Synthesis and biological evaluation of new simple indolic non peptidic HIV Protease inhibitors: The effect of different substitution patterns

New structurally simple indolic non peptidic HIV Protease inhibitors were synthesized from (S)- glycidol by regioselective methods. Following the concept of targeting the protein backbone, different substitution patterns were introduced onto the common stereodefined isopropanolamine core modifying the type of functional group on the indole, the position of the functional group on the indole and the type of the nitrogen containing group (sulfonamides or perhydroisoquinoline), alternatively. The systematic study on in vitro inhibition activity of such compounds confirmed the general beneficial effect of the 5-indolyl substituents in presence of arylsulfonamide moieties, which furnished activities in the micromolar range. Preliminary docking analysis allowed to identify several key features of the binding mode of such compounds to the protease

Feasibility and acceptability of expressive writing with postpartum women: a randomised controlled trial

Abstract Background: Pregnancy, birth and adjusting to a new baby is a potentially stressful time that can negatively affect women’s mental and physical health. Expressive writing, where people write about a stressful event for at least 15 minutes on three consecutive days, has been associated with improved health in some groups but it is not clear whether it is feasible and acceptable for use with postpartum women. This study therefore examined the feasibility and acceptability of expressive writing for postpartum women as part of a randomised controlled trial (RCT). Methods: The Health After Birth Trial (HABiT) was an RCT evaluating expressive writing for postpartum women which included measures of feasibility and acceptability. At 6 to 12 weeks after birth 854 women were randomised to expressive writing, a control writing task or normal care, and outcome measures of health were measured at baseline, one month later and six months later. Feasibility was measured by recruitment, attrition, and adherence to the intervention. Quantitative and qualitative measures of acceptability of the materials and the task were completed six months after the intervention. Results: Recruitment was low (10.7% of those invited to participate) and the recruited sample was from a restricted sociodemographic range. Attrition was high, increased as the study progressed (35.8% at baseline, 57.5% at one month, and 68.1% at six months) and was higher in the writing groups than in the normal care group. Women complied with instructions to write expressively or not, but adherence to the instruction to write for 15 minutes per day for three days was low (Expressive writing: 29.3%; Control writing: 23.5%). Acceptability measures showed that women who wrote expressively rated the materials/task both more positively and more negatively than those in the control writing group, and qualitative comments revealed that women enjoyed the writing and/or found it helpful even when it was upsetting. Conclusions: The feasibility of offering expressive writing as a universal self-help intervention to all postpartum women 6 to 12 weeks after birth in the HABiT trial was low, but the expressive writing intervention was acceptable to the majority of women who completed it

On the asymptotic behaviour of solutions to the fractional porous medium equation with variable density

We are concerned with the long time behaviour of solutions to the fractional porous medium equation with a variable spatial density. We prove that if the density decays slowly at infinity, then the solution approaches the Barenblatt-type solution of a proper singular fractional problem. If, on the contrary, the density decays rapidly at infinity, we show that the minimal solution multiplied by a suitable power of the time variable converges to the minimal solution of a certain fractional sublinear elliptic equation.Comment: To appear in DCDS-

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells.

Osteosarcoma is a highly metastatic tumor affecting adolescents, for which there is no second-line chemotherapy. As suggested for most tumors, its capability to overgrow is probably driven by cancer stem cells (CSCs), and finding new targets to kill CSCs may be critical for improving patient survival. TP53 is the most frequently mutated tumor suppressor gene in cancers and mutant p53 protein (mutp53) can acquire gain of function (GOF) strongly contributing to malignancy. Studies thus far have not shown p53-GOF in osteosarcoma. Here, we investigated TP53 gene status/role in 3AB-OS cells-a highly aggressive CSC line previously selected from human osteosarcoma MG63 cells-to evaluate its involvement in promoting proliferation, invasiveness, resistance to apoptosis and stemness. By RT-PCR, methylation-specific PCR, fluorescent in situ hybridization, DNA sequence, western blot and immunofluorescence analyses, we have shown that-in comparison with parental MG63 cells where TP53 gene is hypermethylated, rearranged and in single copy-in 3AB-OS cells, TP53 is unmethylated, rearranged and in multiple copies, and mutp53 (p53-R248W/P72R) is post-translationally modified and with nuclear localization. p53-R248W/P72R-knockdown by short-interfering RNA reduced the growth and replication rate of 3AB-OS cells, markedly increasing cell cycle inhibitor levels and sensitized 3AB-OS cells to TRAIL-induced apoptosis by DR5 up-regulation; moreover, it strongly decreased the levels of stemness and invasiveness genes. We have also found that the ectopic expression of p53-R248W/P72R in MG63 cells promoted cancer stem-like features, as high proliferation rate, sphere formation, clonogenic growth, high migration and invasive ability; furthermore, it strongly increased the levels of stemness proteins. Overall, the findings suggest the involvement of p53-R248W/P72R at the origin of the aberrant characters of the 3AB-OS cells with the hypothesis that its GOF can be at the root of the dedifferentiation of MG63 cells into CSCs

Neuromuscular strategies in stretch–shortening exercises with increasing drop heights: The role of muscle coactivation in leg stiffness and power propulsion

When applying drop jump exercises, knowing the magnitude of the stimulus is fundamental to stabilize the leg joints and to generate movements with the highest power. The effects of different drop heights on leg muscles coactivation, leg stiffness and power propulsion were investigated in fifteen sport science students. Drop jumps from heights of 20, 30, 40, 50, and 60 cm in a random order were performed on a force platform. During each drop jump, the ground reaction force, knee angle displacement, and synchronized surface-electromyography root-mean-square (sEMGRMS) activity (vastus lateralis, VL; vastus medialis, VM; rectus femoris, RF; biceps femoris, BF; tibialis anterior, TA and lateral gastrocnemius, LG) were recorded. The coactivation in the pre-contact phase, between VL and BF, VM and BF as well as RF and BF, was dependent on the drop height (p < 0.01; effect size (ES) ranged from 0.45 to 0.90). Leg stiffness was dependent on the drop height (p < 0.001; ES = 0.27–0.28) and was modulated by the coactivation of VM–BF (p = 0.034) and RF–BF (p = 0.046) during the braking phase. Power propulsion was also dependent on the drop height (p < 0.001; ES = 0.34); however, it was primarily modulated by the coactivation of LG–TA during the braking phase (p = 0.002). The coactivation of thigh muscles explains leg stiffness adjustments at different drop heights. On the contrary, the coactivation of shank muscles is mostly responsible for the power propulsion

Quale analisi cefalometrica per la chirurgia maxillo-mandibolare in pazienti con sindrome delle apnee ostruttive notturne?

L’avanzamento maxillo-mandibolare (AMM) è un trattamento efficace per pazienti affetti da sindrome delle apnee ostruttive notturne (OSAS) di grado severo. Sebbene il miglioramento dell’OSAS sia l’obiettivo principale di tale chirurgia, è necessario evitare un avanzamento maxillo-mandibolare eccessivo per garantire un gradevole risultato in termini di estetica facciale. A tale scopo, è necessario programmare preoperatoriamente l’entità dell’AMM mediante un’analisi estetica e cefalometrica. Le analisi cefalometriche di Steiner e Delaire vengono comunemente impiegate nella programmazione della chirurgia ortognatica per deformità dentofaciali, tuttavia resta controverso il ruolo di tali analisi nei pazienti con OSAS candidati a AMM. Quarantotto pazienti con OSAS severa sono stati sottoposti a AMM. Abbiamo effettuato le analisi cefalometriche di Steiner e Delaire in tutti i soggetti. Per il tracciato di Steiner, abbiamo misurato la variazione degli angoli SNA e SNB, mentre per l’analisi di Delaire, abbiamo misurato la variazione degli angoli C3/FM-CPA e C3/ FM-Me. L’AMM medio è stato di 6,9 + 3,8 mm per il mascellare superiore e 13,6 + 5 mm per la mandibola. Dopo l’intervento abbiamo riscontrato un miglioramento dell’Indice di Apnea-Ipopnea (40,47 + 7,64 preoperatoriamente vs. 12,56 + 5,78 postoperatoriamente). In tutti i pazienti, entrambe le tecniche cefalometriche hanno dimostrato una retrusione bimascellare preoperatoria. Dopo l’intervento, l’angolo SNA medio è aumentato da 78,18° a 85,58° (p < 0,001), mentre l’angolo C3/FM-CPA medio è aumentato da 81,19° a 89,71° (p < 0,001). Il valore medio dell’angolo SNB è aumentato da 74,33° a 80,73° (p < 0,001), mentre l’angolo medio C3/FM-CPA è passato da 80,10° a 87,29° (p < 0,001). Postoperatoriamente, sia il mascellare superiore che la mandibola risultavano in una posizione più protrusa (p < 0,001) se analizzati secondo l’analisi di Steiner rispetto al tracciato di Delaire. L’utilizzo dell’analisi cefalometrica di Delaire nella programmazione dell’AMM in pazienti con OSAS comporta un avanzamento maxillo-mandibolare superiore rispetto al tracciato di Steiner. È opportuno considerare le conseguenze di tale risulto sull’estetica facciale durante la programmazione chirurgica e nel consenso informato preoperatorio in pazienti con OSAS candidati a AMM

Using concept mapping in the development of the EU-PAD framework (EUropean-Physical Activity Determinants across the life course): a DEDIPAC-study.

BACKGROUND: A large proportion of European children, adults and older adults do not engage in sufficient physical activity (PA). Understanding individual and contextual factors associated with PA behaviours is essential for the identification and implementation of effective preventative environments, policies, and programmes that can promote an active lifestyle across life course and can potentially improve health. The current paper intends to provide 1) a multi-disciplinary, Pan-European and life course view of key determinants of PA behaviours and 2) a proposal of how these factors may cluster. METHODS: After gathering a list of 183 potential PA behaviours-associated factors and a consensus meeting to unify/consolidate terminology, a concept mapping software was used to collate European experts' views of 106 identified factors for youth (<19 years), adults (19-64 years), and older adults (≥65 years). The analysis evaluated common trends in the clustering of factors and the ratings of the distinct factors' expected modifiability and population-level impact on PA behaviours across the life course. Priority for research was also assessed for each cluster. RESULTS: The concept mapping resulted in six distinct clusters, broadly merged in two themes: 1) the 'Person', which included clusters 'Intra-Personal Context and Wellbeing' and 'Family and Social Economic Status' (42 % of all factors) and 2) the 'Society', which included the remaining four clusters 'Policy and Provision', 'Cultural Context and Media', 'Social Support and Modelling', and 'Supportive Environment' (58 % of all factors). Overall, 25 factors were rated as the most impactful on PA behaviours across the life course and being the most modifiable. They were mostly situated in the 'Intra-Personal Context and Wellbeing' cluster. Furthermore, 16 of them were rated as top priority for research. CONCLUSIONS: The current framework provides a preliminary overview of factors which may account for PA behaviour across the life course and are most relevant to the European community. These insights could potentially be a foundation for future Pan-European research on how these factors might interact with each other, and assist policy makers to identify appropriate interventions to maximize PA behaviours and thus the health of European citizens

Pilot Study of a New Mandibular Advancement Device

This study was conducted to determine the efficacy of a customized mandibular advancement device (MAD) in the treatment of obstructive sleep apnea (OSA). Eight patients (M = 3; F = 5; mean age = 56.3 ± 9.4) with a diagnosis of OSA confirmed by polysomnography (PSG) were re-cruited on the basis of the following inclusion criteria: apnea-hypopnea index (AHI) &gt; 5, age between 18 and 75 years, body mass index (BMI) &lt; 25, and PSG data available at baseline (T0). All were treated with the new NOA® MAD by OrthoApnea (NOA® ) for at least 3 months; PSG with NOA in situ was performed after 3 months of treatment (T1). The following parameters were calculated at T0 and T1: AHI, supine AHI, oxygen desaturation index (ODI), percentage of recording time spent with oxygen saturation &lt;90% (SpO2 &lt; 90%), and mean oxygen desaturation (MeanSpO2%). Data were submitted for statistical analysis. The baseline values were AHI = 21.33 ± 14.79, supine AHI = 35.64 ± 12.80, ODI = 17.51 ± 13.5, SpO2 &lt; 90% = 7.82 ± 17.08, and MeanSpO2% = 93.45 ± 1.86. Four patients had mild OSA (5 &gt; AHI &lt; 15), one moderate OSA (15 &gt; AHI &lt; 30), and three severe OSA (AHI &gt; 30). After treatment with NOA®, statistically significant improvements in AHI (8.6 ± 4.21) and supine AHI (11.21 ± 7.26) were recorded. OrthoApnea NOA® could be an effective alternative in the treatment of OSA: the device improved the PSG parameters assessed

Stochastic Reaction-diffusion Equations Driven by Jump Processes

We establish the existence of weak martingale solutions to a class of second order parabolic stochastic partial differential equations. The equations are driven by multiplicative jump type noise, with a non-Lipschitz multiplicative functional. The drift in the equations contains a dissipative nonlinearity of polynomial growth.Comment: See journal reference for teh final published versio