Serpin overexpression in Plasmodium-infected midgut cells

Summary The design of effective, vector-based malaria transmission blocking strategies relies on a thorough understanding of the molecular and cellular interactions that occur during the parasite sporogonic cycle in the mosquito. During Plasmodium berghei invasion, transcription from the SRPN10 locus, encoding four serine protease inhibitors of the ovalbumin family, is strongly induced in the mosquito midgut. Herein we demonstrate that intense induction as well as redistribution of SRPN10 occurs specifically in the parasite-invaded midgut epithelial cells. Quantitative analysis establishes that in response to epithelial invasion, SRPN10 translocates from the nucleus to the cytoplasm and this is followed by strong SRPN10 overexpression. The invaded cells exhibit signs of apoptosis, suggesting a link between this type of intracellular serpin and epithelial damage. The SRPN10 gene products constitute a novel, robust and cell-autonomous marker of midgut invasion by ookinetes. The SRPN10 dynamics at the subcellular level confirm and further elaborate the 'time bomb' model of P. berghei invasion in both Anopheles stephensi and Anopheles gambiae. In contrast, this syndrome of responses is not elicited by mutant P. berghei ookinetes lacking the major ookinete surface proteins, P28 and P25. Molecular markers with defined expression patterns, in combination with mutant parasite strains, will facilitate dissection of the molecular mechanisms underlying vector competence and development of effective transmission blocking strategies

Activity monitor placed at the non-paretic ankle is accurate in measuring step counts during community walking in post-stroke individuals : a validation study

Background: Different environmental factors may affect the accuracy of step-count activity monitors (AM). However, the validationconditions for AM accuracy largely differ from ecological environments.Objectives: To assess and compare the accuracy of AM in counting steps among poststroke individuals: during different locomotortasks, with AM placed at the nonparetic ankle or hip, and when walking in a laboratory or inside a mall.Design: Validation study.Settings: Laboratory and community settings.Participants: Twenty persons with chronic hemiparesis, independent walkers.Methods: First session: participants performed level walking (6-minute walk test [6MWT]), ramps, and stairs in the laboratory withAM placed at the nonparetic ankle and hip. Second session: participants walked a mall circuit, including the three tasks, with AMplaced at the nonparetic ankle. The sessions were video recorded.Main Outcome Measurements: Absolute difference between the steps counted by AM and the steps viewed on the video recordings(errors, %); occurrence of errors greater than 10%.Results: Median errors were similar for the 6MWT (0.86 [0.22, 7.70]%), ramps (2.17 [0.89, 9.61]%), and stairs (8.33 [2.65, 19.22]%)with AM at the ankle. Step-count error was lower when AM was placed at the ankle (8.33 [ 2.65, 19.22]%) than at the hip (9.26[3.25, 42.63]%, P = .03). The greatest errors were observed among the slowest participants (≤0.4 m/s) on ramps and stairs, whereassome faster participants (>1 m/s) experienced the greatest error during the 6MWT. Median error was slightly increased in the mallcircuit (2.67 [0.61, 12.54]%) compared with the 6MWT (0.50 [0.24, 6.79]%, P = .04), with more participants showing errors >10% dur-ing the circuit (7 vs 2, P = .05).Conclusions: Step counts are accurately measured with AM placed at the nonparetic ankle in laboratory and community settings.Accuracy can be altered by stairs and ramps among the slowest walkers and by prolonged walking tasks among faster walkers.Level of Evidence: III

Baseline serum TSH levels predict the absence of thyroid dysfunction in cancer patients treated with immunotherapy

Purpose Immunotherapy against immune checkpoints has significantly improved survival both in metastatic and adjuvant setting in several types of cancers. Thyroid dysfunction is the most common endocrine adverse event reported. Patients who are at risk of developing thyroid dysfunction remain to be defined. We aimed to identify predictive factors for the develop- ment of thyroid dysfunction during immunotherapy. Methods This is a retrospective study including a total of 68 patients who were treated with immune checkpoint inhibi- tors (ICIs) for metastatic or unresectable advanced cancers. The majority of patients were treated with anti-PD1 drugs in monotherapy or in combination with anti-CTLA4 inhibitors. Thyroid function and anti-thyroid antibodies, before starting immunotherapy and during treatment, were evaluated. Thyroid ultrasound was also performed in a subgroup of patients at the time of enrolment in the study. Results Eleven out of 68 patients (16.1%) developed immune-related overt thyroid dysfunction. By ROC curve analysis, we found that a serum TSH cut-off of 1.72 mUI/l, at baseline, had a good diagnostic accuracy in identifying patients without overt thyroid dysfunction (NPV = 100%, p = 0.0029). At multivariate analysis, both TSH and positive anti-thyroid antibod- ies (ATAbs) levels, before ICIs treatment, were independently associated with the development of overt thyroid dysfunction during immunotherapy (p = 0.0001 and p = 0.009, respectively). Conclusions Pre-treatment serum TSH and ATAbs levels may help to identify patients at high risk for primary thyroid dysfunction. Our study suggests guidance for an appropriate timely screening and for a tailored management of thyroid dysfunctions in patients treated with ICIs

Antihyperglycemic effect of casearia sylvestris leaves extract in streptozotocin induced diabetic rats

The antihyperglycaemic effect of Casearia sylvestris aqueous extract (CS) and its flavonoidic fraction using in vivo models in streptozotocin-induced diabetic rats was evaluated. CS (500 mg/kg) reduced blood glucose in rats three weeks after a single oral dose. The blood glucose significantly decreased in a test of tolerance to insulin. Phytochemical investigation on TLC, HPLC-DAD and NMR spectral analysis of extract and fractions confirmed the presence of flavonoids. These results direct the hypothesis that CS improves glucose metabolism by reducing insulin resistance, and it may be useful for the treatment of type 2 diabetes.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Antihyperglycemic effect of casearia sylvestris leaves extract in streptozotocin induced diabetic rats

The antihyperglycaemic effect of Casearia sylvestris aqueous extract (CS) and its flavonoidic fraction using in vivo models in streptozotocin-induced diabetic rats was evaluated. CS (500 mg/kg) reduced blood glucose in rats three weeks after a single oral dose. The blood glucose significantly decreased in a test of tolerance to insulin. Phytochemical investigation on TLC, HPLC-DAD and NMR spectral analysis of extract and fractions confirmed the presence of flavonoids. These results direct the hypothesis that CS improves glucose metabolism by reducing insulin resistance, and it may be useful for the treatment of type 2 diabetes.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Meanings and Experiences of Prisoners and Family Members Affected by the COVID-19 Pandemic in a Brazilian Prison Unit: A Grounded Theory Analysis

Funding: This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES) (finance code 001). This work was also supported by the Fundaçãopara a Ciência e a Tecnologia (FCT), I.P. (UIDB/05704/2020 and UIDP/05704/2020), and the Scientific Employment Stimulus—Institutional Call (CEECINST/00051/2018).Worldwide, the COVID-19 pandemic represented a health emergency for prisons. This study sought to understand the meanings and experiences through the narratives of prisoners and family members affected by the COVID-19 pandemic in the context of a maximum-security state penitentiary complex in southern Brazil. For this purpose, a qualitative study was developed based on the methodological framework of constructivist grounded theory. Data were collected between February and August 2022 through individual in-depth interviews and field notes. The sample consisted of 41 participants: 28 male prisoners, and 13 family members. Guided by the Charmaz method of grounded theory analysis, the study afforded the core category “Feeling trapped in prison during the COVID-19 pandemic” with three interrelated phases: “Triggering”, “Escalating”, and “Readjustment”. The “Triggering” phase refers to COVID-19-related elements or events that triggered certain reactions, processes, or changes in prison. During the “Escalating” phase, participants became overwhelmed by the suffering caused by incarceration and the pandemic crisis. The “Readjustment” phase involved adapting, reorienting, or reformulating previous approaches or strategies for dealing with a specific situation. Prisons faced complex challenges during the pandemic and were forced to prioritize protecting public health. However, the measures adopted must be carefully evaluated, ensuring their needs and that they are based on scientific evidence. The punitive approach can undermine inmate trust in prison authorities, making it difficult to report symptoms and adhere to preventive measures. © 2023 by the authors.info:eu-repo/semantics/publishedVersio

Light-Enhanced Cytotoxicity of Doxorubicin by Photoactivation

The combination of photodynamic therapy with chemotherapy (photochemotherapy, PCT) can lead to additive or synergistic antitumor effects. Usually, two different molecules, a photosensitizer (PS) and a chemotherapeutic drug are used in PCT. Doxorubicin is one of the most successful chemotherapy drugs. Despite its high efficacy, two factors limit its clinical use: severe side effects and the development of chemoresistance. Doxorubicin is a chromophore, able to absorb light in the visible range, making it a potential PS. Here, we exploited the intrinsic photosensitizing properties of doxorubicin to enhance its anticancer activity in leukemia, breast, and epidermoid carcinoma cells, upon irradiation. Light can selectively trigger the local generation of reactive oxygen species (ROS), following photophysical pathways. Doxorubicin showed a concentration-dependent ability to generate peroxides and singlet oxygen upon irradiation. The underlying mechanisms leading to the increase in its cytotoxic activity were intracellular ROS generation and the induction of necrotic cell death. The nuclear localization of doxorubicin represents an added value for its use as a PS. The use of doxorubicin in PCT, simultaneously acting as a chemotherapeutic agent and a PS, may allow (i) an increase in the anticancer effects of the drug, and (ii) a decrease in its dose, and thus, its dose-related adverse effects

Local behavior of p-harmonic Green's functions in metric spaces

We describe the behavior of p-harmonic Green's functions near a singularity in metric measure spaces equipped with a doubling measure and supporting a Poincar\'e inequality