Knowledge, attitudes and practices of malaria control among communities from the health district of Forécariah in the Republic of Guinea, West Africa.

BACKGROUND & OBJECTIVES: Malaria is the leading cause of death in children under 5-yr of age in the Republic of Guinea. This study aimed at investigating the knowledge, attitudes and practices of malaria control in urban and rural communities in Guinea in order to better target future health interventions. METHODS: A cross-sectional survey of 200 randomly selected households was conducted in an urban site and in three rural villages within the health district of Forιcariah using two semi-structured questionnaires. RESULTS: Only 18.5% of the respondents were aware of the role of mosquitoes in the transmission of malaria in both urban and rural households. Mosquito nets were identified as a malaria prevention method by 11.5% of the participants and only 8.5% of the respondents mentioned stagnant water as a potential mosquito breeding site. Households' heads were more aware of mosquito control methods, with 56 and 42% of the respondents recognizing that bednets or insecticidal coils can protect from mosquitoes, respectively. Despite the limited knowledge of malaria transmission and prevention, 55% of the households owned at least one long-lasting insecticide-treated net (LLIN) and 79% of the net-owning households slept under a net/LLIN the night before the survey. INTERPRETATION & CONCLUSION: In order to maximize the benefits of malaria control strategies, health education should be implemented, building on the higher awareness of mosquito control methods and stressing the role of vectors in transmitting the disease

Functional dissection of T. brucei Protein Tyrosine Phosphatase 1 and investigation of its development as a therapeutic target

Trypanosoma brucei undergoes developmentally regulated morphological and biochemical changes during its life cycle, being transmitted between the mammalian host and the tsetse fly. It is generally recognized that cellular responses to environmental changes are mediated through signalling pathways, but our understanding of trypanosome signal transduction during differentiation is limited. Protein Tyrosine Phosphatase 1 (TbPTP1) is the one of the few factors identified to be responsible for differentiation from stumpy to procyclic form parasite, whereby TbPTP1 inhibition stimulates transition to insect-form cells (Szoor et al., 2006). In order to characterize the TbPTP1 signalling pathway, a substratetrapping approach was used, which identified a phosphatase TbPIP39 as substrate of TbPTP1. TbPIP39 interacts with, and is dephosphorylated by TbPTP1 in stumpy form cells. Additionally, it has been shown that upon citrate/cis-aconitate (CCA) treatment, phosphorylated TbPIP39 localizes to the parasite glycosomes, the organelles responsible for bloodstream forms metabolism, thereby promoting cellular differentiation to procyclic forms (Szoor et al., 2010). With the aim of further dissecting the TbPTP1 signalling pathway, the substrate-trapping approach was used, which identified one novel TbPTP1 substrate candidate, potentially involved in regulation of differentiation. In addition, the effect of other differentiation triggers, namely protease treatment or mild acid exposure, on the level of TbPIP39 phosphorylation was analyzed, to determine whether these stimuli operate via the same TbPIP39–dependent pathway as CCA signalling. Specifically, changes in the phosphorylation status of TbPIP39 were visualized and quantitated by the use of antibodies detecting either TbPIP39 or the Y278 phosphorylated form of TbPIP39 generated during CCA-dependent differentiation. Both protease treatment and mild acid exposure generated a different pattern of TbPIP39 phosphorylation, thus suggesting a different mechanism of action than CCA. Finally, the possibility of using piggyback strategies targeting TbPTP1 was investigated, as a means to decrease the number of the fly-transmissible stumpy form cells in the bloodstream, thereby controlling parasite transmission. For this purpose, natural and synthetic inhibitors of human PTP1B were tested against the parasite enzyme, since they are being developed by pharmaceutical companies for the treatment of diabetes and obesity. The compounds tested showed a moderate in vitro inhibitory activity against recombinant TbPTP1 and mainly a non-competitive type of inhibition, similarly to that observed for human PTP1B. However, none of the compounds showed in vivo specificity for TbPTP1, indicating that further studies will be needed to identify more specific inhibitors

Knowledge and material analysis for conservation actions related to the Maida castle in Calabria (Italy)

[EN] The Maida castle is located in a hill site in historical center of the Maida City, facing two sea gulfs: Squillace gulf on the east side and Sant’Eufemia gulf on the west side. The position is strategic moreover because the castle is located in the center of Calabria between the Tyrrhenian and the Ionian Seas. Hidden in an inner area, the castle was erected on a rock which has a wide perspective view, giving the ability to control a stretch of territory between the two coasts and allowing to make an easier defense. Although today the fortress appears mainly as a ruin, it is still possible to distinguish one of the quadrangular towers as used as district prison, some inaccessible underground spaces and part of the walls. The state of degradation is evident, caused by the time action and, unfortunately, by inadequate maintenance activity. Most of the external surfaces have evident signs of deterioration, caused by bad weather conditions, but above all by weed vegetation. To better understand the role of the factors as biological aggression, a study has been carried out focusing on most common and widespread biological degradation present on the external surfaces of the castle. Samples of biological materials were taken and examined in the laboratory in order to acquire useful information about the state of the monument. This knowledge is necessary because it provides a first picture of the main causes of degradation of the castle and useful information for developing more aware and respectful restorations of its identity.Gattuso, C.; Palermo, A.; Castagnaro, I.; Ruberto, F. (2020). Conoscenza e analisi dei materiali per la conservazione del castello di Maida in Calabria (Italia). Editorial Universitat Politècnica de València. 1201-1208. https://doi.org/10.4995/FORTMED2020.2020.11437OCS1201120

Independent Pathways Can Transduce the Life-Cycle Differentiation Signal in Trypanosoma brucei

African trypanosomes cause disease in humans and livestock, generating significant health and welfare problems throughout sub-Saharan Africa. When ingested in a tsetse fly bloodmeal, trypanosomes must detect their new environment and initiate the developmental responses that ensure transmission. The best-established environmental signal is citrate/cis aconitate (CCA), this being transmitted through a protein phosphorylation cascade involving two phosphatases: one that inhibits differentiation (TbPTP1) and one that activates differentiation (TbPIP39). Other cues have been also proposed (mild acid, trypsin exposure, glucose depletion) but their physiological relevance and relationship to TbPTP1/TbPIP39 signalling is unknown. Here we demonstrate that mild acid and CCA operate through TbPIP39 phosphorylation, whereas trypsin attack of the parasite surface uses an alternative pathway that is dispensable in tsetse flies. Surprisingly, glucose depletion is not an important signal. Mechanistic analysis through biophysical methods suggests that citrate promotes differentiation by causing TbPTP1 and TbPIP39 to interact

Antipsychotic dose mediates the association between polypharmacy and corrected QT interval

Antipsychotic (AP) drugs have the potential to cause prolongation of the QT interval corrected for heart rate (QTc). As this risk is dose-dependent, it may be associated with the number of AP drugs concurrently prescribed, which is known to be associated with increased cumulative equivalent AP dosage. This study analysed whether AP dose mediates the relationship between polypharmacy and QTc interval. We used data from a crosssectional survey that investigated the prevalence of QTc lengthening among people with psychiatric illnesses in Italy. AP polypharmacy was tested for evidence of association with AP dose and QTc interval using the Baron and Kenny mediational model. A total of 725 patients were included in this analysis. Of these, 186 (26%) were treated with two or more AP drugs (AP polypharmacy). The mean cumulative AP dose was significantly higher in those receiving AP polypharmacy (prescribed daily dose/defined daily dose = 2.93, standard deviation 1.31) than monotherapy (prescribed daily dose/defined daily dose = 0.82, standard deviation 0.77) (z = -12.62, p < 0.001). Similarly, the mean QTc interval was significantly longer in those receiving AP polypharmacy (mean = 420.86 milliseconds, standard deviation 27.16) than monotherapy (mean = 413.42 milliseconds, standard deviation 31.54) (z = -2.70, p = 0.006). The Baron and Kenny mediational analysis showed that, after adjustment for confounding variables, AP dose mediates the association between polypharmacy and QTc interval. The present study found that AP polypharmacy is associated with QTc interval, and this effect is mediated by AP dose. Given the high prevalence of AP polypharmacy in real-world clinical practice, clinicians should consider not only the myriad risk factors for QTc prolongation in their patients, but also that adding a second AP drug may further increase risk as compared with monotherapy

Functional dissection of T. brucei Protein Tyrosine Phosphatase 1 and investigation of its development as a therapeutic target

Trypanosoma brucei undergoes developmentally regulated morphological and biochemical changes during its life cycle, being transmitted between the mammalian host and the tsetse fly. It is generally recognized that cellular responses to environmental changes are mediated through signalling pathways, but our understanding of trypanosome signal transduction during differentiation is limited. Protein Tyrosine Phosphatase 1 (TbPTP1) is the one of the few factors identified to be responsible for differentiation from stumpy to procyclic form parasite, whereby TbPTP1 inhibition stimulates transition to insect-form cells (Szoor et al., 2006). In order to characterize the TbPTP1 signalling pathway, a substratetrapping approach was used, which identified a phosphatase TbPIP39 as substrate of TbPTP1. TbPIP39 interacts with, and is dephosphorylated by TbPTP1 in stumpy form cells. Additionally, it has been shown that upon citrate/cis-aconitate (CCA) treatment, phosphorylated TbPIP39 localizes to the parasite glycosomes, the organelles responsible for bloodstream forms metabolism, thereby promoting cellular differentiation to procyclic forms (Szoor et al., 2010). With the aim of further dissecting the TbPTP1 signalling pathway, the substrate-trapping approach was used, which identified one novel TbPTP1 substrate candidate, potentially involved in regulation of differentiation. In addition, the effect of other differentiation triggers, namely protease treatment or mild acid exposure, on the level of TbPIP39 phosphorylation was analyzed, to determine whether these stimuli operate via the same TbPIP39–dependent pathway as CCA signalling. Specifically, changes in the phosphorylation status of TbPIP39 were visualized and quantitated by the use of antibodies detecting either TbPIP39 or the Y278 phosphorylated form of TbPIP39 generated during CCA-dependent differentiation. Both protease treatment and mild acid exposure generated a different pattern of TbPIP39 phosphorylation, thus suggesting a different mechanism of action than CCA. Finally, the possibility of using piggyback strategies targeting TbPTP1 was investigated, as a means to decrease the number of the fly-transmissible stumpy form cells in the bloodstream, thereby controlling parasite transmission. For this purpose, natural and synthetic inhibitors of human PTP1B were tested against the parasite enzyme, since they are being developed by pharmaceutical companies for the treatment of diabetes and obesity. The compounds tested showed a moderate in vitro inhibitory activity against recombinant TbPTP1 and mainly a non-competitive type of inhibition, similarly to that observed for human PTP1B. However, none of the compounds showed in vivo specificity for TbPTP1, indicating that further studies will be needed to identify more specific inhibitors.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A novel phosphatase cascade regulates differentiation in Trypanosoma brucei via a glycosomal signaling pathway

In the mammalian bloodstream, the sleeping sickness parasite Trypanosoma brucei is held poised for transmission by the activity of a tyrosine phosphatase, TbPTP1. This prevents differentiation of the transmissible “stumpy forms” until entry into the tsetse fly, whereupon TbPTP1 is inactivated and major changes in parasite physiology are initiated to allow colonization of the arthropod vector. Using a substrate-trapping approach, we identified the downstream step in this developmental signaling pathway as a DxDxT phosphatase, TbPIP39, which is activated upon tyrosine phosphorylation, and hence is negatively regulated by TbPTP1. In vitro, TbPIP39 promotes the activity of TbPTP1, thereby reinforcing its own repression, this being alleviated by the trypanosome differentiation triggers citrate and cis-aconitate, generating a potentially bistable regulatory switch. Supporting a role in signal transduction, TbPIP39 becomes rapidly tyrosine-phosphorylated during differentiation, and RNAi-mediated transcript ablation in stumpy forms inhibits parasite development. Interestingly, TbPIP39 localizes in glycosomes, peroxisome-like organelles that compartmentalize the trypanosome glycolytic reactions among other enzymatic activities. Our results invoke a phosphatase signaling cascade in which the developmental signal is trafficked to a unique metabolic organelle in the parasite: the glycosome. This is the first characterized environmental signaling pathway targeted directly to a peroxisome-like organelle in any eukaryotic cell