Non-dioxin-like organic toxicant PCB153 modulates sphingolipid metabolism in liver progenitor cells: its role in Cx43-formed gap junction impairment.

The non-dioxin-like environmental toxicant 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153), member of a group of persistent organic pollutants wide-spread throughout the environment, reduces gap junction intercellular communication (GJIC), an event possibly associated with tumor promotion. Since very few studies have investigated the signaling effectors and mode(s) of action of PCB153, and it is known that the gap junction (GJ) protein Cx43 can be regulated by the bioactive sphingolipid (SL) sphingosine 1-phosphate (S1P), this in vitro study mainly addresses whether SL metabolism is affected by PCB153 in rat liver epithelial WB-F344 cells. PCB153 treatment obtained significant changes in the S1P/ceramide (Cer) ratio, known to be crucial in determining cell fate. In particular, an increase in S1P at 30 min and a decrease of the bioactive lipid at 3 h were observed, whereas Cer level increased at 1 h and 24 h. Notably, a time-dependent modulation of sphingosine kinase (SphK), the enzyme responsible for S1P synthesis, and of its regulators, ERK1/2 and protein phosphatase PP2A, supports the involvement of these signaling effectors in PCB153 toxicity. Electrophysiological analyses, furthermore, indicated that the lipophilic environmental toxicant significantly reduced GJ biophysical properties, affecting both voltage-dependent (such as those formed by Cx43 and/or Cx32) and voltage-independent channels, thereby demonstrating that PCB153 may act differently on GJs formed by distinct Cx isoforms. SphK down-regulation alone induced GJIC impairment, and, when combined with PCB153, the acute effect on GJ suppression was additive. Moreover, after enzyme-specific gene silencing, the SphK1 isoform appears to be responsible for down-regulating Cx43 expression, while being the target of PCB153 at short-term exposure. In conclusion, we provide the first evidence of novel effectors in PCB153 toxic action in rat liver stem-like cells, leading us to consider SLs as potential markers for preventing GJIC deregulation and, thus, the tumorigenic action elicited by this environmental toxicant.

Carbohydrates in diversity-oriented synthesis: challenges and opportunities.

Over the last decade, Diversity-Oriented Synthesis (DOS) has become a new paradigm for developing large collections of structurally diverse small molecules as probes to investigate biological pathways, and to provide a larger array of the chemical space. Drug discovery and chemical biology are taking advantage of DOS approaches to exploit highly-diverse and complex molecular platforms, producing advances in both target and ligand discovery. In this view, carbohydrates are attractive building blocks for DOS libraries, due to their stereochemical diversity and high density of polar functional groups, thus offering many possibilities for chemical manipulation and scaffold decoration. This review will discuss research contributions and perspectives on the application of carbohydrate chemistry to explore the accessible chemical space through appendage, stereochemical and scaffold diversity.

[From evidence to practice: a difficult but not impossible itinerary]. / Dalla evidenza alla pratica: un percorso difficile ma non impossibile.

In recent years, evidence-based medicine (EBM) has acquired its own dignity and cultural identity, and increasing importance. EBM helps doctors understand that the uncertainties of medicine must be analyzed quantitatively in order to rationalize and systematize the information gathered from clinical observation; on the other hand, it provides them with suitable instruments to estimate the performance of diagnostic tests and the efficacy of drugs. One of the main merits of EBM has been the progressive spread of randomized controlled trials as the gold standard for evaluating the effectiveness of treatments. EBM's primary objectives can be summarized by the following points: 1) To transform the physicians' need for information into questions that may be answered (ie, formulate the questions); 2) To find in an as efficient way as possible the best evidence to answer these questions; 3) To critically evaluate the evidence obtained (ie, assign a weight to it) in order to determine its validity (ie, its approximation to the truth) and its usefulness (ie, its concrete clinical applicability); 4) To introduce into clinical practice the conclusions drawn from the results; 5) To estimate individual physicians' performance (ie, one's own conduct and efficiency). EBM's advantages are not only that physicians have acquired a method to search for the right evidence and to apply diagnostic and therapeutic procedures, but, more importantly, that it has provided them with the only tool for true quality improvement, namely the critical appraisal of their own work. Unfortunately, the latter is too often based on a different type of EBM: Evidence-Based Medicine.

[Nurses' professional responsibility]. / La responsabilità professionale dell'infermiere.

As managed care relevance is growing, several old issues related to personal institutional responsibility are increasing among practitioners. Therefore, as a professional figure a nurse bases his/her job on a mix of personal knowledge and skills along with training, and he/she is responsible for giving advice in line with professional care standards. In addition, he/she is in charge of the treatment pattern agreed with the patient. However, nursing is a much more complex job, which leads professional figures facing the controversial issue of combining institutional responsibility and nursing professional tasks and duties daily. As far as nursing institutional responsibility is concerned, different view points or approaches can be applied to investigate it. The most common one is the legal approach, yet this is not the most appropriate one. Therefore, our professional background is mainly based on a management prospective rather than a legal one; dealing with the issue legally would lead, essentially, to a summary of laws and regulations without any kind of argumentative discussion. Consequently, this study aimed to analyze nurses' institutional responsibility by approaching the issue from an innovative human resources management prospective; therefore, defining the gap between nursing institutional responsibility and its tasks.