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Purpose The current randomized, double-blind, placebo-controlled clinical trial addressed the effects on penile erectile function of relatively high daily oral doses (6 g/day) of l-ARG for 3 months (N = 51) compared to placebo (N = 47), in patients with vasculogenic ED, with comparison between mild–moderate and severe vasculogenic ED. Methods The outcome measures included IIEF-6 score and cavernous arteries peak systolic flow velocity (PSV) at dynamic penile duplex ultrasonography (PDU). Results l-ARG supplementation for 3 months significantly increased IIEF-6 score in the overall cohort (p p p = 0.007) vasculogenic ED; PSV was significantly increased in the overall cohort (p p Conclusion The results of the current study demonstrated that supplementation with relatively high doses of l-ARG as a single compound for 3 months significantly improved penile erectile function, assessed by both IIEF-6 score and PSV at dynamic PDU in patients with mild–moderate, and improved IIEF-6 score, but not PSV, in patients with severe vasculogenic ED, therefore suggesting that l-ARG might be an alternative treatment in mild–moderate vasculogenic ED patients experiencing adverse effects or with contraindications for chronic treatment with PDE5i compounds.

Background Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disorder, leading to mainly arterial complications, caused by COL3A1 pathogenic variations. Ong et al. (Lancet 2010) showed that the introduction of celiprolol significantly reduced arterial events in a predominantly symptomatic population on arterial level. We reported the benefit of full dose of Celiprolol in longitudinal study to prevent arterial events in Frank et al. (JACC 2019). To our knowledge, there is no data regarding the benefit of celiprolol in patients without any arterial event. Purpose The aim of this study was to assess the occurrence of arterial events during follow-up in vEDS patients without arterial event. Methods All patients – probands and relatives – with a pathogenic variation in COL3A1 diagnosed at the Referral Centre for Rare Vascular Diseases since 2001 and at least one arterial tree assessment were included. We then focused on vEDS patients without any arterial event. We retrospectively analyzed the duration of follow-up, the occurrence of arterial events during follow-up, and the introduction and dose of celiprolol, especially at the time of occurrence of an arterial event. Results Among the 230 patients included, 144 (63%) had at least one symptomatic arterial event, 44 (19%) had only silent arterial event and 67 (29%) had no arterial event at the first arterial tree assessment event. Patients with no arterial event were significantly younger at this visit compared with the two other groups with a median age of 23 vs. 38 and 39 years (silent and symptomatic) (p Conclusions Genetic testing of the relatives of probands with vEDS remains of utmost importance as one quarter presented with symptomatic arterial event and one fifth had silent arterial event at initial arterial tree assessment. For patients with no arterial event, those without celiprolol have a similar incidence of arterial events than those with celiprolol, however their follow-up duration was twice shorter suggesting a higher incidence rate or arterial event in the absence of celiprolol. Funding Acknowledgement Type of funding sources: None.

To elicit oncology nurse leaders' perceptions and experiences of accessing, using and interpreting report data at the unit level, and their suggestions for future reports.Nurse leaders are expected to use data reports for decisions about unit-level operations, yet data may be inaccessible, unavailable and lack relevance for improving patient care and unit-level outcomes.A purposeful sampling was used to recruit 12 unit-level nurse leaders. Qualitative data were collected through semi-structured interviews and analysed using thematic content analysis.Consistent themes included the lack of accurate, useful and meaningful data specifically related to patient care. Accessibility Challenges, Limits to Applicability and Suggestions for Improvement were the main themes.Nurse leaders require real-time data to effectively implement clinical interventions and practice changes for improving unit-level patient care.Nurse leaders emphasized that their insight into the development of customizable reports is crucial for obtaining meaningful data relevant to the varied unit-level health care setting. Reports targeting unit-level outcomes would provide meaningful data to facilitate clinical improvement where patient care is provided. Improved reports increase the likelihood of their use and the potential for enhancing the quality and safe care outcomes.

This study will test the feasibility and effectiveness of mobile technology intervention on the patients' self-management of oral anticancer medication. Secondary objectives include acceptability, the usefulness of text messages, and satisfaction by participants and nurses.This prospective two-arm study will recruit patients (N = 220) with metastatic breast cancer and initiating treatment with palbociclib (Ibrance ®). Allowing for attrition, patients will be randomized into the control (N = 100) or intervention (N = 100) group. Unidirectional text message reminders will be sent during the treatment cycle through a secure web application using the patient's smartphone. Self-reported survey responses will be collected at three time points; at consent, end of treatment cycles, and the follow-up clinic visit and include a demographic questionnaire, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Post study questionnaire and the R-15 Patient Satisfaction Questionnaire. Nurses providing care for study patients will complete the Adaptation of Stamps Nurse Workload questionnaire. Data will be analysed an intent-to-treat analysis comparing the two arms. Study approval was obtained in December 2019 and funded in January 2020.Smartphones are globally available and have text messaging capability which is increasingly being used as an intervention in healthcare studies. This study will test a low-cost, nurse-led intervention that enhances the patient's experience with oral anti-cancer medications, improves access to care, reduces costs, and improves the satisfaction of nurses caring for oncology patients.Despite the ease of administering oral anti-cancer medications, oncology patients maynot take them as prescribed and consequently, these factors affect patient outcomes and disease control. Given the importance of taking oral anti-cancer medications and the difficulties patients experience in achieving it, the effective use of mobile technology interventions can actively engage patients in their care and improve medication self-management of anticancer treatment regimens.目的: 本项研究旨在验证移动技术干预对患者口服抗癌药物自我管理的可行性和有效性。次要目的包括可接受性, 短信的有用性, 以及参与者和护士的满意度。 方法: 这项前瞻性双臂研究将招募转移性乳腺癌患者 (N=220) , 并开始使用帕博西尼(爱博新®) 进行治疗。考虑到损耗, 患者将被随机分为对照组 (N=100) 或干预组 (N=100) 。在治疗周期内, 将使用患者智能手机的安全web应用程序发送单向短信提醒。将在三个时间点收集自我报告的调查结果: 同意时、治疗周期结束时和随访门诊就诊, 包括人口统计问卷、欧洲癌症研究与治疗组织生活质量调查问卷, 研究后调查问卷和R-15患者满意度调查问卷。护理研究病人的护士将完成护士工作量调查问卷的改编。将分析数据, 并对两组数据进行意向-治疗分析比较。该项研究于2019年12月获得批准, 于2020年1月获得资助。 讨论: 智能手机在全球范围内均可使用, 并具有短信功能, 因此其越来越多地被用作医疗保健研究的干预手段。此项研究将测试一种低成本的、护士主导的干预措施, 以提高患者口服抗癌药物的经验、改善获得护理的机会、降低成本, 以及提高护理人员对肿瘤患者的满意度。 影响: 尽管口服抗癌药物很容易服用, 但肿瘤患者可能不按医嘱服用, 因此, 这些因素会影响患者恢复结果和疾病控制。考虑到口服抗癌药物的重要性以及患者在服用过程中遇到的困难, 有效地使用移动技术干预可以有效地让患者参与到他们的护理中, 并改善抗癌治疗方案的药物自我管理。.

Objective: This article describes how one comprehensive cancer center in the Northeast United States reorganized their nursing research fellowship (NRF) with the goals of engaging nurses in research processes, developing a culture of inquiry, building nursing research capacity, and sustaining infrastructures for facilitating high-quality, nurse-led oncology research studies. Methods: The basis for the curriculum, course work, and research practicum is derived from academic courses taught at the undergraduate, graduate, and doctoral levels. Evidence from the current literature, expertise of nurse-scientists, and feedback from former fellows provided the background for a fellowship model that included: (1) amending curriculum timeframes; (2) incorporating protected time; (3) improving access to resources; (4) enhancing the protection, data sharing, and accessibility of data; and (5) involving nurse-scientists as mentors and facilitators of research processes. These factors were incorporated over 3 years. Metrics included individual class and overall course evaluations and ongoing assessments. Results: In three cohorts from 2016 to 2019, a total of 21 nurses were accepted, and 18 (86%) nurses completed the NRF. In cohort 1 through cohort 3, 17 fellows presented their research findings internally, and a total of nine projects were presented at external forums. There were seven fellows whose manuscript submissions resulted in 21 journal publications. Of the 18 fellows, 15 (83%) conducted institutional review board-approved studies and three (17%) fellows developed studies involving one concept analysis and two systematic reviews. Conclusions: Utilizing technology, the fellowship improved access beyond the classroom setting. Improved application processes, the inclusion of protected time for nurses, and mentoring from nurse-scientists demonstrate a commitment to fostering a culture supporting new knowledge and innovation for improving patient care.

Objective The primary objective of this review is to analyze and synthesize the best available evidence on the experiences and perceptions of psychological stress reported by pancreatic cancer patients at any time point from pre-diagnosis, diagnosis, treatment, post-treatment and/or follow-up care. Introduction A cancer diagnosis is known to be life-threatening, altering and limiting, and negatively affects an individual's activities of daily living. Despite developments in treatment options for pancreatic cancer patients, it represents the highest mortality and morbidity among cancers. Stress is a subjective phenomenon that negatively impacts an individual's psychological and emotional well-being, and interferes with the ability to cope with cancer symptoms and treatments. Identifying a patient's experience of stress could facilitate educational, spiritual and social resources to address his or her emotional and psychological needs. Inclusion criteria Qualitative studies that include individuals with pancreatic cancers, regardless of age, sex or ethnicity, will be considered for inclusion in this review. Methods The databases to be searched include PubMed, CINAHL, Cochrane, Web of Science, Embase, Scopus, BioMed Central and PsycINFO. The search for gray literature will include Biosis, OpenGrey, Open Access Theses and Dissertations, and WorldCat. This systematic review will consider all published and unpublished studies with no date limitations. Selected studies will be assessed for methodological quality by two independent reviewers. Coding will be assigned to synthesize any differences in the experiences and perceptions of psychological stress at four time points. Where textual pooling is not possible, conclusions will be presented in narrative form.

Retinal degenerative diseases (RDD) such as retinitis pigmentosa (RP) have no treatment. Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. We investigated a novel approach in which human retinal progenitor cells (RPCs) derived from primitive mesenchymal stem cells (pMSCs) were examined to treat retinal degeneration in an rd12 mouse model of RP. Intravitreally transplanted cells improved retinal function and significantly increased retinal thickness. Transplanted cells homed, survived, and integrated to various retinal layers. They also induced anti-inflammatory and neuroprotective responses and upregulated neurogenesis genes. We found that RPCs were more efficacious than pMSCs in improving the retinal structure and function. RNA analyses suggest that RPCs promote neuroprotection and neuronal differentiation by activating JAK/STAT and MAPK, and inhibiting BMP signaling pathways. These promising results provide the basis for clinical studies to treat RDD using RPCs derived from pMSCs.

Sudden cardiac death, mostly related to ventricular arrhythmia, is a major public health issue, with still very poor survival at hospital discharge. Although coronary artery disease remains the leading cause, other etiologies should be systematically investigated. Exhaustive and standardized exploration is required to eventually offer specific therapeutics and management to the patient as well as his/her family members in case of inherited cardiac disease. Identification and establishing direct causality of the detected cardiac anomaly may remain challenging, underlying the need for a multidisciplinary and experimented team.

Resume Les pathologies genetiques sont la premiere cause d’atteinte anevrysmale et dissequante de l’aorte chez le sujet jeune, l’aorte ascendante etant touchee dans plus de 90 % des cas. Bien qu’hereditaires, ces pathologies sont genetiquement tres heterogenes, et peuvent paraitre sporadiques du fait de nombreux cas de mutations dites « de novo ». Elles sont classees en formes syndromiques et non syndromiques, l’examen clinique adapte etant un element cle de cette distinction. Les formes syndromiques sont majoritairement liees a un defaut de fonctionnement de la matrice extracellulaire. Elles sont parfois complexes a caracteriser cliniquement, car elles presentent une grande diversite d’atteintes y compris au sein d’une meme famille. Les formes non syndromiques sont de fait plus homogenes dans leur presentation, le mecanisme predominant etant un defaut de l’appareil contractile des cellules musculaires lisses aortiques. L’evaluation du risque genetique doit etre proposee devant tout atteinte aortique ascendante chez un patient de moins de 50 ans ou presentant peu de facteurs de risque cardiovasculaires, afin d’identifier la pathologie sous-jacente, assurer une surveillance et une prevention adaptee chez le patient et ses apparentes a risque. Une revue de ces syndromes avec leurs principales caracteristiques cliniques, physiopathologiques et genetiques est presentee, accompagnee de precisions sur les demarches genetiques a effectuer face a une suspicion diagnostique.

Background Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). Objectives This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. Methods This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. Results Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. Conclusions In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253)

OBJECTIVES: Associations between the varying levels of emotional intelligence in newly hired oncology nurses and their responses to stress and coping were examined. The secondary aim was to analyze whether emotional intelligence could moderate their choice of problem-focused or emotion-focused coping strategies. METHODS: Newly hired nurses (n = 114) were recruited from a national cancer institute. Data were collected through surveys using the Ways of Coping Questionnaire, the Nursing Stress Scale and the Emotional Quotient Inventory between the eighth and twelfth weeks post-hire date. Descriptive and bivariate statistical analyses were conducted on all variables. Regression models determined whether emotional intelligence moderated the choice of coping strategies. RESULTS: Emotional intelligence had a mean value of M = 105.24, SD = 13.02 and occupational stress scores were M = 65.57, SD =15.68. Significant negative correlations were found for occupational stress and problem-focused coping (r = −.189, p = .022), emotional intelligence and emotion-focused coping (r = − .340, p = .000) and emotional intelligence and occupational stress (r = − .428, p < 0 .001). Positive correlations were noted between occupational stress and emotion-focused coping (r = .189, p = .022) and emotional intelligence and problem-focused coping (r = .340, p = .000). Emotional intelligence did not predict the choice of coping strategies. CONCLUSIONS: Though emotional intelligence did not moderate coping strategies in newly hired nurses, using problem focused coping to address occupational stress during the initial employment period may be a protective factor for coping with stress in the oncology workplace.

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E19) deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E19 in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E19 in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E19 and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway. © 2018 by The American Society of Hematology.

Riassunto Obiettivi Descrivere l’atteggiamento clinico nella risoluzione dei piu frequenti difetti di cresta da riabilitare con implantologia, sulla base delle metodiche maggiormente validate dalla letteratura scientifica. Materiali e metodi La rigenerazione guidata dell’osso attraverso membrane barriera ad azione occlusiva e praticabile in differenti difetti ossei alveolari. Tale fenomeno si puo comprendere se si conosce la cascata degli eventi biologici a carico dei tessuti duri e molli che si innesca durante la rigenerazione guidata. E indispensabile classificare i difetti localizzati delle creste edentule per poter adottare protocolli chirurgici appropriati laddove la morfologia non si associ a una rigenerazione spontanea. Risultati Mediante casi clinici esemplificativi il lavoro mostra i risultati ottenibili con l’applicazione dei principi della GBR, inserendo gli impianti in maniera protesicamente guidata e non costringendo il protesista a realizzare una protesi di compromesso. Conclusioni I casi clinici trattati, usando un protocollo ripetibile e validato, sono l’esempio che non e solo l’anatomia del difetto l’elemento discriminante la quota di GBR ottenibile quanto il mantenimento dell’“effetto tenda” che il Gore-Tex ® con rinforzo in titanio puo fornire se opportunamente sagomato.

Objective Bicuspid aortic valve (BAV) is associated with high incidence of ascending aortic aneurysm. In BAV sporadic form, changes in outflow's hemodynamic secondary to the valvular morphotype are said to play a prominent role in the aortic dilatation. We aimed at comparing the different ascending aorta segment diameters according to the morphotype and the function of the BAV. Methods We evaluated 174 patients with sporadic BAV by transthoracic echocardiography. The valvular function was defined as either Aortic Insufficiency (AI) if Grade ≥ 2 and aortic Stenosis (AS) if mean gradient > 20 mmHg. Aortic diameters were measured at the Valsalva sinus, tubular ascending aorta and at the aortic arch. Kruskal-Wallis, Mann–Whitney and Spearman tests were used for comparisons. Results Among the non-operated patients, Sievers’ morphotype was type 1LR for 63%, type 1NR for 18%, and other types counted for 19%. The Valsalva sinus diameter did not differ according to the Sievers’ type (P = 0.78). The type 1LR type compared to the type1NR appeared to have a wider tubular aorta, but not significantly (42.3 ± 8.5 vs. 36.4 ± 7.3 mm; P = 0.06). Aortic valve function was distributed as follows: AI: 39%, AS: 20%, Both: 9%, Normal: 32%. Comparison of the different valve dysfunctions revealed a difference at the Valsalva (P Conclusion Our results showed the tremendous role of AI in the aortic dilation of all segments except the arch. However no influence of BAV morphotype was noticed on aortic diameters. Our results give rise to the relatively limited influence of the valvular morphology in the development of aortic dilation.

Many five membered etherocyclic rings attract attention as their non planar structures leads to a variety of desirable unique features in the so called “banana” mesogens, for their slightly bent structures. Thiophene in particular has emerged as a core unit that is receiving increasing attention, both in organic and in coordination compounds. Thiophene based polymers are often employed in optics and opto-electronics for its unique properties. Here we present the synthesis of two types of polymers. Their LC behaviour is investigated. The polymers are characterized by the presence of flexible chains and of a thiophene unit in the rigid molecular segment: -C6H4-CH=N-2,5-(C4H2S)-N=N-C6H4-. One type of polymer is a simply organic main-chain LC polymer, eventually bearing functions suited for crosslinking. The second type is a coordination polymer of Pd(II) or Cu(II) where the coordination environment is given by two chelating N,O- moieties.

Purpose. To develop gastroretentive microspheres for the oral administration of bromelain (BRO). Methods. Microspheres containing BRO were prepared with two different polymers, i.e. chitosan (CHI) and Eudragit® L 100 (EuL100). CHI-based microspheres were prepared by emulsification of an aqueous solution of BRO in paraffin, followed by cross-linking with Na2SO4 and solvent evaporation under nitrogen. The EuL100-based microspheres were prepared by dispersing solid BRO in a organic solution containing the polymer. The resulting suspension was then dispersed in paraffin oil to form a solid-in-oil-in-oil dispersion and the solvent was then evaporated under stirring. The microspheres were characterized in terms of dimensions, morphology, BRO actual loading and photolytic activity of the encapsulated BRO. In the case of CHI-based microspheres, release studies were evaluated in HCl 0.1N, in intestinal simulated fluid (SIF) and in rat cecal content (CCR). In vitro studies of BRO from the EuL100-based microspheres were investigated in PBS at different pH (i.e. 3.0, 6.8 and 7.2). Results. We prepared CHI-based microspheres characterised by mean diameter of 17.7 microm ± 9.1, and with an BRO encapsulation efficiency of 99.3 ± 1.5%. The proteolitic activity assay demonstrated that the BRO was encapsulated in its active form. However, the in vitro release studies showed absence of BRO release upon microsphere incubation in HCl 0.1 N, in SIF ed in CCR. In the case of the EuL100, we obtained microspheres with a mean diameter of 254 microm ± 47.4, with a BRO encapsulation efficiency of 87.0 ± 2.0%. In the in vitro release studies, BRO release from microspheres was not observed at pH 3.0, while a fast BRO release was obtained at pH 6.8 e 7.2. Conclusions. The EuL100-based microspheres have showed the release properties suitable to be used in the following in vivo experiments on rats.

Introduzione. Gli siRNA sono frammenti di RNA a doppio filamento in grado di inibire in maniera selettiva l’espressione di un gene specifico. Recentemente, è stato proposto l’impiego di siRNA per inibire l’espressione del fattore di necrosi tumorale alfa (TNF-alpha) nel trattamento dell’artrite reumatoide (AR). L’Impiego terapeutico degli siRNA è però ostacolato dalla loro rapida degradazione in vivo e dalla scarsa penetrazione nelle cellule. Tra le strategie proposte per migliorare il profilo farmacocinetico degli siRNA, le microsfere biodegradabili offrono vantaggi quali possibilità di essere iniettate nel sito di somministrazione senza necessità di rimozione chirurgica dopo il completo rilascio della molecola incapsulata. È stato dimostrato che tali sistemi possono proteggere, in presenza di nucleasi, gli acidi nucleici incapsulati, rilasciarli per tempi lunghi e aumentarne la penetrazione all’interno delle cellule. Scopo del lavoro. Studiare il potenziale applicativo di microsfere biodegradabili a base di acido poli(lattico-co-glicolico) (PLGA), per il rilascio prolungato di siRNA contro TNF-alpha nel trattamento dell’AR. Metodi. Sono state sviluppate microsfere di PLGA contenenti un siRNA con sequenza specifica anti-TNF-alpha. Le microsfere sono state preparate mediante la tecnica di emulsione multipla/evaporazione del solvente. Le dimensione delle microsfere sono strate valutate mediante Laser Light Scattering, mentre la loro morfologia è stata studiata mediante microscopia elettronica a scansione. La quantità di siRNA incapsulato ed il profilo di rilascio in vitro sono stati valutati mediante spettrofotometria UV. Risultati. Sono state preparate microsfere di PLGA contenenti siRNA anti-TNF-alpha. Le microsfere appaiono sferiche, omogenee e non porose con un diametro medio di circa 30 microm. Le microsfere sono caratterizzate da un elevato contentuo di siRNA (0,200 nmoli siRNA/mg PLGA) dovuto ad un‘efficienza di incapsulazione di circa 70%. In studi di rilascio in vitro del siRNA dalle miscrosfere è stato osservato dopo un lieve effetto burst, seguito da un rilascio lento e costante per oltre 40 giorni. Conclusioni. Le microsfere di PLGA hanno mostrato caratteristiche tecnologiche ottimali come sistema di veicolazione per siRNA nel trattamento di patologie quali l’AR. Sono attualmente in corso studi per valutare il potenziale applicativo delle microsfere di PLGA per il rilascio di siRNA anti-TNF-alpha in un modello animale di AR.

Introduzione. La bromelaina (BRO), droga estratta dal gambo di Ananas comosus, è una miscela di enzimi ad attività antinfiammatoria ed antidiarroica. Per via orale, la BRO è poco assorbita, soprattutto a causa dell’idrolisi acida ed enzimatica che avviene nello stomaco. Tra strategie per la veicolazione di sostanze all’intestino, l’impiego di polimeri gastroresistenti consente di liberare il principio attivo in seguito a variazioni di pH che si verificano nel tratto gastrointestinale. Un approccio più innovativo prevede l’impiego di polimeri sensibili alla presenza di enzimi presenti nell’intestino. Scopo del lavoro. Progettazione e sviluppo di microsfere gastroresistenti a base di un polimeri pH-sensile, Eudragit® L 100 (EuL100), e di un polimero, il chitosano (CHI), degradabile per azione di enzimi intestinali per la somministrazione orale della BRO. Metodi: Sono state preparate microsfere contenenti BRO a base di due diversi polimeri, il CHI e l’EuL100. Le microsfere (MS) di CHI sono state preparate con una tecnica di emulsione acqua-in-olio, reticolazione con Na2SO4 ed evaporazione del solvente in corrente di azoto. Le MS di Eu L100, invece, sono state preparate mediante una tecnica di dispersione solido-in-olio-in olio ed evaporazione del solvente. Tutte le MS sono state caratterizzate per dimensioni, morfologia, efficienza d’incapsulazione, attività proteolitica della BRO incapsulata. Per le MS di CHI, sono stati eseguiti studi di rilascio in HCl 0,1N, in fluido intestinale simulato (SIF), ed in contenuto cecale di ratto (CCR), mentre per MS di Eu L100 la liberazione della BRO è stata valuata in PBS a pH di 3,0, 6,8 e 7,2. Risultati e discussione. Sono state preparate MS di CHI con un diametro medio di 17,7 microm ± 9,1, con un’efficienza di incapsulazione del 99,3% ± 1,5. Il saggio per l’attività proteolitica ha dimostrato che la BRO, dopo incapsulazione, è ancora integra. Studi in vitro hanno dimostrato l’assenza di rilascio in in HCl 0,1 N, in SIF ed in CCR. Sono poi state preparate microsfere di EuL100 contenenti BRO. Le miscrosfere di forma sferica hanno un diametro medio di 254 mm ± 47,4. L’efficienza di incapsulazione della BRO nelle MS è di 87 ± 2%. Non è stato osservato rilascio di BRO a pH 3,0, mentre si osserva una rapida liberazione a pH 6,8 e 7,2, che si completa in 4 ore. Conclusioni. Le MS di di Eu L100 hanno mostrato caratteristiche di rilascio adatte alla veicolazione di BRO all’intestino, a differenza delle Ms di CHI con le quali non è stata osservata liberazione di BRO anche in CCR. Le MS di Eu L100 saranno utilizzate per anche successivi studi in vivo.

Acute erythroleukemia is a relatively rare disorder of a multilineal nature. Patients with this type of leukemia traditionally have been treated with a standard myeloid protocol, with a wide variation in prognosis between M6a, which has a similar prognosis to acute myelogenous leukemias, and M6b, with an extremely poor outcome despite aggressive therapy. Forty-eight archival cases of acute erythroleukemia, subtypes M6a (the traditional FAB-M6), M6b (pure erythroleukemia), and M6c (>30% myeloblasts and >30% pronormoblasts by FAB exclusion criteria), were evaluated for multidrug resistance gene (MDR-1) status. Findings were correlated with clinical course and karyotypes. Immunohistochemical stain for the protein product of MDR-1, P-glycoprotein, was variably positive in 11 of 23 patients with M6a, as well as in all of the patients with M6b (strongly positive) and M6c (weakly positive). P-glycoprotein expression positively correlated with unfavorable cytogenetic aberrations, poor response to chemotherapeutic agents, and short survival. Most significant was that P-glycoprotein expression demonstrated a negative additive effect on response to treatment and prognosis with unfavorable cytogenetic anomalies. P-glycoprotein expression and multiple cytogenetic anomalies most probably contribute to the resistance to chemotherapy and poor survival characteristic of the patients with M6b (mean survival, 3.15 +/- 4.2 mo) and M6c (mean survival, 10.5 +/- 12.7 mo). Because patients with M6b and M6c have increased numbers of pronormoblasts in their bone marrow and past chemotherapeutic attempts have failed, chemotherapy directed at these cells is appropriate. Additional therapy directed toward the MDR-1 gene and its protein product seems indicated from our findings.

Acute erythroleukemia is an aggressive leukemia derived from a multipotential stem cell. Three subtypes have been described: (1) M6a with greater than or equal to 30% blasts of the nonerythrocytic component, (2) M6b with greater than or equal to 30% pronormoblasts of the erythrocytic elements, and (3) M6c with greater than or equal to 30% blasts and greater than or equal to 30% pronormoblasts by the aforementioned exclusion criteria. The poor prognosis associated with this disorder positively correlates with a high pronormoblast:myeloblast ratio; unfavorable cytogenetic aberrations; a high proliferative index; and the presence of P-glycoprotein expression (multidrug resistance phenotype). Chemotherapeutic regimens directed toward these specific parameters should be devised in order to improve the characteristically poor outcome of this patient population.

Acute erythroleukemia (FAB M6) is a rare heterogeneous disease with an increase in red cell precursors and myeloblasts. Three subsets have been described: M6A (myeloblast-rich erythroleukemia); M6B (proerythroblast-rich erythroleukemia); and M6C (myeloblast- and proerythroblast-rich mixed variant). This study was undertaken to define and compare the clinical courses and survival outcomes among M6A, M6B, and M6C variants of erythroleukemia. Sixty-nine cases of M6 leukemia were categorized as consisting of ≥50% erythroid of all nucleated cells and M6A with ≥30% myeloblasts/nonerythroid component; M6B with ≥30% proerythroblasts/erythroid component; and M6C with ≥30% myeloblasts and ≥30% proerythroblasts. The demographics, cell type distribution, and survival (mean ± sd) of these groups were compared. There were 32 M6A, 26 M6B, and 11 M6C patients. No significant difference was seen among the groups in age, sex, or treatment. Compared to M6A, both the M6B (P< 0.0001) and M6C (P< 0.0001) variants showed a statistically significant increase in the percentage of bone marrow erythroid cells, proerythroblasts, and the proerythroblasts/erythroid ratios. Comparing the groups for survival, M6B (3 ± 3.6 months) versus M6A (25 ± 28 months), P< 0.002, and M6C (10 ± 13 months) versus M6A, P< 0.01 had a poorer prognosis. Calculating the proerythroblasts as a component of total bone marrow erythroids provides a complimentary method for delineating the pure red cell erythroleukemia (M6B) and mixed variant (M6C), similar to that for the myeloid/erythroid (M6A) leukemia. Now that it is possible to delineate erythroleukemia subtypes, innovative treatments are indicated to target the malignant erythroid population, which is resistant to myeloid-based therapies. Am. J. Hematol. 65:5–13, 2000. © 2000 Wiley-Liss, Inc.

This article summarizes the European Union (EU) activities in the ACTS program satellite component of the UMTS. The projects INSURED, NEWTEST, SECOMS, SINUS, and TOMAS are introduced, and their R&D work on the services implemented in the different test platforms, the network integration scenario into the UMTS network, the studies performed for the air interface, the mobile terminals implemented, and the demonstrated applications are summarized. Furthermore, a new approach using neural networks for adaptive channel equalization and the concept for an EHF/Ka-band system are introduced.

A variety of hybrid systems combining third-generation mobile communication networks with broadcast systems have been proposed for the delivery of multimedia broadcast multicast services (MBMS) to mobile users. The article discusses one of these alternatives, which involves the use of a geostationary satellite component for MBMS delivery. In particular, it proposes a radio access scheme for the satellite component of the system that features maximum commonalities with the standardized T-UMTS WCDMA-based interface. The ultimate advantages of this approach are more efficient delivery of MBMS as far as the mobile network operator is concerned. The required adaptations at the interface layers are described, and the radio resource management strategy that fulfills the particular requirements of the satellite system is presented.

Background and Aims: During the last decade several studies reported an increase in the incidence of type I diabetes mellitus (TlDM). Such increase varies among the European countries in both age groups and gender. Furthermore, in some countries a rising incidence of TI DM has been reported in children

Bromelain (BR) is a cysteine protease with inhibitory effects on intestinal secretion and inflammation. However, its effects on intestinal motility are largely unexplored. Thus, we investigated the effect of this plant-derived compound on intestinal contractility and transit in mice.Contractility in vitro was evaluated by stimulating the mouse isolated ileum, in an organ bath, with acetylcholine, barium chloride, or electrical field stimulation. Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine. Transit was also evaluated in pathophysiologic states induced by the pro-inflammatory compound croton oil or by the diabetogenic agent streptozotocin.Bromelain inhibited the contractions induced by different spasmogenic compounds in the mouse ileum with similar potency. The antispasmodic effect was reduced or counteracted by the proteolytic enzyme inhibitor, gabexate (15 × 10(-6) mol L(-1) ), protease-activated receptor-2 (PAR-2) antagonist, N(1) -3-methylbutyryl-N(4) -6-aminohexanoyl-piperazine (10(-4) mol L(-1) ), phospholipase C (PLC) inhibitor, neomycin (3 × 10(-3) mol L(-1) ), and phosphodiesterase 4 (PDE4) inhibitor, rolipram (10(-6) mol L(-1) ). In vivo, BR preferentially inhibited motility in pathophysiologic states in a PAR-2-antagonist-sensitive manner.Our data suggest that BR inhibits intestinal motility - preferentially in pathophysiologic conditions - with a mechanism possibly involving membrane PAR-2 and PLC and PDE4 as intracellular signals. Bromelain could be a lead compound for the development of new drugs, able to normalize the intestinal motility in inflammation and diabetes.

BACKGROUND: Acne vulgaris is a complex, chronic, and common skin disorder of pilosebaceous units. The major pathogenic factors involved are ductal hyperkeratinization, obstruction of sebaceous follicles resulting from abnormal keratinization of the infundibular epithelium, stimulation of sebaceous gland secretion by androgens, and microbial colonization of pilosebaceous units by Propionibacterium acnes, which promotes perifollicular inflammation. AIM: The aim of the study was to investigate the therapeutic effects of resveratrol, a natural phytoalexin produced by some spermatophytes, such as grapes and other plants, on acneic skin. METHODS: Resveratrol was incorporated in a carboxymethylcellulose-based gel. The chemical stability of resveratrol after storage at 4°C for 30 days was investigated by high-performance liquid chromatography (HPLC). The resveratrol-containing hydrogel was administered to 20 patients affected by acne vulgaris enrolled in this single-blind study. The resveratrol-containing formulation was applied daily as a solo treatment on the right side of the face for 60 days, while the hydrogel vehicle was applied to the left side of the face as a control. To objectively evaluate the results, a digital photographic database was used to collect images. The number and type of lesions were recorded for each patient, to compare the Global Acne Grading System (GAGS) score before treatment with that obtained at the end of the study. Moreover, with the innovative technique of follicular biopsy, areas of acneic skin were prepared for histopathology. The average area occupied by microcomedones at baseline was compared with that at the end of treatment. RESULTS: HPLC analysis demonstrated that resveratrol, upon incorporation into the gel, did not convert to its cis-isomer when stored at 4°C for 30 days. All patients were satisfied with the active treatment and none experienced adverse effects. Clinical evaluation showed a 53.75% mean reduction in the GAGS score on the resveratrol-treated sides of the face compared with 6.10% on the vehicle-treated sides of the face. These data were supported by histologic analysis, which showed a 66.7% mean reduction in the average area of microcomedones on the resveratrol-treated sides of the face. The comparison with the vehicle-treated side of the face (9.7% reduction) showed a clinically relevant and statistically significant decrease of lesions in areas treated with resveratrol-containing hydrogel. CONCLUSION: This pilot study showed positive results for resveratrol gel in acne, and should be considered a valid starting point for further testing of the effectiveness of this molecule in different concentrations and formulations and in a larger group of patients.

Satellites are expected to play an essential role in bridging the ldquodigital dividerdquo; satellite networks are likely to be the only way to provide broadband services to regions that cannot be economically reached by terrestrial networks, in particular the more remote regions of Europe and the rest of the world. Security can be a problem for such global services. This paper presents a link layer security solution and how it is implemented for the unidirectional lightweight encapsulation (ULE). A satellite testbed is constructed where the ULE security implementation is validated. The experiments results are presented in this paper.

SUMMARY In the last decade, there has been an increased awareness that secondary metabolites produced by marine diatoms negatively impact the reproductive success of their principal predators, the copepods. Several oxylipins,products of the enzymatic oxidation of fatty acids, are produced when these unicellular algae are damaged, as occurs during grazing. In the past, the dinoflagellate Prorocentrum minimum, which does not produce the oxylipin 2-trans,4-trans-decadienal (DD), has been used as a live carrier to calculate daily ingestion rates of this molecule by copepod crustaceans. However, since the interaction between oxylipins and live carriers is unknown, the question as to how much and for how long ingestion of these molecules affects copepod reproduction remains a critical point to understanding the functional role of such compounds at sea. In the investigation presented here we used giant liposomes (∼7 μm) as a delivery system for the oxylipin DD, prepared in the same size range as copepod food and containing known amounts of DD. The aim of this work was to relate the ingestion of DD to the reproductive failure of the copepods Temora stylifera and Calanus helgolandicus. Liposomes were very stable over time and after 10 days of feeding, liposomes encapsulating DD reduced egg hatching success and female survival with a concomitant appearance of apoptosis in both copepod embryos and female tissues. Concentrations of DD inducing blockage were one order of magnitude lower that those used in classical feeding experiments demonstrating that liposomes are a useful tool to quantitatively analyze the impact of toxins on copepods.

The diagnosis of granular acute lymphoblastic leukemia (ALL) can be problematic as the cytoplasmic granules found in many blast cells may mimic those seen in acute myelogenous leukemia (AML). This rare variant of B-cell ALL is more commonly diagnosed in children, but may occur in adults. We report a case of granular B-ALL in a 56-year-old female and review the literature.

Recent studies of acute erythroleukemias have reaffirmed DiGuglielmo's syndrome (M6a, myeloblast-predominant) and disease (M6b, pronormoblast-predominant). M6c (mixed myeloblast/pronormoblast) has also been described. However, MDS is still defined according to the percentage of myeloblasts (% myeloblasts) without including the pronormoblast count. A 20-year retrospective study was performed to identify cases demonstrating >or=50% erythrocytic component and