Cardiovascular risk factors, anxiety symptoms and inflammation markers: Evidence of association from a cross-sectional study

Introduction Anxiety disorders and Cardiovascular (CV) diseases, among the most common disorders in Western World, are often comorbid. A chronic systemic inflammatory state might be a shared underlining pathophysiological mechanism. Aims To investigate the association between anxiety symptoms, CV risks factors and inflammatory markers in an outpatient sample. Methods Cross-sectional study. Inclusion criteria: outpatients aged ≥40 years, attending colonoscopy after positive faecal occult blood test, negative medical history for cancer. Collected data: blood pressure, glycaemia, lipid profile, waist circumference, BMI, PCR (C Reactive Protein), LPS (bacterial Lipopolysaccharide). Psychometric tests: HADS, TCI, IMSA, SF36. Statistical analysis performed with STATA13. Results Fifty four patients enrolled (27 males, 27 females). Sixteen patients (30.19%) were positive for anxiety symptoms. Thirty-three patients (61.11%) had hypertension, 14 (25.93%) hyperglycaemia and 64.81% were overweight, with frank obesity (BMI≥ 30) in 11 subjects (20.37%). Anxiety symptoms were associated with low hematic HDL values (OR = 0.01; P = 0.01) and high concentration of triglycerides (OR = 0.023; P = 0.02) at the multiple regression model. At the univariate logistic analysis, anxiety was associated with LPS (OR = 1.06; P = 0.04). Conclusions Further evidence over the epidemiological link between common mental disorders and CV diseases was collected, with possible hints on pathophysiology and causative mechanisms related to inflammation. The importance of screening for anxiety and depression in medical populations is confirmed. Suggestions on future availability of screening tools based on inflammatory-related indicators should be the focus of future research

The monoclonal antibody nBT062 conjugated to maytansinoids has potent and selective cytotoxicity against CD138 positive multiple myeloma cells _in vitro_ and _in vivo_

CD138 (Syndecan1) is highly expressed on multiple myeloma (MM) cells. In this study, we examined the anti-MM effect of murine/human chimeric CD138-specific monoclonal antibody (mAb) nBT062 conjugated with highly cytotoxic maytansinoid derivatives _in vitro_ and _in vivo_. These agents significantly inhibited growth of CD138-positive MM cell lines and primary tumor cells from MM patients, without cytotoxicity against peripheral blood mononuclear cells from healthy volunteers. In MM cells, they induced G2/M cell cycle arrest followed by apoptosis associated with cleavage of PARP and caspase-3, -8 and -9. Non-conjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells (BMSCs). Co-culture of MM cells with BMSCs, which protects against dexamethasone-induced death, had no impact on the cytotoxicity of the immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth _in vivo_ in both human multiple myeloma xenograft mouse models and in SCID-human bone grafts (SCID-hu mouse model). These studies provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM

Applying lean methodologies to improve the OEE of a manufacturing line : a case study in a pharmaceutical company

LAUREA MAGISTRALENel settore farmaceutico, specialmente quando si tratta di iniettabili, è presente un alto livello di attenzione verso i processi produttivi. Il focus di questo studio è il miglioramento dell’ OEE di una linea automatica di produzione strategica all’interno di un azienda farmaceutica di medie dimensioni tramite l’utilizzo di tecniche Lean. Durante lo svolgimento del progetto siamo stati supportati da un team che ci ha fornito la conoscenza e le capacità necessarie. L’uso della struttura A3 ci ha permesso di sviluppare il progetto in maniera metodologica, cominciando da una misurazione dettagliata dei processi e un graduale aumento del focus sui problemi fino a quando non siamo riusciti a trovare le cause radice e a eliminarle con le contromisure più efficaci possibili. Questo ci ha permesso di raggiungere gli obbiettivi prefissati. Le soluzioni implementate sono poi diventate lo standard dell’ azienda, le strategie sviluppate per favorire il sostenimento nel tempo, permetteranno il miglioramento continuo e un maggior controllo sui processi da parte dei capi reparto. Le soluzioni sviluppate hanno avuto effetto sia sul macchinario che l’organizzazione degli operatori : i miglioramenti hardware hanno richiesto un grande sforzo di studio della linea e di identificazione delle cause radice, mentre le pratiche manageriali come 5s e Visual Management sono state proposte agli operatori e ai capi reparto e validate più volte, e grazie ai feedback ricevuti siamo riusciti a trovare le soluzioni più adatte. Per assicurarci che i risultati raggiunti diventino il nuovo standard dei processi, abbiamo sviluppato degli indicatori di performance e un sistema di monitoraggio capace di trovare velocemente dei discostamenti dalla condizione raggiunta e permettere di reagire prontamente per evitare la deriva dei processi. Per concludere possiamo dire che specialmente per linee automatiche datate, degli interventi concentrati ed efficaci possono permettere di ottenere miglioramenti considerevoli della produttività. Per quanto riguarda l’aspetto manageriale invece, una gestione delle operazioni più standardizzata e la trasmissione dei giusti valori porta ad una maggiore consapevolezza da parte dell’operatore riguardo al suo ruolo nel dipartimento e un attenzione maggiore rispetto alla performance della linea, che viene poi tradotta in OEE.In the Pharmaceutical industry, especially for injectables, there is a high focus on the production processes. The focus of this study is the improvement of the OEE of a strategic automated filling line in a medium sized Pharmaceutical company through the use of Lean techniques. In order to do so we were supported by a team that provided the knowledge and the skills required for the project development. The use of the A3 logic allowed us to methodologically develop the project starting from a detailed measurement of the processes and gradually narrowing our focus until we were able to find the main root causes and we were able to assess them with the most effective countermeasures. This allowed us to achieve the results set for the project. The solutions implemented then became company standards and, thanks to strategies developed for their sustaining, will allow continuous improvement and a higher control over the processes for the managerial level in the long period. The countermeasures impacted both the machine hardware and the operator’s organization: the hardware improvements required onerous measuring and a long process of root cause identification, while the managerial practices such as visual management and 5S have been proposed and validated multiple times, and thanks to the multiple feedbacks received by the operators and production managers we were able to find the most fitting solutions. To make sure that the achieved results became the new standard for the processes, we developed KPIs and also a monitoring system able to quickly detect any deviations from the reached condition and act accordingly to avoid returning to the initial situation. In conclusion, we can say that especially for outdated automated lines, focused and effective hardware changes allow to obtain considerable improvements in productivity. For what concerns the managerial aspect instead, a more standardized operations management and the transmission of the right values leads to a higher awareness of the operator’s role inside the department and a higher attention to the line performance which is then translated into a higher OEE

Design, stereoselective synthesis, configurational stability and biological activity of 7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide

Chiral 5-arylbenzothiadiazine derivatives have recently attracted particular attention because they exhibit an interesting pharmacological activity as AMPA receptor (AMPAr) positive modulators. However, investigations on their configurational stability suggest a rapid enantiomerization in physiological conditions. In order to enhance configurational stability, preserving AMPAr activity, we have designed the novel compound (R,S)-7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide bearing a pyrrolo moiety coupled with the 5-(furan-3-yl) substituent on benzothiadiazine core. A stereoselective synthesis was projected to obtain single enantiomer of the latter compound. Absolute configuration was assigned by X-ray crystal structure. Patch clamp experiments evaluating the activity of single enantiomers as AMPAr positive allosteric modulator showed that R stereoisomer is the active component. Molecular modeling studies were performed to explain biological results. An on-column stopped-flow bidimensional recycling HPLC procedure was applied to obtain on a large scale the active enantiomer with enantiomeric enrichment starting from the racemic mixture of the compound

Crimini online come risultato di un sistema di interconnessione digitale. Una riflessione cyber criminologica

I cybercrime, in cui il dispositivo elettronico è lo strumento utilizzato nell’esecuzione dell’azione criminale, nonché il comportamento del cyber-criminale, specialmente se adolescente, sono stretta-mente connessi ai nuovi comportamenti devianti in rete ed entrambi dipendono fortemente dal contesto in cui si sono sviluppati: il cyber-spazio. La riflessione parte dall’analisi dell’unicità del contesto virtuale ovvero della sua capacità pervasiva, analizzando i mutamenti in ambito personale, relazionale, emotivo e sessuale, dovuti alla trasposizione di tali ambiti nel contesto online, al fine di comprendere come questi influenzino il comportamento degli utenti. Tale riflessione ha permesso di delineare un sistema di connessioni in cui diversi fattori, tra i tanti la possibilità di agire in anonimato unitamente all’effetto disinibente del Web, facilitano l’assunzione di comportamenti devianti e a rischio online, come quello del sexting, nonché la commissione di alcuni dei cyber-reati di grande interesse criminologico, come il revenge porn o, più in generale, la pornografia non consensuale. Gli utenti, in tale prospettiva, influenzati dall’enorme potenza persuasiva e pervasiva del Web, in cui i rapporti, digitalizzati, sono alleggeriti dalla loro componente emotiva ed investiti da una conseguente riduzione empatica. L’enorme sistema di interconnessioni digitali delineato vuole mettere in luce le alterazioni percettive alle quali gli utenti sono soggetti e che rendono indispensabile la sensibilizzazione ad uso consapevole del Web, al fine di prevenire la – probabile – crescita dei fenomeni criminali online

The still under-investigated role of cognitive deficits in PML diagnosis

Background: Despite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML. Methods: Thirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail. Result: After symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc). Conclusion: Cognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment