Pharmacological assessment of the antineoplastic and immunomodulatory properties of a new spiroindolone derivative (7',8'-Dimethoxy-1',3'-dimethyl-1,2,3',4'-tetrahydrospiro[indole-3,5'-pyrazolo[3,4-c]isoquinolin]-2-one) in chronic myeloid leukemia.

The discovery and development of effective novel compounds is paramount in oncology for improving cancer therapy. In this study, we developed a new derivative of spiroindolone (7',8'-Dimethoxy-1',3'-dimethyl-1,2,3',4'-tetrahydrospiro[indole-3,5'- pyrazolo[3,4-c]isoquinolin]-2-one) and evaluated its anticancer- and immunomodulatory potential in a vitro model of chronic leukemia. We utilized the chronic leukemia cell line K562, as well as non-cancerous peripheral blood mononuclear cells (PBMC) and Vero cells (kidney epithelium of Cercopithecus aethiops). We assessed the cytotoxicity of the compound using the MTT assay, and performed cell cycle assays to determine its impact on different stages of the cell cycle. To evaluate its antineoplastic activity, we conducted a colony formation test to measure the effect of the compound on the clonal growth of cancer cells. Furthermore, we evaluated the immunomodulatory activity of the compound by measuring the levels of pro and anti-inflammatory cytokines. The study findings demonstrate that the spiroindolone-derived compound exerted noteworthy cytotoxic effects against K562 cells, with an IC50 value of 25.27 µg/mL. Additionally, it was observed that the compound inhibited the clonal proliferation of K562 cells while displaying minimal toxicity to normal cells. The compound exhibited its antiproliferative activity by inducing G2/M cell cycle arrest, preventing the entry of K562 cells into mitosis. Notably, the compound demonstrated an immunomodulatory effect by upregulating the production of cytokines IL-6 and IL-12/23p40. In conclusion, the spiroindolone-derived compound evaluated in this study has demonstrated significant potential as a therapeutic agent for the treatment of chronic myeloid leukemia. Further investigations are warranted to explore its clinical applications.

Fish and macroinvertebrate assemblages reveal extensive degradation of the world's rivers.

Rivers suffer from multiple stressors acting simultaneously on their biota, but the consequences are poorly quantified at the global scale. We evaluated the biological condition of rivers globally, including the largest proportion of countries from the Global South published to date. We gathered macroinvertebrate- and fish-based assessments from 72,275 and 37,676 sites, respectively, from 64 study regions across six continents and 45 nations. Because assessments were based on differing methods, different systems were consolidated into a 3-class system: Good, Impaired, or Severely Impaired, following common guidelines. The proportion of sites in each class by study area was calculated and each region was assigned a Köppen-Geiger climate type, Human Footprint score (addressing landscape alterations), Human Development Index (HDI) score (addressing social welfare), % rivers with good ambient water quality, % protected freshwater key biodiversity areas; and % of forest area net change rate. We found that 50% of macroinvertebrate sites and 42% of fish sites were in Good condition, whereas 21% and 29% were Severely Impaired, respectively. The poorest biological conditions occurred in Arid and Equatorial climates and the best conditions occurred in Snow climates. Severely Impaired conditions were associated (Pearson correlation coefficient) with higher HDI scores, poorer physico-chemical water quality, and lower proportions of protected freshwater areas. Good biological conditions were associated with good water quality and increased forested areas. It is essential to implement statutory bioassessment programs in Asian, African, and South American countries, and continue them in Oceania, Europe, and North America. There is a need to invest in assessments based on fish, as there is less information globally and fish were strong indicators of degradation. Our study highlights a need to increase the extent and number of protected river catchments, preserve and restore natural forested areas in the catchments, treat wastewater discharges, and improve river connectivity.

Performance of Aptima-HPV in the cervical cancer screening program of Portugal: a cost-analysis.

BACKGROUND: Cervical cancer is a major concern to women's health, being the fourth most common cancer worldwide. A great percentage of these cancer is consequence of an HPV infection, namely from specific genotypes such as 16/18. Portuguese screening program subjects women to a reflex cytology triage every 5 years. Aptima® HPV is a screening test which presents better specificity than other tests which are used in Portugal (Hybrid Capture® 2 and Cobas® 4800) and still have a comparable sensitivity. The present study aims to estimate the number of diagnostic tests and costs that are avoided using Aptima® HPV compared to the use of two other tests, Hybrid Capture® 2 and Cobas® 4800, within the cervical cancer screening programme in Portugal. METHODS: A model, consisting of a decision-tree, was developed to represent the full Portuguese screening program for cervical cancer. This model is used to compare the costs resulting from using Aptima® HPV test versus the other tests used in Portugal, during 2 years. Other outcomes such as the number of additional tests and exams were also computed. This comparison considers the performance of each test (sensitivity and specificity) and assumes an equal price for every test compared. RESULTS: Cost savings resulting from the use of Aptima® HPV are estimated at approximately €382 million versus Hybrid Capture® 2 and €2.8 million versus Cobas® 4800. Moreover, Aptima® HPV prevents 265,443 and 269,856 additional tests and exams when compared with Hybrid Capture® 2 and Cobas® 4800. CONCLUSIONS: The use of Aptima® HPV resulted in lower costs as well as less additional test and exams. These values result from the greater specificity of Aptima® HPV, which signals less false positive cases and consequently avoids carrying out additional tests.

Assessing nystatin cream treatment efficacy against Leishmania (L.) amazonensis infection in BALB/c model.

The current scenario for cutaneous leishmaniasis treatment includes the use of first and second-choice drugs, both therapeutic strategies presenting several adverse effects and being related to an increment of treatment-refractory parasite strains. These facts encourage the search for new treatment approaches, including repositioning drugs, such as nystatin. Although in vitro assays show that this polyene macrolide compound has leishmanicidal activity, no in vivo evidence for a similar activity has been shown so far for the commercial nystatin cream formulation. This work assessed the effects of nystatin cream (25,000 IU/g) administered on mice in an amount to completely cover the paw surface of BALB/c mice infected with Leishmania (L.) amazonensis once a day, until a total of up to 20 doses. The data presented herein points to unequivocal evidence that treatment with this formulation causes a statistically significant reduction of swelling/edema in mice paws when compared to animal groups not submitted to this treatment regimen after the fourth week of infection: lesion sizes at the sixth (p = 0.0159), seventh (p = 0.0079) and eighth (p = 0.0079) week. Furthermore, swelling/edema reduction relates to a decrease in parasite load in the footpad (∼48%) and in draining lymph nodes (∼68%) at eight weeks post-infection. This is the first report of the effectiveness of nystatin cream used as a topical treatment in BALB/c model for cutaneous leishmaniasis.

A New Strategy for Mapping Epitopes of LACK and PEPCK Proteins of Leishmania amazonensis Specific for Major Histocompatibility Complex Class I.

Leishmaniasis represents a complex of diseases with a broad clinical spectrum and epidemiological diversity, considered a major public health problem. Although there is treatment, there are still no vaccines for cutaneous leishmaniasis. Because Leishmania spp. is an intracellular protozoan with several escape mechanisms, a vaccine must provoke cellular and humoral immune responses. Previously, we identified the Leishmania homolog of receptors for activated C kinase (LACK) and phosphoenolpyruvate carboxykinase (PEPCK) proteins as strong immunogens and candidates for the development of a vaccine strategy. The present work focuses on the in silico prediction and characterization of antigenic epitopes that might interact with mice or human major histocompatibility complex class I. After immunogenicity prediction on the Immune Epitope Database (IEDB) and the Database of MHC Ligands and Peptide Motifs (SYFPEITHI), 26 peptides were selected for interaction assays with infected mouse lymphocytes by flow cytometry and ELISpot. This strategy identified nine antigenic peptides (pL1-H2, pPL3-H2, pL10-HLA, pP13-H2, pP14-H2, pP15-H2, pP16-H2, pP17-H2, pP18-H2, pP26-HLA), which are strong candidates for developing a peptide vaccine against leishmaniasis.

Ibandronate in the Prevention of Vertebral and Nonvertebral Osteoporotic Fractures: A Systematic Review of Experimental and Observational Studies.

BACKGROUND/OBJECTIVE: This study aims to evaluate ibandronate clinical effectiveness in the prevention of osteoporosis-related vertebral fractures (VFs) and nonvertebral fractures (NVFs) in the treatment of postmenopausal osteoporosis. METHODS: This systematic review was conducted in accordance with the Centre for Reviews and Dissemination's guidance and reporting in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement 2020. A literature search was performed in PubMed and EMBASE since their inception until February 7, 2022. Randomized controlled trials (RCTs), meta-analysis, experimental, and observational studies evaluating adult patients treated with ibandronate and assessed to osteoporotic fractures prevention were included. The risk of bias was assessed according to study design. Data were analyzed using descriptive statistics. RESULTS: Eight references from 4 RCTs, 7 meta-analyses, and 6 observational studies were included. In RCTs, oral ibandronate was superior to placebo in the prevention of VF. However, the doses were lower than those approved. The meta-analyses confirmed these results and showed that adequate doses of oral ibandronate reduce the risk of NVF compared with insufficient doses. In observational studies, oral ibandronate (in approved doses) reduced the risk of VF compared with no treatment or risedronate or alendronate and the risk of NVF versus risedronate or alendronate; the risk of hip fractures was similar between ibandronate and other oral bisphosphonates. CONCLUSIONS: There is strong evidence that ibandronate reduces the risk of VF in postmenopausal osteoporosis. The available evidence further suggests that ibandronate may reduce the risk of NVF versus insufficient doses of ibandronate, as well as risedronate or alendronate.

Influence of atherosclerosis risk factors on the anatomical distribution of peripheral arterial disease in patients with chronic limb-threatening ischemia: a cross-sectional study.

Background: Atherosclerosis risk factors can have different impacts on cardiovascular diseases and on the anatomical distribution of Peripheral Arterial Disease (PAD). Objectives: To study the influence of atherosclerosis risk factors on the anatomical distribution of PAD in patients with chronic limb-threatening ischemia (CLTI). Methods: We performed an observational, cross-sectional, and analytical study that included 476 hospitalized patients with CLTI due to PAD. We compared the presence of atherosclerosis risk factors (age, gender, diabetes mellitus, smoking, and hypertension) in patients with PAD involving three different anatomic areas (aortoiliac, femoropopliteal, and infrapopliteal). Multivariate analysis was performed to identify associations between atherosclerosis risk factors and PAD distribution. Results: The mean age of the 476 patients was 69 years, 249 (52%) were men, and 273 (57%) had diabetes. Seventy-four percent (353) had minor tissue loss. Multivariate analysis identified three risk factors associated with PAD anatomical distribution (gender, smoking, and DM). Women had a 2.7 (CI: 1.75-4.26) times greater chance of having femoropopliteal disease. Smokers had a 3.6-fold (CI: 1.54-8.30) greater risk of aortoiliac disease. Diabetic patients were 1.8 (CI: 1.04-3.19) times more likely to have isolated infrapopliteal occlusive disease. Conclusions: The study showed that gender, DM, and smoking impact on the anatomical distribution of PAD in patients with CLTI. Diabetic patients were more likely to have only infrapopliteal disease, women had a greater risk of femoropopliteal PAD, and smokers had a greater risk of aortoiliac occlusive disease.

Host-microbiome interactions regarding peri-implantitis and dental implant loss.

In the last decades, the ortho-aesthetic-functional rehabilitation had significant advances with the advent of implantology. Despite the success in implantology surgeries, there is a percentage of failures mainly due to in loco infections, through bacterial proliferation, presence of fungi and biofilm formation, originating peri-implantitis. In this sense, several studies have been conducted since then, seeking answers to numerous questions that remain unknown. Thus, the present work aims to discuss the interaction between host-oral microbiome and the development of peri-implantitis. Peri-implantitis was associated with a diversity of bacterial species, being Porphiromonas gingivalis, Treponema denticola and Tannerella forsythia described in higher proportion of peri-implantitis samples. In a parallel role, the injury of peri-implant tissue causes an inflammatory response mediated by activation of innate immune cells such as macrophages, dendritic cells, mast cells, and neutrophils. In summary, the host immune system activation may lead to imbalance of oral microbiota, and, in turn, the oral microbiota dysbiosis is reported leading to cytokines, chemokines, prostaglandins, and proteolytic enzymes production. These biological processes may be responsible for implant loss.

Impact of collaborative actions of Leishmania (Viannia) braziliensis subpopulations on the infection profile.

This study focuses on the role of the population structure of Leishmania spp. on the adaptive capacity of the parasite. Herein, we investigate the contribution of subpopulations of the L. (V.) braziliensis Thor strain (Thor03, Thor10 and Thor22) in the profile of murine macrophages infection. Infection assays were performed with binary combinations of these subpopulations at stationary phases. The initial interaction time showed major effects on the combination assays, as demonstrated by the significant increase in the infection rate at 5 h. Based on the endocytic index (EI), Thor10 (EI = 563.6) and Thor03 (EI = 497) showed a higher infection load compared to Thor22 (EI = 227.3). However, the EI decreased in Thor03 after 48 h (EI = 447) and 72 h (EI = 388.3) of infection, and showed changes in the infection level in all Thor10/Thor22 combinations. Assays with CellTrace CFSE-labelled Thor22 promastigotes indicated an increase (~1.5 fold) in infection by this subpopulation in the presence of Thor10 when compared to the infection profile of Thor03/Thor22 combinations in the same proportions. In addition, the potential of these subpopulations, alone or in binary combinations, to modulate the expression of cytokines and nitric oxide (NO) in vitro was investigated. Lower NO and tumour necrosis factor-α production levels were observed for all Thor10/Thor22 combinations at 24 h compared to these subpopulations alone. In contrast, Thor03/Thor22 combination assays increased IL-10 production at this time. Collectively, these results provide in vitro evidence on the potential of L. (V.) braziliensis population structure to play a relevant role in a host infection by this parasite.

The safety of systemic Janus kinase inhibitors in atopic dermatitis: a systematic review and network meta-analysis.

PURPOSE: Janus kinase (JAK) inhibitors have been developed to treat moderate to severe atopic dermatitis, but there is little evidence comparing the safety profile of these drugs. The aim of this study is to compare the relative safety of the different systemic JAK inhibitors in atopic dermatitis. METHODS: Medline, EMBASE, and clinicaltrials.gov were searched to identify phase 2/3, clinical trials (RCTs) designed to evaluate the efficacy and safety of systemic JAK inhibitors in atopic dermatitis. Outcomes were the risk of any adverse event (AE), serious AEs, AEs leading to treatment discontinuation, any infection, serious infections, herpes zoster infection, and any cardiac or vascular event. RESULTS: Eighteen RCTs were included. Compared with placebo, baricitinib (odds ratio [OR] 1.25, 95% credible interval [CrI] 1.03-1.55), abrocitinib (OR 1.54, 95% CrI 1.25-1.90), and upadacitinib (OR 1.46, 95% CrI 1.19-1.81) increase the risk of any adverse event. Abrocitinib (OR 1.62, 95% CrI 1.7-2.72), upadacitinib (OR 1.67, 95% CrI 1.19-2.43), and dupilumab (OR 1.69, 95% CrI 1.02-2.79) increase the risk of infections when compared with placebo. Dupilumab has a reduced risk of herpes zoster infection when compared with upadacitinib (OR 0.23; 95% CrI 0.08-0.81) No further statistically significant risk differences between treatments were identified. CONCLUSIONS: The results suggest systemic JAK inhibitors for atopic dermatitis have a similar safety profile. However, as current data present limitations, postmarketing safety evidence will be crucial to draw definitive conclusions regarding the safety of JAK inhibitors.

First report of Leishmania RNA virus 1 in Leishmania (Viannia) braziliensis clinical isolates from Rio de Janeiro State - Brazil.

BACKGROUND: Leishmania parasites carry a double-stranded RNA virus (Leishmania RNA virus - LRV) that has been divided in LRV1 and LRV2. OBJECTIVES: Leishmania (Viannia) braziliensis clinical isolates were assessed in order to determine LRV presence. METHODS: Two-round polymerase chain reaction (PCR and nested PCR) was performed to detect LRV1 or LRV2 in L. (V.) braziliensis clinical isolates (n = 12). FINDINGS: LRV1 was detected in three clinical isolates which was phylogenetically related to other sequences reported from other American tegumentary leishmaniasis (ATL) endemic areas of Brazil. Patients infected with L. (V.) braziliensis LRV-negative showed only cutaneous lesions while LRV-positive reported different manifestations. MAIN CONCLUSION: Data presented here show for the first time that LRV1 is circulating in L. (V.) braziliensis clinical isolates from Rio de Janeiro State in Brazil.

Seroprevalence of Epstein-Barr virus and cytomegalovirus infections in Presidente Figueiredo, Amazonas, Brazil.

Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections affect around 95% of the world's population. In Brazil, there are few epidemiological reports related to EBV and CMV infection, especially in the western Amazon region. This study aimed to estimate the seroprevalence of EBV and CMV infection in individuals residents in Presidente Figueiredo, Amazonas, Brazil. Blood samples of 443 individuals were tested for the presence of anti-EBV and anti-CMV IgG antibodies through an enzyme-linked immunosorbent assay. EBV (95.9%; 95% CI: 0.94;0.98), CMV (96.8%; 95% CI: 0.95;0.98) and CMV/EBV (93%;95% CI: 0.91-0.95) coinfection were highly prevalent in the study population. Children (1 to 5 years) not attending school were less susceptible to EBV (OR 0.15; 95% CI: 0.05-0.52; p = 0.017) and CMV infections (OR 0.05; 95% CI: 0.02 - 0.17; p < 0.0001). Teenagers at high school showed increased susceptibility to CMV infection (OR 4.65; 95%CI: 1.43-15.08; p = .013) and EBV/CMV co-infection (OR 3.04; 95%CI: 1.44-6.45; p = 0.005). The seroprevalence of CMV and EBV infections were preeminent and tend to increase with age in the study population. Either attendance to a daycare facility or primary school before the age of 5 years may increase the susceptibility to EBV or CMV infection.

P-Glycoprotein and Androgen Receptor Expression Reveals Independence of Canine Prostate Cancer from Androgen Hormone Stimulation.

Canine prostate cancer (PC) is an aggressive disease, and dogs can be considered comparative models for human PC. In recent years, canine PC has been shown to resemble human castrate-resistant prostate cancer. The influx and efflux of testosterone in prostatic luminal cells are regulated by P-glycoprotein (P-gp). Therefore, human PC generally lacks P-gp expression and maintains the expression of androgen receptors (ARs). However, this co-expression has not previously been investigated in dogs. Therefore, this study aimed to evaluate AR and P-gp co-expression to elucidate these protein patterns in canine prostate samples. We identified AR/P-gp double immunofluorescence co-expression of both proteins in normal luminal cells. However, in canine PC, cells lack AR expression and exhibit increased P-gp expression. These results were confirmed by gene expression analyses. Overall, our results strongly suggest that normal canine prostate testosterone influx may be regulated by P-gp expression, and that during progression to PC, prostatic cells lack AR expression and P-gp overexpress. P-gp expression in canine PC may be related to a phenotype of multiple drug resistance.

The Risk of Infections Associated With JAK Inhibitors in Rheumatoid Arthritis: A Systematic Review and Network Meta-analysis.

BACKGROUND/OBJECTIVE: The Janus kinases (JAKs) are cytoplasmic tyrosine kinases associated with membrane cytokine receptors that mediate signaling of multiple cytokines and growth factors, contributing to the pathogenesis of multiple autoimmune disorders. The JAK inhibitors are a new class of targeted therapies with proven efficacy in treating rheumatoid arthritis but are associated with an increased risk of infections. This study is aimed at comparing the relative safety of the different JAK inhibitors with regard to the risk of serious infections in patients with rheumatoid arthritis. METHODS: PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov were searched to identify randomized controlled trials evaluating the efficacy and safety of JAK inhibitors in patients with rheumatoid arthritis. The outcomes assessed were the risk of total and serious infections, tuberculosis, and herpes zoster. Sensitivity analysis disaggregated the results according to background therapy and licensed doses of JAK inhibitors. RESULTS: Thirty-seven randomized controlled trials that were included met the inclusion criteria. Compared with filgotinib, adalimumab (4.81; 95% confidence interval [CI], 1.39-16.66), etanercept (6.04; 95% CI, 1.79-20.37), peficitinib (7.56; 95% CI, 1.63-35.12), tofacitinib (4.29; 95% CI, 1.43-12.88), and upadacitinib (4.35; 95% CI, 1.46-13.00) have an increased risk of herpes zoster infection. Risk differences between the drugs became statistically nonsignificant when the sensitivity analysis was conducted. CONCLUSIONS: The risk of infections seems to be similar among the currently approved JAK inhibitor drugs. Although the initial results suggested that filgotinib could have a reduced risk of herpes zoster, the sensitivity analyses did not support those findings.

Risk of Cardiovascular and Venous Thromboembolic Events Associated With Janus Kinase Inhibitors in Rheumatoid Arthritis: A Systematic Review and Network Meta-analysis.

BACKGROUND/OBJECTIVE: The Janus kinases are cytoplasmic tyrosine kinases associated with membrane cytokine receptors that mediate signaling of multiple cytokines and growth factors, contributing to the pathogenesis of multiple autoimmune disorders. Janus kinase inhibitors (JKIs) are a new class of targeted therapies with proven efficacy in treating rheumatoid arthritis but are associated with an increased risk of infections. This study is aimed at assessing the risk of cardiovascular and venous thromboembolic events associated with JKIs in patients with rheumatoid arthritis. METHODS: PUBMED, EMBASE, Cochrane Library, and clinicaltrials.gov were searched to identify randomized controlled trials evaluating the efficacy and safety of JKIs in patients with rheumatoid arthritis. The outcomes assessed were the risk of major adverse cardiovascular events, venous thromboembolic events, and any cardiovascular event. Sensitivity analysis disaggregated the results according to background therapy, JKI licensed doses, and studies' methodological quality. RESULTS: Forty-two randomized controlled trials met the inclusion criteria. No statistically significant risk differences were observed between the JKIs for any of the assessed outcomes. Compared with placebo, tofacitinib (odds ratio, 0.32; 95% confidence interval, 0.11-0.89) reduces the risk of venous thromboembolism. The results of the sensitivity analysis are in line with the initial findings. CONCLUSIONS: Current evidence suggests that the risk of cardiovascular and venous thromboembolic events is similar among the JKIs. Postmarketing pharmacovigilance evidence will be of utmost importance in confirming the cardiovascular safety of these drugs.

Simultaneous occurrence of inflammatory bowel disease and trichomonosis in a Maine coon cat.

A 2-year-old, 4.2 kg, spayed female, Maine coon cat was referred to the veterinary hospital for evaluation of hyporexia, slow growth, and chronic, intermittent, mucoid, bloody, voluminous, and fetid diarrhea. The diarrhea had been observed since the cat was acquired from a cattery at 4 months of age; with acute worsening in the 5 d before presentation. Abdominal palpation revealed moderate pain. Ultrasonographic examination showed thickening of the jejunal wall and ileal loops, increased echogenicity of the jejunal mucosa, and enlargement of the jejunal and ileocolic lymph nodes. Histopathology of full-thickness intestinal biopsies showed moderate, diffuse, lymphoplasmacytic, erosive enteritis with hemorrhage and edema. Diffuse, lymphoplasmacytic, erosive colitis with mild, interstitial fibrosis and hemorrhage was also noted. The ileocecal lymph node biopsy showed eosinophilic lymphadenitis. Based on the immunohistochemical evaluation of intestinal samples with CD3 and CD79a antibodies, a diagnosis of lymphoma was ruled out. Fecal polymerase chain reaction testing was positive for Tritrichomonas foetus. Based on these results, inflammatory bowel disease and trichomonosis were diagnosed. Treatment for the cat included a hypoallergenic diet and an oral omega-3 fatty acid supplement, in conjunction with prednisolone, to manage the inflammatory bowel disease. Ronidazole was administered to target the Tritrichomonas foetus. The cat was clinically normal during a follow-up examination after 6 months of treatment.

Apparition simultanée d'une maladie inflammatoire de l'intestin et d'une trichomonose chez un chat Maine coon. Une chatte Maine coon de 2 ans, pesant 4,2 kg, stérilisée, a été référée à l'hôpital vétérinaire pour une évaluation d'hyporexie, de croissance lente et de diarrhée chronique, intermittente, mucoïde, sanglante, volumineuse et fétide. La diarrhée avait été observée depuis que le chat avait été acquis en chatterie à l'âge de 4 mois; avec une aggravation aiguë dans les 5 jours avant la présentation. La palpation abdominale a révélé une douleur modérée. L'examen échographique a montré un épaississement de la paroi jéjunale et des anses iléales, une augmentation de l'échogénicité de la muqueuse jéjunale et une hypertrophie des ganglions lymphatiques jéjunaux et iléocoliques. L'histopathologie des biopsies intestinales de pleine épaisseur a montré une entérite modérée, diffuse, lymphoplasmocytaire, érosive avec hémorragie et oedème. Une colite érosive diffuse, lymphoplasmocytaire avec fibrose interstitielle légère et hémorragie a également été notée. La biopsie ganglionnaire iléo-caecale montrait une lymphadénite à éosinophiles. Sur la base de l'évaluation immunohistochimique d'échantillons intestinaux avec des anticorps CD3 et CD79a, un diagnostic de lymphome a été écarté. Le test de réaction en chaîne par la polymérase sur les matières fécales était positif pour Tritrichomonas foetus. Sur la base de ces résultats, une maladie inflammatoire de l'intestin et une trichomonose ont été diagnostiquées. Le traitement du chat comprenait un régime hypoallergénique et un supplément oral d'acides gras oméga-3, en association avec de la prednisolone, pour gérer la maladie inflammatoire de l'intestin. Le ronidazole a été administré pour cibler Tritrichomonas foetus. Le chat était cliniquement normal lors d'un examen de suivi après 6 mois de traitement.(Traduit par Dr Serge Messier).

Chemical typicity of tropical tannat red wines from sub-middle São Francisco Valley, Brazil.

Tannat is a Vitis vinifera cultivar with typically high phenolic compound contents, showing intense coloration, well-bodied, and great aging potential. However, even with this great potential, this variety is still commercially underexplored in the Sub-middle São Francisco Valley (SSFV). This work aimed to characterize the typicity of Tannat red wines from Sub-middle São Francisco Valley (SSFV), Brazil. In addition, the present work represents the first study featuring phenolic compounds quantification and antioxidant activity of Tannat in tropical climate wine-producing regions. Considering the condition of a short-applied maceration time during the winemaking, the tropical Tannat wine showed significant antioxidant activity and high phenolic contents. Trans-caftaric, malvidin-3-O-glucoside, and procyanidin B1 stood out among the phenolic compounds quantified, presenting Tannat with the potential to be an important grape variety to tropical wine-producing regions in Brazil, containing high contents of bioactive compounds. Previously results to compounds (-)-epigallocatechin gallate, procyanidin B2, quercetin-3-ß-D-glucoside, pelargonidin-3-O-glucoside, chlorogenic acid, and piceatannol were not found in Tannat wines. Further studies are necessary to make the Tannat grape's adaptation better in tropical climate conditions, including investigating the phenolic profile and antioxidant activity of Tannat red wines with longer maceration times during the winemaking.

Expression and prognostic significance of vascular endothelial growth factor-A (VEGF-A) and its receptor in canine prostate cancer.

BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) and its receptor, VEGF receptor-2 (VEGFR-2), represent a complex family of angiogenic molecules consisting of different ligands and receptors. Due to the importance of VEGF-A/VEGFR-2 signaling in tumor proliferation and angiogenesis, this study aimed to evaluate the protein and gene expression levels of VEGF-A and VEGFR-2 in canine prostate cancer (PC). METHODS: We analyzed VEGF-A and VEGFR-2 expression in 87 PC samples by immunohistochemistry and quantitative-polymerase chain reaction. PC samples were graded according to the Gleason score and the immunohistochemical staining for VEGF-A and VEGFR-2 was quantified using a selected threshold from the ImageJ Software. Microvascular density was assessed by cluster of differentiation 31 staining and counting the number of positive vessels. Additionally, the homology of VEGF-A and VEGFR-2 between humans and dogs was assessed, followed by the construction of a protein structure homology model to compare the tertiary structures of these proteins in both species. RESULTS: Negative to weakly positive expression levels of VEGF-A and VEGFR-2 were observed in the epithelial cells of the normal prostate (NP) and prostatic hyperplasia samples. In contrast, the canine proliferative atrophy and PC samples exhibited higher VEGF-A (p < .0001) and VEGFR-2 (p < .0001) compared to NP. Moreover, positive correlations between the expression levels of VEGF-A and VEGFR-2 (Spearman's coefficient (r) = .68, p = .013) and the expression levels of VEGF-A and VEGFR-2 proteins (r = .8, p < .0001) were also observed in the NP samples. Additionally, the patients with PC exhibiting higher VEGFR-2 expression levels experienced a shorter survival period (p = .0372). Furthermore, we found an association between the microvascular density and overall survival. Dogs with a higher number of vessels showed a shorter survival time. We further demonstrated that the VEGF-A and VEGFR-2 exhibited high homology between humans and dogs, and identified their protein structures in both species. CONCLUSIONS: In conclusion, VEGFR-2 appears to be an independent prognostic factor in animals with PC. VEGF-A and VEGFR-2 are highly conserved between humans and dogs, which can be investigated further in future cross-species studies to explore their therapeutic applications.

Nitrogen pollution promotes changes in the niche space of fish communities.

Historically, anthropogenic fixed nitrogen has been purposely increased to benefit food production and global development. One consequence of this increase has been to raise concentrations of nitrogen in aquatic ecosystems. To evaluate whether nitrogen pollution promotes changes in the estimates of niche space of fish communities, we examined 16 sites along a Brazilian river basin highly impacted by anthropogenic activities, especially discharge of domestic and industrial sewage from a region with more than 5 million inhabitants. We analysed the carbon (δ13C) and nitrogen (δ15N) isotope ratios of fish species and both autochthonous (periphyton) and allochthonous (course and fine particulate organic matter) basal food resources. To estimate the magnitude of nitrogen pollution, we measured the nitrate and ammonium concentrations at each site. Sampling was conducted in the dry and wet seasons to evaluate the influence of seasonality. Nitrogen pollution generally increased estimates of niche space, and seasonality influenced only the niche estimates of fish communities from polluted sites. In addition, isotopic analyses of nitrogen polluted sites yielded unrealistic estimates of trophic positioning (detritivores at the top of the food web). We conclude that changes in niche space estimates reflect both alterations in baseline isotopic values and differential trophic behaviour among fishes. Our study suggests that under conditions of high pollution, other factors appear to influence isotopic estimates of niche, such as isotopically distinct sources that have not been sampled, and/or differences in δ15N turnover rates between fish tissue and basal resources, creating isotopic baselines that are challenging to interpret.

Real-world intensive safety monitoring of biosimilars rituximab and trastuzumab in a Portuguese oncology hospital.

PURPOSE: The aim of this study was to assess the safety profiles of two biosimilar medicines (rituximab and trastuzumab) in the treatment of cancer patients within a Portuguese oncology hospital. METHODS: This hospital-based prospective observational study followed a cohort event monitoring approach focused on signalling suspected adverse drug reactions (ADRs). Patients undergoing treatment with rituximab biosimilar CT-P10 (Truxima®) or trastuzumab biosimilar CT-P6 (Herzuma®) were recruited over an 11-month and a 6-month period, respectively. Clinicians identified eligible patients and used paper-based forms to report all ADRs associated with biosimilar medicines. ADR case reports were assessed for seriousness, expectedness and causality in the Pharmacovigilance Unit of Coimbra. RESULTS: Ninety-four patients received biosimilar medicines (rituximab, n = 35; trastuzumab, n = 59). Of those, 4 patients (11.4%) experienced 16 ADRs with rituximab and 1 patient (1.7%) experienced 5 ADRs with trastuzumab. All case reports contained serious and expected ADRs that were at least probably related with biosimilar medicines under study. Based on the MedDRA PT coding, the most reported ADR for rituximab CT-P10 was chest discomfort (n = 4; 19.1%), followed by odynophagia (n = 2; 9.5%). Trastuzumab CT-P6 was associated with back pain, headache, pain in extremity, tachypnoea and tremor (each, n = 1; 4.8%). CONCLUSION: The results of this study suggest that using biosimilar rituximab and biosimilar trastuzumab to treat cancer patients in the real-world clinical setting is associated with acceptable safety profiles. No new safety problems were identified.