The phytocannabinoid, Δ(9) -tetrahydrocannabivarin, can act through 5-HT1 A receptors to produce antipsychotic effects

Funded by: •GW Pharmaceuticals Acknowledgements: The authors wish to thank Mrs Lesley Stevenson for technical support and Dr John Raymond, Dr Keith Parker and Dr Ethan Russo for providing human 5-HT1A CHO cells. This research was supported by a grant from GW Pharmaceuticals to M. G. C. and R. G. P.Peer reviewedPostprin

Galactosylated Prodrugs: A Strategy to Improve the Profile of Nonsteroidal Anti-Inflammatory Drugs

Carbohydrates are one of the most abundant and important classes of biomolecules. The variety in their structures makes them valuable carriers that can improve the pharmaceutical phase, pharmacokinetics and pharmacodynamics of well-known drugs. D-galactose is a simple, naturally occurring monosaccharide sugar that has been extensively studied for use as a carrier and has proven to be valuable in this role. With the aim of validating the galactose-prodrug approach, we have investigated the galactosylated prodrugs ibuprofen, ketoprofen, flurbiprofen and indomethacin, which we have named IbuGAL, OkyGAL, FluGAL and IndoGAL, respectively. Their physicochemical profiles in terms of lipophilicity, solubility and chemical stability have been evaluated at different physiological pH values, as have human serum stability and serum protein binding. Ex vivo intestinal permeation experiments were performed to provide preliminary insights into the oral bioavailability of the galactosylated prodrugs. Finally, their anti-inflammatory, analgesic and ulcerogenic activities were investigated in vivo in mice after oral treatment. The present results, taken together with those of previous studies, undoubtedly validate the galactosylated prodrug strategy as a problem-solving technique that can overcome the disadvantages of NSAIDs

Role of physical activity program in the tertiary prevention of female breast cancer: a pilot study

Physical activity is recognised internationally as a key factor in breast cancer prevention that is worldwide the major cause of cancer incidence and mortality in women. It is likely that physical activity is associated with decreased breast cancer risk via multiple interrelated biologic pathway that may involve adiposity, sex hormones, insulin resistence, adipokines and chronic inflammation (Recent Results Cancer Res, 2011). Although women diagnosed with breast cancer are living longer for treatment improvements, concerns about functional limitations, recurrence and survival remain paramount. Recent researches support the beneficial role that physical activity plays in reducing the risk for developing breast cancer and preventing or attenuating disease and treatment-related impairments (Methods Mol Biol, 2009). Post-diagnosis physical activity has been associated with improved quality of life and survivors should be encouraged to initiate and maintain a program of physical activity (Cancer Prev Res, 2011). However, actually it is not yet clear which duration, frequency and intensity of physical activities provide the benefits in primary or tertiary prevention; studies are also limited by incomplete reporting and methodological limitations (Cancer Treat Rev, 2010). We provided a physical activity program in breast cancer survivors (60 women; mean age 59,5 ± 9,8) recruited by Cancer Rehabilitation Center in Florence to investigate the role of physical activity on psychophysical wellness. The subjects were evaluated at the baseline and after the 8-week study period. The anthropometric parameters were measured and the subjects underwent a battery of fitness tests to assess shoulder-arm mobility and range of motion, and back flexibility. All partecipants filled out numerical rating scale and Short-Form 12 questionnaires to quantify the pain intensity to back and the shoulder of the operated arm, and to assess the quality of life, respectively. Our results demonstrated that an organized specific program of adapted physical activity may be an effective countermeasure to reduce the adverse effects after surgery and oncological therapy

Efficacy of a specific program of adapted physical activity in breast cancer survivors: a 5-year single center experience in Florence

Physical activity has been proposed as a nonpharmacological intervention to improve the quality of life in breast cancer survivors. Breast cancer is the most commonly diagnosed malignancy among women worldwide. Recently, earlier detection and advances in therapies have substantially improved the survival rate of breast cancer patients, many of which will have a normal life expectancy. However, cancer treatments can produce negative short- and/or long-term physical and psychological effects (i.e. shoulder and arm decresed mobility, pain, mood disturbance), which heavily contribute to the reduction of life quality. In previous study, we carefully described the exercise methodology of a planned and personalized program of adapted physical activity (APA) demonstrating its efficacy in reducing the shoulderarm complications and improving the quality of life in breast cancer survivors (1). In the present study, we evaluted a higher numbers of breast cancer survivors and a long-time follow up to verify the effectiveness of our protocol. For this pourpose, 140 breast cancer survivors (mean age 56.8±10.2) were recruited by Cancer Rehabilitation Center in Florence between February 2009 and November 2014. The women were evaluated at the baseline and after the 8-week physical activity. The anthropometric parameters were measured and the subjects underwent a battery of fitness tests to assess shoulder-arm mobility and range of motion (ROM), and back flexibility (sit and reach test). All partecipants filled out numerical rating scale and Short-Form 12 questionnaires to quantify the pain intensity to back and the shoulder of the operated arm, and to assess the quality of life, respectively. The evaluation of shoulderarm mobility and self-reported questionnaire data revealed a statistically significant improvement after completion of our specific exercise program. After one year from APA, participants were subjected again to this evaluation protocol. Moreover, to evaluate the APA long-term effects (i.e. physically active lifestyle and shoulder-arm disability), a structured questionnaire was administered to all participants

Effects of a specific adapted exercise on chronic cancerrelated arm lymphedema: a pilot study

Secondary arm lymphedema (LE) is among the most dreaded chronic complications in cancer patients that occurs when axillary lymphatic drainage from the arm is interrupted because of axillary lymph node dissection and/or axillary radiation (Ikeda et al., 2014). LE is characterized by accumulation of protein-rich interstitial fluid in the arm, resulting in tissue swelling. Subsequent swelling can cause pain, discomfort, heaviness, distortion, and reduced mobility and function, thereby affecting quality of life. With increased survival rates there is greater emphasis on enhancing quality of life after treatments (Armer et al., 2003), but the secondary LE remains a problem even with modern treatment modalities. Many treatment options for lymphedema are available, but none offer a permanent reduction or elimination of arm swelling (McKenzie and Kalda, 2003). Recent researches support the positive effects deriving from the regular participation in structured adapted physical activity programs in preventing or attenuating cancer treatment-related impairments improving the quality of life (Mirandola et al., 2013). In this context, the aim of our study was to propose and evaluate a specific exercise, planned by an adapted exercise specialist, to reduce LE and improve strenght and mobility of the arm, as well as quality of life in cancers survivors. We recruited by Cancer Rehabilitation Center of Florence 20 cancer survivors with chronic moderate-severe arm lymphedema, divided randomly into 4 groups according to the different protocol for duration, frequency and intensity of proposed exercise. Outcome measures, included the arm circumference, ROM of arm and hand-wrist, strenght (hand grip test) and quality of life (ULL27 questionaire), were assessed at baseline, in itinere (1, 2 and 3 months) and post-intervention (6 months). Our preliminary results demonstrated that a structured exercise (10 repetitions x 3 with 1 minute break once a day for 3 times per week) improved shoulder function, reduced and managed LE cancer survivors

High habitat richness reduces the risk of tick-borne encephalitis in Europe: a multi-scale study

Background The natural transmission cycle of tick-borne encephalitis (TBE) virus is enhanced by complex interactions between ticks and key hosts strongly connected to habitat characteristics. The diversity of wildlife host species and their relative abundance is known to affect transmission of tick-borne diseases. Therefore, in the current context of global biodiversity loss, we explored the relationship between habitat richness and the pattern of human TBE cases in Europe to assess biodiversity's role in disease risk mitigation. Methods We assessed human TBE case distribution across 879 European regions using official epidemiological data reported to The European Surveillance System (TESSy) between 2017 and 2021 from 15 countries. We explored the relationship between TBE presence and the habitat richness index (HRI1) by means of binomial regression. We validated our findings at local scale using data collected between 2017 and 2021 in 227 municipalities located in Trento and Belluno provinces, two known TBE foci in northern Italy. Findings Our results showed a significant parabolic effect of HRI on the probability of presence of human TBE cases in the European regions included in our dataset, and a significant, negative effect of HRI on the local presence of TBE in northern Italy. At both spatial scales, TBE risk decreases in areas with higher values of HRI. Interpretation To our knowledge, no efforts have yet been made to explore the relationship between biodiversity and TBE risk, probably due to the scarcity of high-resolution, large-scale data about the abundance or density of critical host species. Hence, in this study we considered habitat richness as proxy for vertebrate host diversity. The results suggest that in highly diverse habitats TBE risk decreases. Hence, biodiversity loss could enhance TBE risk for both humans and wildlife. This association is relevant to support the hypothesis that the maintenance of highly diverse ecosystems mitigates disease ris

Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with {MeCP}2 non-sense mutations

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder which affects about 1: 10000 live births. In >95% of subjects RTT is caused by a mutation in Methyl-CpG binding protein-2 (MECP2) gene, which encodes for a transcription regulator with pleiotropic genetic/epigenetic activities. The molecular mechanisms underscoring the phenotypic alteration of RTT are largely unknown and this has impaired the development of therapeutic approaches to alleviate signs and symptoms during disease progression. A defective proteasome biogenesis into two skin primary fibroblasts isolated from RTT subjects harbouring non-sense (early-truncating) MeCP2 mutations (i.e., R190fs and R255X) is herewith reported. Proteasome is the proteolytic machinery of Ubiquitin Proteasome System (UPS), a pathway of overwhelming relevance for post-mitotic cells metabolism. Molecular, transcription and proteomic analyses indicate that MeCP2 mutations down-regulate the expression of one proteasome subunit, α7, and of two chaperones, PAC1 and PAC2, which bind each other in the earliest step of proteasome biogenesis. Furthermore, this molecular alteration recapitulates in neuron-like SH-SY5Y cells upon silencing of MeCP2 expression, envisaging a general significance of this transcription regulator in proteasome biogenesis

Contribution of factor H-Binding protein sequence to the cross-reactivity of meningococcal native outer membrane vesicle vaccines with over-expressed fHbp variant group 1

Factor H-binding protein (fHbp) is an important meningococcal vaccine antigen. Native outer membrane vesicles with over-expressed fHbp (NOMV OE fHbp) have been shown to induce antibodies with broader functional activity than recombinant fHbp (rfHbp). Improved understanding of this broad coverage would facilitate rational vaccine design. We performed a pair-wise analysis of 48 surface-exposed amino acids involved in interacting with factor H, among 383 fHbp variant group 1 sequences. We generated isogenic NOMV-producing meningococcal strains from an African serogroup W isolate, each over-expressing one of four fHbp variant group 1 sequences (ID 1, 5, 9, or 74), including those most common among invasive African meningococcal isolates. Mice were immunised with each NOMV, and sera tested for IgG levels against each of the rfHbp ID and for ability to kill a panel of heterologous meningococcal isolates. At the fH-binding site, ID pairs differed by a maximum of 13 (27%) amino acids. ID 9 shared an amino acid sequence common to 83 ID types. The selected ID types differed by up to 6 amino acids, in the fH-binding site. All NOMV and rfHbp induced high IgG levels against each rfHbp. Serum killing from mice immunised with rfHbp was generally less efficient and more restricted compared to NOMV, which induced antibodies that killed most meningococci tested, with decreased stringency for ID type differences. Breadth of killing was mostly due to anti-fHbp antibodies, with some restriction according to ID type sequence differences. Nevertheless, under our experimental conditions, no relationship between antibody cross-reactivity and variation fH-binding site sequence was identified. NOMV over-expressing different fHbp IDs belonging to variant group 1 induce antibodies with fine specificities against fHbp, and ability to kill broadly meningococci expressing heterologous fHbp IDs. The work reinforces that meningococcal NOMV with OE fHbp is a promising vaccine strategy, and provides a basis for rational selection of antigen sequence types for over-expression on NOMV

Status of faecal pollution in ports: A basin-wide investigation in the Adriatic Sea

Ports are subject to a variety of anthropogenic impacts, and there is mounting evidence of faecal contamination through several routes. Yet, little is known about pollution in ports by faecal indicator bacteria (FIB). FIB spatio-temporal dynamics were assessed in 12 ports of the Adriatic Sea, a semi-enclosed basin under strong anthropogenic pressure, and their relationships with environmental variables were explored to gain insight into pollution sources. FIB were abundant in ports, often more so than in adjacent areas ; their abundance patterns were related to salinity, oxygen, and nutrient levels. In addition, a molecular method, quantitative (q)PCR, was used to quantify FIB. qPCR enabled faster FIB determination and water quality monitoring that culture-based methods. These data provide robust baseline evidence of faecal contamination in ports and can be used to improve the management of routine port activities (dredging and ballast water exchange), having potential to spread pathogens in the sea