-α, Interleukin-6, and Elastase during Acute Endotoxinemia

Plasma levels of tumor necrosis factor-α (TNFα), interleukin-1 (IL-1),and interleukin-6 (IL-6) were monitored after intravenous administration of Escherichia coli endotoxin with or without ibuprofen pretreatment to healthy volunteers. Intravenous endotoxin (n = 7) resulted in elevated plasma TNFα concentrations with maximal levelsat 90 min (369 ± 44 pg/ml, P < .001 vs. saline controls, n = 7). The rise in TNF-α was followed by a rise in plasma IL-6 (27 ± 12.8 ng/ml), peaking 30-90 min thereafter. Pretreatment with ibuprofen (n = 6) caused a significant augmentation and temporal shift in cytokine elaboration with maximal TNFα levels(627 ± 136 pg/ml) at 120 min and IL-6 peaks (113 ± 66 ng/ml) at 180 min. In ibuprofen-treated volunteers, the additional increase in TNFα was paralleled by increased levels of circulating elastase. In vitro experiments suggest a causal relationship between these events. Thus, the cyclooxygenaseinhibitor ibuprofen blunts the clinical response to endotoxin but augments circulating cytokine levels and leukocyte degranulatio

Follow-up ecografico in pazienti ospedalizzati per polmonite da SARS-CoV-2 presso l'Azienda Ospedaliera Universitaria Pisana

Introduzione La patologia da SARS-CoV-2 (COVID-19) si manifesta con differenti quadri clinici, da infezione paucisintomatica a polmonite interstiziale, fino ad arrivare a forme più severe di insufficienza respiratoria acuta e coinvolgimento multiorgano. La patologia determina una imponente cascata infiammatoria, responsabile delle sue manifestazioni cliniche più temibili. L’ecografia polmonare (LUS) è una metodica di facile applicazione ampiamente utilizzata durante la pandemia per valutare bed-side l’impegno polmonare nel COVID-19 e i suoi specifici patterns (light beam sign, linee B confluenti) dimostrando un ruolo cruciale nella diagnosi e nel monitoraggio dei pazienti ospedalizzati. I dati relativi al follow-up a distanza risultano ancora limitati, così come studi che indentifichino gli elementi cinici o anamnestici responsabili di sequele a lungo termine. Scopo L’obiettivo primario dello studio è stato descrivere l’evoluzione dell’impegno polmonare e dei tipici pattern ecografici della polmonite COVID-19 valutati con LUS standardizzata dopo 3 mesi dalla dimissione ospedaliera. Secondariamente, è stato valutato l’impatto di età, comorbilità, setting di ricovero e indici laboratoristici di flogosi al momento del ricovero nell’esito della valutazione ecografica di follow-up. Pazienti e metodi Lo studio è stato condotto su 80 pazienti con diagnosi di COVID-19 ricoverati presso l’Azienda Ospedaliero-Universitaria Pisana (AOUP) nel periodo da marzo a novembre 2020, che hanno aderito al follow-up a 3 mesi dalla dimissione. La metodologia ecografica impiegata sia durante la degenza (T0) che al follow-up (T1) prevedeva l’esplorazione di 16 spazi toracici da parte di operatori esperti, con assegnazione di un punteggio di tipo sia qualitativo (interessamento pleurico/sottopleurico, interstiziale, consolidamento) che quantitativo (numero di sedi impegnate, punteggio crescente in base al grado di deaerazione polmonare). Sono state inoltre valutate le caratteristiche anamnestiche, cliniche, laboratoristiche e la gestione ospedaliera dei pazienti durante il loro periodo di ospedalizzazione. Risultati È stata osservata una riduzione significativa del LUS score (da 14.4 ± 8.5 a 5.1± 5.6, p 65 anni, con comorbilità cardiovascolari e respiratorie, presentano un LUS score a T1 significativamente più elevato del gruppo non patologico (rispettivamente LUS score medio 8.6 ± 6.6 vs 2.7 ± 2.9, p = 0.36; 6.6 ± 6.1 vs 2.8 ± 3.7, p < 0.003; 9.2 ± 6.6 vs 4.6 ± 4.9, p 0,04). Analogamente, quando la popolazione è stata suddivisa in base al valore di mediana dei principali indici di flogosi valutati in DEA e all’ammissione in reparto, è stato evidenziato che i pazienti con valori più elevati di PCR (p=0.05), IL6 (p=0.01), TNF (p=0.03), MCP1 (p =0.01) avevano valori medi di LUS score significativamente più elevati alla valutazione ecografica di follow-up. Ciò non si verifica per IL10 (p=0,87). Discussione e conclusioni Al controllo di follow-up a 3 mesi l’ecografia polmonare eseguita con modalità standardizzata mette in evidenza una significativa riduzione del LUS score, la scomparsa del light beam e la riduzione significativa delle linee B confluenti. Tali reperti ecografici identificano pertanto la polmonite da SARS-CoV-2 nella sua fase acuta. L’età più elevata, le comorbilità e una più spiccata risposta infiammatoria all’ammissione ospedaliera, sembrano elementi che influiscono sulla persistenza di alterazioni patologiche all’ecografia polmonare eseguita a distanza dall’ospedalizzazione per COVID-19

Molecular analysis of the APC gene in Sicilian patients with familial adenomatous polyposis (F.A.P.)

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome, caused by germline mutations in the adenomatous polyposis coli (APC) suppressor gene. Patients with colorectal polyps are more likely to develop a malignant condition with poor prognosis. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extra-colonic manifestations; an attenuated form of polyposis (AFAP), presenting less than 100 adenomas and later onset, has been reported. In this study we have examined five Sicilian families affected by FAP syndrome, in order to provide predictive genetic testing for the affected families, as well as to contribute to mutation catalog enrichment. We have detected different APC mutations in these five pedigrees, confirming the remarkable heterogeneity of the mutational spectrum in FAP

Molecular screening in Sicilian families with hereditary non-poliposis colorectal cancer (H.N.P.C.C.) syndrome: identification of a novel mutation in MSH2 gene

HNPCC is an autosomal inherited cancer syndrome characterized by germinal and somatic mutations of DNA mismatch repair (MMR) genes. The inherited mutation in one allele together with an acquired defect in the other allele of an MMR gene leads to accelerate tumor progression. In this study we analyzed a cohort of 11 subjects belonging to four Sicilian families with HNPCC suspected by molecular analysis of coding regions of hMSH2 (NC_000002) and hMLH1 (NC_000003) genes. Molecular analysis has detected the presence of two mutations in gene MSH2 and one mutation in MHL1 gene. In addition, we found a novel mutation consisting in a G deletion at 914 codon of the exon 16 in the MSH2 gene. This deletion leads to a stop codon due to a frame-shift, resulting in a truncated protein. We extended genetic analysis to the other family members and the same mutation was detected in three sisters and in one of the two healthy daughters. This mutation is correlated with clinical findings revealed in genealogic tree and it represents a novel mutation responsible of HNPCC

A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma.

One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity