Antisense Oligonucleotides, A Novel Developing Targeting Therapy

Antisense oligonucleotides (ASOs) have been validated as therapeutic agents and an important tool in molecular biology. Indeed, ASOs are used either in vitro or in vivo to generate mRNA selective knockouts. They can be used for human therapy since ASOs can inhibit specifically target genes especially whose are difficult to target with small molecules inhibitors or neutralizing antibodies. However, despite their specificity and broadness of use, some practical obstacles remain unsolved in antisense pharmacology, such as insufficient stability due to nucleases degradation activity, and poor cellular delivery as a result of low cellular uptake difficult biological membrane crossing. Moreover, in many cases, potential off-target effects and immunostimulation are also part of the problems derived from their use. In this review, we will discuss ASOs, their chemistry, limitation of use, some solutions to increase stability, and finally some of their therapeutical application

The organizational reasons for wrongdoing. The case of Italy’s Superior Council of the Judiciary (CSM)

Many scholars have highlighted the individual, organizational and inter-organizational causes of organizational wrongdoing; others have focused on its (negative) consequences or have analyzed how it can persist and spread between organizations. An underlining assumption shared by many of those studies is that organizational wrongdoing is a deviant, society-damaging phenomenon originating from individual and organizational actors' pursuit of undue advantages. We argue that, at least in some cases, actors may also have "organizational reasons" for wrongdoing, besides self-interest. This article aims at analyzing the organizational reasons for wrongdoing in the CSM affair, a scandal that shed light on the deviant practices for career paths within the Italian judiciary system. By relying on documents and several semi-structured interviews to judges, public prosecutors, and experts in the field, we reconstructed actual practices for career advancement (extra-legal governance) and compared them with formal policies (legal governance). Our analysis shows that deviant practices were not merely occasional episodes of favoritism, but were part of an extra-legal governance system that involved virtually all of Italy's judges. We also found that the CSM decoupled formal policies from actual practices to manage two organizational trade-offs - bureaucratic rules vs. efficiency, and independence vs. accountability. Therefore, besides individual gain, actors had two major "organizational reasons" for wrongdoing: first, they needed to cope with a lack of organizational capabilities and resources; second, they needed to address calls for greater accountability. In the light of our findings, we conclude with some considerations about organizational learning and the relation between law, organizations, and wrongdoing

G6PD deficiency does not enhance susceptibility for acquiring <i>Helicobacter pylori</i> infection in Sardinian patients

Background: Subjects with glucose-6-phosphate dehydrogenase (G6PD) deficiency may be more susceptible to infections due to impaired leukocyte bactericidal activity. The disorder is common in the Mediterranean area. The aim of this study was to investigate whether G6PD deficiency may be a risk factor for acquiring H. pylori infection. Methods: We performed a retrospective study. Data from clinical records of 6565 patients (2278 men and 4287 women, median age 51, range 7‒94) who underwent upper endoscopy between 2002 and 2014 were collected. H. pylori status, assessed by histology plus rapid urease test or 13C-urea breath test, and G6PD status were also reported. A multiple logistic regression model was used to investigate the association between G6PD deficiency and H. pylori infection. Results: Enzyme deficiency was detected in 12% (789/6565) of the entire cohort, and more specifically in 8.3% of men and in 14.0% of women. Overall, the proportion of patients positive for H. pylori was 50.6% and 51.5% among G6PD deficient and non-deficient patients (χ² = 0.271; p = 0.315). Moreover, among G6PD-deficient and normal patients the frequency of previous H. pylori infection was similar. After adjustment for age and gender the risk for acquiring H. pylori infection was similar in G6PD-deficient and normal patients. Only age was a strong statistically significant risk predictor. Conclusions: These results demonstrate for the first time that G6PD deficiency does not enhance patients’ susceptibility to acquire H. pylori infection in Sardinia

Patients Specific Spine Simulators for Surgical Training and Rehearsal in Pedicle Screws Placement: A New Way for Surgical Education

In pedicle screws placement using a free-hand technique or a fluoroscopic guided technique the main difficulties are facing to the bone morphology (i.e in deformity cases) and it could be easily reproduced in a patient’s specific spine simulator (we can choose the case). The aim of this work is to evaluate the use of 3D printed patient- specific models (3D printing) not only as a surgical planning tool but also as a surgical training tool in spine surgery and in particular in pedicle screws placement. The manufacturing of patient-specific physical replica involves the elaboration of CT dataset and rapid prototyping techniques. . Five resident surgeons were involved in different training sessions on simulators. To evaluate the exact screws position we performed a CT evaluation of each instrumented simulators. Statistical analysis was conducted using SPSS software. A total of 120 pedicle screws were positioned, 90 screws were well-positioned and 30 screws were bad-positioned. There were a significant difference (p = 0.000008) between the bad-positioning screw rate of the “senior” resident (13/72) and those of “young” participants (17/48). Timeline analysis of pedicle instrumentation training showed the presence of a learning effect, with a lower error rate in the latest session (p=000001). We believe that the use of patient- specific surgical simulators, especially for those surgical tasks in which the complexity is mainly linked to the spine morphology (i.e. deformity), may represent a valid alternative to the use of cadavers that generally present a standard or otherwise poorly predictable anatomy

Berberine and Dyslipidemia: Different Applications and Biopharmaceutical Formulations Without Statin-Like Molecules—A Meta-Analysis

The aim of this study was to analyze the efficacy of berberine taken alone or in other formulations (with silymarin or other mixtures) on dyslipidemia through a systematic review of the literature and a meta-analysis. A systematic investigation was conducted on 19 studies that were selected based on inclusion and exclusion criteria. Both controlled trials (n = 12) and cross-sectional trials (n = 7) were included. The following formulations were examined: berberine used alone (n = 5), berberine combined with silymarin (n = 8), and other mixture containing berberine (n = 6). A meta-analysis was performed using a fixed-effects model and meta-regression. Total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were considered. Moreover, possible associations of each parameter with age and the dose and duration of the treatment were analyzed. The data obtained showed a significant reduction in TC and LDL cholesterol for each formulation. A reduction in triglycerides was also observed for both TC and LDL but with a smaller impact. As regards HDL, a slight increase was observed, but it was not statistically significant. The formulation of berberine in association with silymarin was found to have the greatest impact on TC, LDL, HDL, and triglycerides. The greater efficacy of the formulation consisting of berberine associated with silymarin can probably be accounted for by the fact that the latter increases the bioavailability of berberine. However, it is necessary to carry out further clinical studies to better define the efficacy of the treatment and which patients show the best response

Recent advances and public health implications for environmental exposure to Chlamydia abortus: from enzootic to zoonotic disease

Environmental transmission of Chlamydia abortus as a result of enzootic disease or disease outbreaks and the threats posed by this pathogen has been previously reported, however a state-of-the-science review of these reports and the identification of future research priorities in this area is still lacking. This study provides an overview of the current knowledge of host–pathogen–environment interactions, addressing public health risks and identifying critical questions and research gaps. We performed a systematic PubMed and Web of Science search for publications related to Chlamydia abortus in the past four decades, and we reviewed and combined the evidence critically discussing and commenting the results. A total of 182 studies, 5 chapters of specific books and the “OIE terrestrial manual” were included in this review. There were substantial variations between the studies in topic addressed and experimental design. Overall, the literature largely supports the crucial role played by environmental exposure on the acquisition of zoonotic disease caused by Chlamydia abortus. We also identify the paucity of information related to interspecies transmission and pathogen adaptation in relation to environmental dissemination and zoonotic risk. This analysis further highlights the need for additional research given that environmental transmission represents a serious risk not only to susceptible patients (pregnant women and immunocompromised individuals), but also for other species including wildlife

Sleep actigraphic patterns and cognitive status

none9noWe performed an actigraphic assessment of sleep characteristics in healthy subjects and patients with cognitive impairment. Thirty subjects were included and classified into controls (10 subjects), mild cognitive impairment (10 patients) and mild-to-moderate Alzheimer's disease (10 patients). Sleep quality was assessed using the Pittsburgh Sleep Quality Index. Participants had a 7-day actigraphic record. Sleep parameters collected were time in bed, total sleep time, sleep efficiency, sleep latency, wakefulness after sleep onset, number of awakenings, and mean motor activity. Significant differences between mild cognitive impairment and controls patients were found for sleep latency (p = 0.05); Alzheimer's disease patients had significantly worse scores for Pittsburgh Sleep Quality Index (p = 0.01), time in bed (p = 0.001), total sleep time (p = 0.04), sleep latency, sleep efficiency, motor activity (p = 0.0001) and wakefulness after sleep onset (p = 0.001) compared to controls. When comparing Alzheimer's disease and mild cognitive impairment, differences were significant for sleep latency (p = 0.01), wakefulness after sleep onset (p = 0.004), sleep efficiency, number of awakenings and motor activity (p = 0.0001). In addition to showing a high prevalence of sleep alterations in subjects with cognitive impairment, our data suggest that they are evident from the earliest stages of cognitive decline. Further studies are needed to assess whether early correction of sleep alterations can positively influence the evolution of cognitive impairment. The opportunity to provide clinically meaningful information with a simple assessment of sleep characteristics based on actigraphy suggests that wider use of the approach in patients with cognitive decline should be considered.openBuratti, Laura; Camilletti, Roberta; Pulcini, Alessandra; Rocchi, Chiara; Viticchi, Giovanna; Falsetti, Lorenzo; Baldinelli, Sara; Fiori, Chiara; Silvestrini, MauroBuratti, Laura; Camilletti, Roberta; Pulcini, Alessandra; Rocchi, Chiara; Viticchi, Giovanna; Falsetti, Lorenzo; Baldinelli, Sara; Fiori, Chiara; Silvestrini, Maur

Action Selection and Motor Decision Making: Insights from Transcranial Magnetic Stimulation

In everyday life, goal-oriented motor behaviour relies on the estimation of the rewards/costs associated with alternative actions and on the appropriate selection of movements. Motor decision making is defined as the process by which a motor plan is chosen among a set of competing actions based on the expected value. In the present literature review we discuss evidence from transcranial magnetic stimulation (TMS) studies of motor control. We focus primarily on studies of action selection for instructed movements and motor decision making. In the first section, we delve into the usefulness of various TMS paradigms to characterise the contribution of motor areas and distributed brain networks to cued action selection. Then, we address the influence of motivational information (e.g., reward and biomechanical cost) in guiding action choices based on TMS findings. Finally, we conclude that TMS represents a powerful tool for elucidating the neurophysiological mechanisms underlying action choices in humans

Targeting Hsp27/eIF4E interaction with phenazine compound: A promising alternative for castration-resistant prostate cancer treatment

The actual strategy to improve current therapies in advanced prostate cancer involves targeting genes activated by androgen withdrawal, either to delay or prevent the emergence of the castration-refractory phenotype. However, these genes are often implicated in several physiological processes, and long-term inhibition of survival proteins might be accompanied with cytotoxic effects. To avoid this problem, an alternative therapeutic strategy relies on the identification and use of compounds that disrupt specific protein-protein interactions involved in androgen withdrawal. Specifically, the interaction of the chaperone protein Hsp27 with the initiation factor eIF4E leads to the protection of protein synthesis initiation process and enhances cell survival during cell stress induced by castration or chemotherapy. Thus, in this work we aimed at i) identifying the interaction site of the Hsp27/eIF4E complex and ii) interfere with the relevant protein/protein association mechanism involved in castration-resistant progression of prostate cancer. By a combination of experimental and modeling techniques, we proved that eIF4E interacts with the C-terminal part of Hsp27, preferentially when Hsp27 is phosphorylated. We also observed that the loss of this interaction increased cell chemo-and hormone-sensitivity. In order to find a potential inhibitor of Hsp27/eIF4E interaction, BRET assays in combination with molecular simulations identified the phenazine derivative 14 as the compound able to efficiently interfere with this protein/protein interaction, thereby inhibiting cell viability and increasing cell death in chemo- and castration-resistant prostate cancer models in vitro and in vivo

Recent Changes in Hydroclimatic Patterns over Medium Niger River Basins at the Origin of the 2020 Flood in Niamey (Niger)

Niamey, the capital of Niger, is particularly prone to floods, since it is on the banks of the Niger River, which in its middle basin has two flood peaks: one in summer (the red flood) and one in winter (the black flood). In 2020, the Niger River in Niamey reached its all-time highest levels following an abundant rainy season. On the other hand, the floods in Niamey have been particularly frequent in the last decade, a symptom of a change in hydroclimatic behaviour already observed since the end of the great droughts of the 1970s and 1980s and which is identified with the name of Sahelian Paradox. This study, starting from the analysis of the 2020 flood and from the update of the rating curve of the Niamey hydrometric station, analyses the rainfall–runoff relationship on the Sahelian basins of the Medium Niger River Basin (MNRB) that are at the origin of the local flood. The comparative analysis of runoffs, annual maximum flows (AMAX) and runoff coefficients with various rainfall indices calculated on gridded datasets allowed to hydroclimatically characterise the last decade as a different period from the wet one before the drought, the dry one and the postdrought one. Compared to the last one, the current period is characterised by a sustained increase in hydrological indicators (AMAX +27%) consistent with the increase in both the accumulation of precipitation (+11%) and the number (+51%) and magnitude (+54%) of extreme events in the MNRB. Furthermore, a greater concentration of rainfall and extremes (+78%) in August contributes to reinforcing the red flood’s positive anomalies (+2.23 st.dev in 2020). The study indicates that under these conditions the frequency of extreme hydrological events in Niamey will tend to increase further also because of the concurrence of drivers such as river-bed silting and levee effects. Consequently, the study concludes with the need for a comprehensive flood-risk assessment on the Niamey city that considers both recent hydroclimatic trends and urbanisation dynamics in flood zones hence defining the most appropriate risk-reduction strategies