Early ontogeny of the freshwater fish Rhytiodus microlepis (Characiformes, Anostomidae) from the Amazon basin.

The early development of the freshwater fish Rhytiodus microlepis is characterized by the description of external morphological, meristic, and morphometric changes, as well as the growth patterns, thereby establishing a reference for the identification of its larvae and juveniles. Specimens were collected from the Amazon river channel and floodplain. Ninety-seven individuals were analysed with standard length varying between 4.31 and 79.23 mm. Rhytiodus microlepis larvae are altricial, with an elongated and fusiform body, anal opening reaching the middle region of the body, and simple nostrils becoming double and tubular during development. The pigments vary from one to two chromatophores in the dorsal region of the head in pre-flexion and flexion, but later the pigmentation pattern intensifies, transverse bands appear along the body, and a conspicuous spot appears in the basal region of the caudal fin. The total number of myomeres ranges from 49 to 50. During the transition from larval (post-flexion) to the juvenile periods, the most significant anatomical changes occur, such as the presence of all fins and increased body pigmentation. Integrated myomere count and pigmentation pattern are effective for the correct identification of the initial life stages of R. microlepis from the Amazon basin. Our results expand the knowledge about the early life history of Neotropical freshwater fish species.

Early ontogeny of the commercially valuable fish red-bellied pacu Piaractus brachypomus (Characiformes, Serrasalmidae) from the Amazon, Brazil.

The initial development of the red-bellied pacu Piaractus brachypomus is described using morphological, meristic and morphometric characteristics. A total of 127 individuals were analysed (47 in the yolk-sac, 35 in pre-flexion, five in flexion, 20 in post-flexion and 20 in juvenile) with standard length varying between 2.92 and 48.61 mm. The larvae are born poorly developed and have a discoidal yolk at ~6.33 mm standard length. During early ontogeny, the mouth passes from terminal to subterminal and the anal opening reaches the vertical line over the midline region of the body. There are changes in body shape from long and moderate to deep, head length from small to large, and eye diameter from moderate to large. Dendritic chromatophores were present in the ventral, dorsal and upper part of the swim bladder in the early larval stages. Rounded spots are evident all over the body in juveniles. The total number of myomeres ranges from 39 to 41 (20-23 pre-anal, 17-20 post-anal). Through the morphometric relationships, it was evidenced that the greatest changes during the initial ontogeny of P. brachypomus occur in the transition from the post-flexion stage to the juvenile period, indicating changes in behaviour, foraging and physiology.

Larval development of the freshwater croaker Pachypops fourcroi (La Cépède 1802) (Perciformes: Sciaenidae).

The larval development of Pachypops fourcroi from the lower Amazon River was described through morphological, meristic and morphometric features. Sixty-five larvae were examined and present a moderate body, slightly elliptical eyes and head ranging from moderate to large. The mouth is initially terminal and becomes subterminal throughout development with three barbels in the mentonian region. The larvae of P. fourcroi can be differentiated from other Sciaenidae in the Amazon basin by the pigmentation pattern, the presence of barbels, head depth, body depth and diameter, and shape of the eye.

Xanthosoma sagittifolium is resistant to Meloidogyne spp. and controls Meloidogyne enterolobii by soil biofumigation.

Meloidogyne is a relevant plant-parasitic nematode that causes enormous damage. It is very challenging to control, and there are not many chemicals available on the market for that. As an alternative method of nematode control, biofumigation is increasingly gaining space. This research aimed to study the reaction of Xanthosoma sagittifolium to Meloidogyne enterolobii, M. incognita, and M. javanica and soil biofumigation with X. sagittifolium leaves for M. enterolobii control. The reaction test was performed in the populations 0 (control), 333, 999, 3,000, 9,000, 27,000 eggs and eventual juveniles. X. sagittifolium did not host the Meloidogyne species studied, even in a high population. X. sagittifolium leaves incorporated in soil at concentrations 0 (control), 0.45, 0.9, 1.8, 3.6 g were also studied to control M. enterolobii, and they were able to reduce galls and eggs. The number of galls and egg masses was reduced to a concentration of 1.8 g. In the maximum concentration, the number of galls was less than 15 galls, and the eggs were also reduced to less than 200 eggs. As these macerates emitted nematicidal volatile organic compounds (VOCs) against M. enterolobii, it reduced the infectivity and reproduction of nematodes.

The nutritional nexus: Linking niche, habitat variability and prey composition in a generalist marine predator.

Our understanding of the niche concept will remain limited while the quantity and range of different food types eaten remain a dominant proxy for niche breadth, as this does not account for the broad ecological context that governs diet. Linking nutrition, physiology and behaviour is critical to predict the extent to which a species adjusts its nutritional niche breadth at the levels of prey ("prey composition niche," defined as the range of prey compositions eaten) and diet ("realized nutritional niche" is the range of diets composed through feeding on the prey). Here, we studied adult chick-rearing Australasian gannets Morus serrator to propose an integrative approach using sea surface temperature anomalies (SSTa), geographic location and bathymetry over different years, to explore their relationship with the nutritional composition of prey and diets (i.e. prey composition and nutritional niche breadth), habitat use and foraging behaviour. We found that gannets feed on prey that varied widely in their nutritional composition (have a broad prey composition niche), and composed diets from these prey that likewise varied in composition (have a broad realized nutritional niche), suggesting generalism at two levels of macronutrient selection. Across seasons, we established "nutritional landscapes" (hereafter nutriscapes), linking the nutritional content of prey (wet mass protein-to-lipid ratio-P:L) to the most likely geographic area of capture and bathymetry. Nutriscapes varied in their P:L from 6.06 to 15.28, over time, space and bathymetry (0-150 m). During warm water events (strong positive SSTa), gannets expanded their foraging habitat, increased their foraging trip duration and consumed prey and diets with low macronutrient content (wet mass proportions of P and L). They were also constrained to the smallest prey composition and realized nutritional niche breadths. Our findings are consistent with previous suggestions that dietary generalism evolves in heterogeneous environments, and provide a framework for understanding the nutritional goals in wild marine predators and how these goals drive ecological interactions and are, in turn, ultimately shaped by environmental fluctuations.

Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids.

We have synthesized a small series of five 3-[4-arylmethoxy)phenyl]propanoic acids employing an easy and short synthetic pathway. The compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: G protein-coupled receptor 40 (GPR40), aldose reductase (AKR1B1), peroxisome proliferator-activated receptor gama (PPARγ) and solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT-4). Compound 1 displayed an EC50 value of 0.075 µM against GPR40 and was an AKR1B1 inhibitor, showing IC50 = 7.4 µM. Compounds 2 and 3 act as slightly AKR1B1 inhibitors, potent GPR40 agonists and showed an increase of 2 to 4-times in the mRNA expression of PPARγ, as well as the GLUT-4 levels. Docking studies were conducted in order to explain the polypharmacological mode of action and the interaction binding mode of the most active molecules on these targets, showing several coincidences with co-crystal ligands. Compounds 1-3 were tested in vivo at an explorative 100 mg/kg dose, being 2 and 3 orally actives, reducing glucose levels in a non-insulin-dependent diabetes mice model. Compounds 2 and 3 displayed robust in vitro potency and in vivo efficacy, and could be considered as promising multitarget antidiabetic candidates. This is the first report of a single molecule with these four polypharmacological target action.

Effects of transcutaneous electrical nerve stimulation on chemotherapy-induced peripheral neuropathy symptoms (CIPN): a preliminary case-control study.

[Purpose] The aim of this double-blind, randomized and placebo-controlled study is to investigate the effects of Transcutaneous Electrical Nerve Stimulation for reducing the side effects of Chemotherapy-induced Peripheral Neuropathy in cancer patients undergoing chemotherapy with oxaloplatin or paclitaxel. [Subjects and Methods] Twenty-four patients were randomly allocated into two groups: active or placebo stimulation. All patients were assessed for pain, numbness/tingiling, frequency of symptoms, and quality of life. The transcutaneous Electrical Nerve Stimulation device was applied daily with modulating frequencies ranging between 7 Hz and 65 Hz in distal limb regions during three cycles of chemotherapy (45 days). The other stimulation parameters were: pulse duration of 200 µsec, intensity at the highest tolerable level, and increases in intensity when it diminished. [Results] The data showed no difference between active or placebo groups in terms of pain, numbness/tingling, frequency of symptoms or impact on daily life activities. [Conclusion] These results suggest that Transcutaneous Electrical Nerve Stimulation applied in the frequency variation mode was not proven to be effective to improve the symptoms of Chemotherapy-induced Peripheral Neuropathy during chemotherapy cycles. There was no worsening of symptoms in subsequent cycles of the onset of symptoms of the disease.

Synthesis of nitro(benzo)thiazole acetamides and in vitro antiprotozoal effect against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis.

We synthesized four 5-nitrothiazole (1-4) and four 6-nitrobenzothiazole acetamides (5-8) using an easy two step synthetic route. All compounds were tested in vitro against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis, showing excellent antiprotozoal effects. IC50's of the most potent compounds range from nanomolar to low micromolar order, being more active than their drugs of choice. Compound 1 (IC50=122 nM), was 44-times more active than Metronidazole, and 10-fold more effective than Nitazoxanide against G. intestinalis and showed good trichomonicidal activity (IC50=2.24 µM). This compound did not display in vitro cytotoxicity against VERO cells. The in vitro inhibitory effect of compounds 1-8 and Nitazoxanide against G. intestinalis fructose-1,6-biphosphate aldolase (GiFBPA) was evaluated as potential drug target, showing a clear inhibitory effect over the enzyme activity. Molecular docking of compounds 1, 4 and Nitazoxanide into the ligand binding pocket of GiFBPA, revealed contacts with the active site residues of the enzyme. Ligand efficiency metrics of 1 revealed optimal combinations of physicochemical and antiprotozoal properties, better than Nitazoxanide.

In vitro antifungal susceptibility of Candida glabrata to caspofungin and the presence of FKS mutations correlate with treatment response in an immunocompromised murine model of invasive infection.

It has been argued that the in vitro activity of caspofungin (CSP) is not a good predictor of the outcome of echinocandin treatment in vivo. We evaluated the in vitro activity of CSP and the presence of FKS mutations in the hot spot 1 (HS1) region of the FKS1 and FKS2 genes in 17 Candida glabrata strains with a wide range of MICs. The efficacy of CSP against systemic infections from each of the 17 strains was evaluated in a murine model. No HS1 mutations were found in the eight strains showing MICs for CSP of ≤ 0.5 µg/ml, but they were present in eight of the nine strains with MICs of ≥ 1 µg/ml, i.e., three in the FKS1 gene and five in the FKS2 gene. CSP was effective for treating mice infected with strains with MICs of ≤ 0.5 µg/ml, showed variable efficacy in animals challenged with strains with MICs of 1 µg/ml, and did not work in those with strains with MICs of >1 µg/ml. In addition, mutations, including one reported for the first time, were found outside the HS1 region in the FKS2 gene of six strains with different MICs, but their presence did not influence drug efficacy. The in vitro activity of CSP was compared with that of another echinocandin, anidulafungin, suggesting that the MICs of both drugs, as well as mutations in the HS1 regions of the FKS1 and FKS2 genes, are predictive of outcome.

Assessing micafungin/triazole combinations for the treatment of invasive scedosporiosis due to Scedosporium apiospermum and Scedosporium boydii.

OBJECTIVES: Scedosporium infections are associated with high therapeutic failure rates. Combination therapy may be an alternative approach to improve outcome. The in vitro and in vivo efficacy of micafungin plus posaconazole or plus voriconazole was investigated herein. METHODS: Scedosporium boydii (n = 17) and Scedosporium apiospermum (n = 26) were tested using the chequerboard method according to CLSI M38-A2 guidelines and the fractional inhibitory concentration index (FICI) was evaluated. In vivo outcome of micafungin plus posaconazole or micafungin plus voriconazole against two isolates of each of the mentioned species was evaluated in a well-established, immunocompromised, haematogenous murine model of systemic scedosporiosis. Survival and tissue burden in kidneys and brain were investigated. RESULTS: The FICI category of 'no interaction' was most frequent, while 'synergism' or 'antagonism' was rarely observed. FICI failed to predict the in vivo outcome of both combinatorial treatment strategies. In vivo outcome was strain-dependent rather than species-dependent, even though effects on fungal tissue burden were more pronounced for S. boydii. Both combinations improved survival significantly when compared with untreated controls and micafungin monotherapy. Voriconazole and posaconazole did not differ in their efficacy and micafungin failed to be effective. Combinations were by trend better than voriconazole and posaconazole as single therapy, but statistically significant differences were lacking. CONCLUSIONS: No benefit of the azole/echinocandin combination was found when compared with voriconazole and posaconazole monotherapies. FICI failed to predict the outcome of in vivo drug combinations in the murine study.

Experimental murine acremoniosis: an emerging opportunistic human infection.

Acremonium is an emerging fungal pathogen causing severe infections. We evaluated the virulence of three clinically relevant species within the genus, i.e., Acremonium kiliense (currently Sarocladium kiliense), Acremonium sclerotigenum-A. egyptiacum complex and Acremonium implicatum in a murine model of disseminated infection. Both immunocompetent and immunosuppresssed mice were infected with two inocula concentrations (2 × 10(6) and 2 × 10(8) conidia/animal) of two strains of each species. Tissue burden, mortality rate, histopathology and levels of (1→3)-ß-D-glucan were used as virulence markers. None of the species of Acremonium tested was able to cause infection in immunocompetent mice. Conversely, severe infections were produced in immunocompromised mice, the spleen being the most affected organ. In general, the virulence of the Acremonium species tested was low, S. kiliense being the most virulent species.

2-acylamino-5-nitro-1,3-thiazoles: preparation and in vitro bioevaluation against four neglected protozoan parasites.

The 2-acylamino-5-nitro-1,3-thiazole derivatives (1-14) were prepared using a one step reaction. All compounds were tested in vitro against four neglected protozoan parasites (Giardia intestinalis, Trichomonas vaginalis, Leishmania amazonensis and Trypanosoma cruzi). Acetamide (9), valeroylamide (10), benzamide (12), methylcarbamate (13) and ethyloxamate (14) derivatives were the most active compounds against G. intestinalis and T. vaginalis, showing nanomolar inhibition. Compound 13 (IC50=10nM), was 536-times more active than metronidazole, and 121-fold more effective than nitazoxanide against G. intestinalis. Compound 14 was 29-times more active than metronidazole and 6.5-fold more potent than nitazoxanide against T. vaginalis. Ureic derivatives 2, 3 and 5 showed moderate activity against L. amazonensis. None of them were active against T. cruzi. Ligand efficiency indexes analysis revealed higher intrinsic quality of the most active 2-acylamino derivatives than nitazoxanide and metronidazole. In silico toxicity profile was also computed for the most active compounds. A very low in vitro mammalian cytotoxicity was obtained for 13 and 14, showing selectivity indexes (SI) of 246,300 and 141,500, respectively. Nitazoxanide showed an excellent leishmanicidal and trypanocidal effect, repurposing this drug as potential new antikinetoplastid parasite compound.

Modest efficacy of voriconazole against murine infections by Sporothrix schenckii and lack of efficacy against Sporothrix brasiliensis.

The efficacy of voriconazole (VRC) was evaluated against two strains of each of the two most common species causing sporotrichosis, Sporothrix schenckii sensu stricto and Sporothrix brasiliensis, using a murine model of disseminated infection. Voriconazole was administered at doses of 20 or 40 mg kg(-1) per day by gavage. The drug showed some efficacy, especially at 40 mg kg(-1) per day, in prolonging the survival and reducing fungal load in spleen and liver in mice infected with S. schenckii, whereas in animals infected with S. brasiliensis the drug did not work.

Evaluation of the efficacies of Amphotericin B, Posaconazole, Voriconazole, and Anidulafungin in a murine disseminated infection by the emerging opportunistic Fungus Sarocladium (Acremonium) kiliense.

We evaluated and compared the efficacies of different antifungal drugs against Sarocladium kiliense (formerly Acremonium kiliense), a clinically relevant opportunistic fungus, in a murine model of systemic infection. Three clinical strains of this fungus were tested, and the therapy administered was as follows: posaconazole at 20 mg/kg of body weight (twice daily), voriconazole at 40 mg/kg, anidulafungin at 10 mg/kg, or amphotericin B at 0.8 mg/kg. The efficacy was evaluated by prolonged animal survival, tissue burden reduction, and (1→3)-ß-d-glucan serum levels. In general, the four antifungal drugs showed high MICs and poor in vitro activity. The efficacy of the different treatments was only modest, since survival rates were never higher than 40% and no drug was able to reduce fungal load in all the organs for the three strains tested. Posaconazole, in spite of its high MICs (≥16 µg/ml), showed the highest efficacy. The (1→3)-ß-d-glucan serum levels were equally reduced by all drugs evaluated.

Factors associated with unsatisfactory cosmetic results in oncoplastic surgery.

Introduction: Oncoplastic surgery (OS) has expanded the indications for breast-conserving surgery associated with an adequate aesthetic result. However, few studies have described the factors associated with unsatisfactory cosmetic outcomes from this surgical modality. Materials and methods: This is a cross-sectional prospective study that included patients undergoing breast-conserving surgery (BCS) with or without OS. The patients self-evaluated the cosmetic results of the breasts posttreatment and had them photographed. The photos were analyzed by BCCT.core. Individual and treatment factors (local and systemic) for all patients were evaluated. These factors were dichotomized according to the use of OS and to the cosmetic result (satisfactory and unsatisfactory). Categorical variables were tested for association with surgical outcome using the chi-square test while numerical variables using the Mann-Whitney U test. Variables with p <0,2 were selected for multivariate analysis. Results: Of the 300 patients evaluated, 72 (24,0%) underwent OS. According to the patient self-evaluations, an unsatisfactory cosmetic result from OS was significantly associated with younger age at diagnosis, higher body mass index (BMI) at the time of evaluation, larger tumor size and greater weight of the surgical specimen. According to the BCCT.core, only the laterality of the tumor (left) was significantly associated with an unsatisfactory cosmetic result. In logistic regression, considering OS as a control variable, the risk of an unsatisfactory outcome according to patient self-evaluation was related to the tumor ≥ T2 odds ratio (OR) 1,85 (1,027-3,34) and age at diagnosis < 40 [OR 5,0 (1,84-13,95)]. However, according to the software, the variables were associated with an increased risk of an unsatisfactory outcome were the time interval between surgery and evaluation [OR 1,27 (1,16-1,39)], the presence of lymphedema [OR 2,97 (1,36-6,46)], surgical wound infection [OR 3,6 (1,22-11,16)], tumor location on the left side [OR 3,06 (1,69-5,53)], overweight [OR 2,93 (1,48-5,8)] and obesity [OR 2,52 (1,2-5,31)]. Conclusion: There is no standard methodology for breast cosmesis evaluation, which influences the factors associated with unsatisfactory results. Younger patients and those with increased BMI, left breast cancer and extensive resections tend to present with unsatisfactory cosmetic results when OS is performed.

Temporal Analysis of COVID-19 Epidemiological Indicators in a Low-Income Brazilian Context: A Retrospective Analysis in Paraiba State.

Northeast Brazil is a region with great international tourist potential. Among the states that make up this region, Paraíba stands out due to the presence of vulnerable groups and factors that contribute to adverse outcomes of COVID-19. Therefore, the aim of this study was to analyze the epidemiological data on the incidence, mortality, and case fatality of COVID-19 in Paraíba. An ecological, population-based study was performed, with data extracted from the Brazilian Ministry of Health database. All cases and deaths from COVID-19 from March 2020 to December 2022 were included. The time series was built by applying the Prais-Winsten regression model, and the daily percent change was calculated to analyze the trends. The highest case fatality of the entire period was in April 2020 (7.8%), but in March 2021, the state broke the dismal record of 1248 deaths and the highest mortality rate (30.5 deaths per 100,000 inhabitants). Stationary mortality and case fatality were better in 2022; however, in February 2022, the mortality rate was at levels similar to the same month of the previous year. These results illustrate that COVID-19 is evolving and needs to be constantly monitored.

Insulin Sensitization by PPARγ and GLUT-4 Overexpression/Translocation Mediates the Antidiabetic Effect of Plantago australis.

Plantago australis Lam. Subsp. hirtella (Kunth) Rahn is a medicinal plant used as a diuretic, anti-inflammatory, antibacterial, throat cancer treatment and for the control of diabetes. P. australis was collected in the state of Morelos, México. The hydroalcoholic extract (HAEPa) of P. australis was obtained by maceration and concentrated in vacuo. Once dry, it was evaluated through an oral glucose tolerance test (OGTT) in normoglycemic mice and in a non-insulin-dependent diabetic mice model. The expression of PPARγ and GLUT-4 mRNA was determined by rt-PCR, and GLUT-4 translocation was confirmed by confocal microscopy. The toxicological studies were conducted in accordance with the guidelines suggested by the OECD, sections 423 and 407, with some modifications. HAEPa significantly decreased glycemia in OGTT curves, as well as in the experimental diabetes model compared to the vehicle group. In vitro tests showed that HAEPa induced an α-glucosidase inhibition and increased PPARγ and GLUT-4 expression in cell culture. The LD50 of HAEPa was greater than 2000 mg/kg, and sub-chronic toxicity studies revealed that 100 mg/kg/day for 28 days did not generate toxicity. Finally, LC-MS analysis led to the identification of verbascoside, caffeic acid and geniposidic acid, and phytochemical approaches allowed for the isolation of ursolic acid, which showed significant PPARγ overexpression and augmented GLUT-4 translocation. In conclusion, HAEPa induced significant antidiabetic action by insulin sensitization through PPARγ/GLUT-4 overexpression.

Efficacy of posaconazole in murine experimental sporotrichosis.

We developed a murine model of systemic sporotrichosis by using three strains of each of the two commonest species causing sporotrichosis, i.e., Sporothrix schenckii sensu stricto and Sporothrix brasiliensis, in order to evaluate the efficacy of posaconazole (PSC). The drug was administered at a dose of 2.5 or 5 mg/kg of body weight twice a day by gavage, and one group was treated with amphotericin B (AMB) as a control treatment. Posaconazole, especially at 5 mg/kg, showed good efficacy against all the strains tested, regardless of their MICs, as measured by prolonged survival, tissue burden reduction, and histopathology.

Mouse Subcutaneous BCG Vaccination and Mycobacterium tuberculosis Infection Alter the Lung and Gut Microbiota.

The objective of this study was to characterize the effect of Bacillus Calmette-Guérin (BCG) vaccination and M. tuberculosis infection on gut and lung microbiota of C57BL/6 mice, a well-characterized mouse model of tuberculosis. BCG vaccination and infection with M. tuberculosis altered the relative abundance of Firmicutes and Bacteroidetes phyla in the lung compared with control group. Vaccination and infection changed the alpha- and beta-diversity in both the gut and the lung. However, lung diversity was the most affected organ after BCG vaccination and M. tuberculosis infection. Focusing on the gut-lung axis, a multivariate regression approach was used to compare profile evolution of gut and lung microbiota. More genera have modified relative abundances associated with BCG vaccination status at gut level compared with lung. Conversely, genera with modified relative abundances associated with M. tuberculosis infection were numerous at lung level. These results indicated that the host local response against infection impacted the whole microbial flora, while the immune response after vaccination modified mainly the gut microbiota. This study showed that a subcutaneous vaccination with a live attenuated microorganism induced both gut and lung dysbiosis that may play a key role in the immunopathogenesis of tuberculosis. IMPORTANCE The microbial communities in gut and lung are important players that may modulate the immunity against tuberculosis or other infections as well as impact the vaccine efficacy. We discovered that vaccination through the subcutaneous route affect the composition of gut and lung bacteria, and this might influence susceptibility and defense mechanisms against tuberculosis. Through these studies, we can identify microbial communities that can be manipulated to improve vaccine response and develop treatment adjuvants.