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BACKGROUND: Pancreatic head cancer patients who undergo pancreatoduodenectomy (PD) often experience disease recurrence, frequently associated with a positive margin status (R1). Total mesopancreas excision (TMpE) has emerged as a potential approach to increase surgical radicality and minimize locoregional recurrence. However, its effectiveness and safety remain under evaluation. METHODS: We conducted a systematic review and meta-analysis to synthesize current evidence on TMpE outcomes. A systematic search of MEDLINE, EMBASE, Cochrane, and Web of Science databases was conducted up to March 2024 to identify studies comparing TMpE with standard pancreatoduodenectomy (sPD). The risk ratio (RR) or mean difference (MD) was pooled using a random effects model. RESULTS: From 452 studies identified, 9 studies with a total of 738 patients were included, with 361 (49%) undergoing TMpE. TMpE significantly improved the R0 resection rate (RR 1.24; 95% CI 1.11-1.38; P < 0.05), reduced blood loss (MD -143.70 ml; 95% CI -247.92, -39.49; P < 0.05), and increased lymph node harvest (MD 7.27 nodes; 95% CI 4.81, 9.73; P < 0.05). No significant differences were observed in hospital stay, postoperative complications, or mortality between TMpE and sPD. TMpE also significantly reduced overall recurrence (RR 0.53; 95% CI 0.35-0.81; P < 0.05) and local recurrence (RR 0.39; 95% CI 0.24-0.63; P < 0.05). Additionally, the risk of pancreatic fistula was lower in the TMpE group (RR 0.66; 95% CI 0.52-0.85; P < 0.05). CONCLUSION: Total mesopancreas excision significantly increases the R0 resection rate and reduces locoregional recurrence while maintaining an acceptable safety profile when compared with standard pancreatoduodenectomy. Further prospective randomized studies are warranted to determine the optimal surgical approach for total mesopancreatic resection.

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Hepatic injuries in COVID-19 are not yet fully understood and indirect pathways (without viral replication in the liver) have been associated with the activation of vascular mechanisms of liver injury in humans infected with SARS-CoV-2. Golden Syrian hamsters are an effective model for experimental reproduction of moderate and self-limiting lung disease during SARS-CoV-2 infection. As observed in humans, this experimental model reproduces lesions of bronchointerstitial pneumonia and pulmonary vascular lesions, including endotheliitis (attachment of lymphoid cells to the luminal surface of endothelium). Extrapulmonary vascular lesions are well documented in COVID-19, but such extrapulmonary vascular lesions have not yet been described in the Golden Syrian hamster model of SARS-CoV-2 infection. The study aimed to evaluate microscopic liver lesions in Golden Syrian hamsters experimentally infected with SARS-CoV-2. In total, 38 conventional Golden Syrian hamsters, divided into infected group (n=24) and mock-infected group (n=14), were euthanized at 2-, 3-, 4-, 5-, 7-, 14-, and 15-days post infection with SARS-CoV-2. Liver fragments were evaluated by histopathology and immunohistochemical detection of SARS-CoV-2 Spike S2 antigens. The frequencies of portal vein endotheliitis, lobular activity, hepatocellular degeneration, and lobular vascular changes were higher among SARS-CoV-2-infected animals. Spike S2 antigen was not detected in liver. The main results indicate that SARS-CoV-2 infection exacerbated vascular and inflammatory lesions in the liver of hamsters with pre-existing hepatitis of unknown origin. A potential application of this animal model in studies of the pathogenesis and evolution of liver lesions associated with SARS-CoV-2 infection still needs further evaluation.

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The aim was to report cases and risk factors for hepatogenous photosensitization in lambs kept on Brachiaria spp. pastures and supplemented with levels of extruded urea (EU). The herd consisted of 69 Texel crossbred lambs with known parentage (fathers and mothers adapted to the consumption of forage of the genus Brachiaria), randomly divided into 5 groups and distributed in individual paddocks for each group. The animals were supplemented with increasing levels of EU (Amireia® 200S): 0, 6, 12, 18, and 24 g of EU per 100 kg-1 of body weight (BW). The concentration of protodioscin was estimated in the mixed pastures of Brachiaria spp. (cv. Marandu and cv. Basilisk), structural components (leaf, stem, and dead material), samples of each cultivar, and in the months of December (2018), February, and April (2019). The animals were examined daily, and when behavioral changes were identified, they underwent clinical examinations and anamnesis. Weighing was performed every 14 days, followed by necropsy and serum biochemical analysis, including gamma-glutamyltransferase (GGT). The highest concentrations of protodioscin (p < 0.0001) were found in the pastures used by animals supplemented without extruded urea (7.07 ± 0.56), in the Basilisk cultivar (11.35 ± 0.06), in the leaf blade components (2.08 ± 0.05), and thatch (2.20 ± 0.00), and in the month of April (7.34 ± 0.29) (the month with the lowest rainfall), respectively. Fourteen (20.29%) cases of photosensitization were observed in lambs, of which six recovered, and eight died. Serum GGT levels ranged from 42.2 to 225 IU/L; however, in animals that died, values ranged from 209.4 to 225 IU/L. The use of levels 12 g and 18 g per 100 kg-1 of body weight of extruded urea may contribute to the lower occurrence of photosensitization, as the animals selected pastures with lower protodioscin content, presenting a smaller number of cases.

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BACKGROUND: Leprosy is a highly neglected disease that is considered a serious public health problem in many countries. This illness is characterised by a variety of clinical and histopathological manifestations that are related to the patient immune response. OBJECTIVES: This work aimed evaluate the profile of circulating immune mediators in the plasma from patients classified clinically as paucibacillary (PB), multibacillary (MB), households contacts (HHC), type1 leprosy reaction (T1R), type2 leprosy reaction (T2R) and control individuals without medical history of leprosy (CTL). METHODS: To assessment of the plasma immune mediators was used multiplex microbeads immunoassay "Luminex". FINDINGS: The results showed that patients (PB) had a regulatory-biased profile, while MB revealed a pro-inflammatory trend of highly expressed biomarkers. HHC display conspicuously increased levels in the plasma of the chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8), pro-inflammatory cytokines (IFN-γ,TNF and IL-1ß), modulating cytokines (IL-9 and IL-1Ra) and growth factors (PDGF, G-CSF and IL-2). Interestingly, HHC displayed superior production of IFN-γ as compared to other leprosy groups, indicating a putative protective role for this cytokine during chronic Mycobacterium leprae exposure. MAIN CONCLUSION: Further investigations are currently underway to elucidate the potential of these mediators as biomarkers applicable to the diagnosis/prognosis of leprosy and also T1R and T2R leprosy reactions.

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BACKGROUND: The prevalence of chronic kidney disease (CKD) has increased in the recent decades, along with the number of patients in the terminal stages of this disease, requiring transplantation. Some skin disorders are more frequent in patients with CKD and in renal transplant recipients (RTR). OBJECTIVES: To evaluate the frequency of skin diseases in RTR and patients with CKD receiving conservative treatment. DESIGN AND SETTING: This observational cross-sectional study recruited consecutive patients with CKD and RTR from a nephrology clinic at a teaching hospital in Brazil between 2015 and 2020. METHODS: Quantitative, descriptive, and analytical approaches were used. The sample was selected based on convenience sampling. Data were collected from dermatological visits and participants' medical records. RESULTS: Overall, 308 participants were included: 206 RTR (66.9%, median age: 48 years, interquartile range [IQR] 38.0-56.0, 63.6% men) and 102 patients with CKD (33.1%, median age: 61.0 years, IQR 50.0-71.2, 48% men). The frequency of infectious skin diseases (39.3% vs. 21.6% P = 0.002) were higher in RTR than in patients with CKD. Neoplastic skin lesions were present in nine (4.4%) RTR and in only one (1.0%) patient with CKD. Among the RTR, the ratio of basal cell carcinoma to squamous cell carcinoma was 2:1. CONCLUSIONS: This study revealed that an increased frequency of infectious skin diseases may be expected in patients who have undergone kidney transplantation. Among skin cancers, BCC is more frequently observed in RTR, especially in those using azathioprine.

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Abstract Background: Pemphigus constitutes a group of autoimmune bullous diseases. A reduction in the incidence of endemic pemphigus foliaceus and an increase in pemphigus vulgaris has been described, but there are no studies in Minas Gerais that address the subject. Objective: To describe the epidemiological and clinical profile of patients with pemphigus treated at the Dermatology Service of a public University Hospital in the state of Minas Gerais, Brazil. Methods: An observational, descriptive, and cross-sectional study was carried out of cases of endemic pemphigus foliaceus and pemphigus vulgaris, for a period of six months. A questionnaire was filled out with epidemiological and clinical data on the disease. Results: A total of 122 patients were included in the study, 64 with endemic pemphigus foliaceus and 58 with pemphigus vulgaris. When comparing patients with endemic pemphigus foliaceus and those with pemphigus vulgaris, a statistical difference was observed between the median age of initial disease manifestation (p = 0.001), patient occupation (p = 0.010), area of residence (p = 0.000), forests (p = 0.000) and rivers/streams close to the dwelling (p = 0.001) and the number of systemic medications required to control the disease (p = 0.002). When comparing patients with endemic pemphigus foliaceus to those evaluated in a study carried out at the same service in 2008, there was a statistical difference in the area of residence (p = 0.030). Study limitations: The assessed population comes from a tertiary care service that is not a reference for the entire state. Conclusions: Patients with endemic pemphigus foliaceus and pemphigus vulgaris maintain statistically significant differences regarding their main variables in the literature, such as age and area of residence. Historically, there has been a reduction in cases of endemic pemphigus foliaceus and an increase in cases of pemphigus vulgaris in this population.

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BACKGROUND: Pemphigus constitutes a group of autoimmune bullous diseases. A reduction in the incidence of endemic pemphigus foliaceus and an increase in pemphigus vulgaris has been described, but there are no studies in Minas Gerais that address the subject. OBJECTIVE: To describe the epidemiological and clinical profile of patients with pemphigus treated at the Dermatology Service of a public University Hospital in the state of Minas Gerais, Brazil. METHODS: An observational, descriptive, and cross-sectional study was carried out of cases of endemic pemphigus foliaceus and pemphigus vulgaris, for a period of six months. A questionnaire was filled out with epidemiological and clinical data on the disease. RESULTS: A total of 122 patients were included in the study, 64 with endemic pemphigus foliaceus and 58 with pemphigus vulgaris. When comparing patients with endemic pemphigus foliaceus and those with pemphigus vulgaris, a statistical difference was observed between the median age of initial disease manifestation (p = 0.001), patient occupation (p = 0.010), area of residence (p = 0.000), forests (p = 0.000) and rivers/streams close to the dwelling (p = 0.001) and the number of systemic medications required to control the disease (p = 0.002). When comparing patients with endemic pemphigus foliaceus to those evaluated in a study carried out at the same service in 2008, there was a statistical difference in the area of residence (p = 0.030). STUDY LIMITATIONS: The assessed population comes from a tertiary care service that is not a reference for the entire state. CONCLUSIONS: Patients with endemic pemphigus foliaceus and pemphigus vulgaris maintain statistically significant differences regarding their main variables in the literature, such as age and area of residence. Historically, there has been a reduction in cases of endemic pemphigus foliaceus and an increase in cases of pemphigus vulgaris in this population.

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BACKGROUND Leprosy is a highly neglected disease that is considered a serious public health problem in many countries. This illness is characterised by a variety of clinical and histopathological manifestations that are related to the patient immune response. OBJECTIVES This work aimed evaluate the profile of circulating immune mediators in the plasma from patients classified clinically as paucibacillary (PB), multibacillary (MB), households contacts (HHC), type1 leprosy reaction (T1R), type2 leprosy reaction (T2R) and control individuals without medical history of leprosy (CTL). METHODS To assessment of the plasma immune mediators was used multiplex microbeads immunoassay "Luminex". FINDINGS The results showed that patients (PB) had a regulatory-biased profile, while MB revealed a pro-inflammatory trend of highly expressed biomarkers. HHC display conspicuously increased levels in the plasma of the chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8), pro-inflammatory cytokines (IFN-γ,TNF and IL-1β), modulating cytokines (IL-9 and IL-1Ra) and growth factors (PDGF, G-CSF and IL-2). Interestingly, HHC displayed superior production of IFN-γ as compared to other leprosy groups, indicating a putative protective role for this cytokine during chronic Mycobacterium leprae exposure. MAIN CONCLUSION Further investigations are currently underway to elucidate the potential of these mediators as biomarkers applicable to the diagnosis/prognosis of leprosy and also T1R and T2R leprosy reactions.

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ABSTRACT BACKGROUND: The prevalence of chronic kidney disease (CKD) has increased in the recent decades, along with the number of patients in the terminal stages of this disease, requiring transplantation. Some skin disorders are more frequent in patients with CKD and in renal transplant recipients (RTR). OBJECTIVES: To evaluate the frequency of skin diseases in RTR and patients with CKD receiving conservative treatment. DESIGN AND SETTING: This observational cross-sectional study recruited consecutive patients with CKD and RTR from a nephrology clinic at a teaching hospital in Brazil between 2015 and 2020. METHODS: Quantitative, descriptive, and analytical approaches were used. The sample was selected based on convenience sampling. Data were collected from dermatological visits and participants' medical records. RESULTS: Overall, 308 participants were included: 206 RTR (66.9%, median age: 48 years, interquartile range [IQR] 38.0-56.0, 63.6% men) and 102 patients with CKD (33.1%, median age: 61.0 years, IQR 50.0-71.2, 48% men). The frequency of infectious skin diseases (39.3% vs. 21.6% P = 0.002) were higher in RTR than in patients with CKD. Neoplastic skin lesions were present in nine (4.4%) RTR and in only one (1.0%) patient with CKD. Among the RTR, the ratio of basal cell carcinoma to squamous cell carcinoma was 2:1. CONCLUSIONS: This study revealed that an increased frequency of infectious skin diseases may be expected in patients who have undergone kidney transplantation. Among skin cancers, BCC is more frequently observed in RTR, especially in those using azathioprine.

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ABSTRACT Hepatic injuries in COVID-19 are not yet fully understood and indirect pathways (without viral replication in the liver) have been associated with the activation of vascular mechanisms of liver injury in humans infected with SARS-CoV-2. Golden Syrian hamsters are an effective model for experimental reproduction of moderate and self-limiting lung disease during SARS-CoV-2 infection. As observed in humans, this experimental model reproduces lesions of bronchointerstitial pneumonia and pulmonary vascular lesions, including endotheliitis (attachment of lymphoid cells to the luminal surface of endothelium). Extrapulmonary vascular lesions are well documented in COVID-19, but such extrapulmonary vascular lesions have not yet been described in the Golden Syrian hamster model of SARS-CoV-2 infection. The study aimed to evaluate microscopic liver lesions in Golden Syrian hamsters experimentally infected with SARS-CoV-2. In total, 38 conventional Golden Syrian hamsters, divided into infected group (n=24) and mock-infected group (n=14), were euthanized at 2-, 3-, 4-, 5-, 7-, 14-, and 15-days post infection with SARS-CoV-2. Liver fragments were evaluated by histopathology and immunohistochemical detection of SARS-CoV-2 Spike S2 antigens. The frequencies of portal vein endotheliitis, lobular activity, hepatocellular degeneration, and lobular vascular changes were higher among SARS-CoV-2-infected animals. Spike S2 antigen was not detected in liver. The main results indicate that SARS-CoV-2 infection exacerbated vascular and inflammatory lesions in the liver of hamsters with pre-existing hepatitis of unknown origin. A potential application of this animal model in studies of the pathogenesis and evolution of liver lesions associated with SARS-CoV-2 infection still needs further evaluation.

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Purpose: Inflammatory bowel disease (IBD) is a disease of increasing prevalence in developing countries. Obesity has emerged as a potential risk for IBD; however, the data in the literature are conflicting, and relevant studies in Brazil are limited. Here, we report body mass index profile (BMI) of patients with IBD treated at reference centers in three states of northeastern Brazil. Patients and Methods: Observational descriptive study conducted from January 2021 through December 2021 in patient with IBD. Results: Of 470 patients with IBD, 194 (41%) were classified as normal weight, 42 (9%) as underweight, 155 (33%) as overweight, and 79 (17%) as obese; CD patients were significantly more likely to be underweight than UC patients (p=0.031)Overweight patients were older (median age: 47 years) than normal-weight and underweight patients at diagnosis (38.5 and 35.5 years, respectively [p<0.0001]). IBD onset and diagnosis among overweight and obese individuals were associated with older age. More extensive disease behavior patterns predominated in UC, while forms associated with complications were prevalent in CD, irrespective of nutritional status. There was a higher frequency of compatible symptoms with axial joint inflammation among obese patients (p=0.005) and a lower frequency of compatible symptoms with peripheral joint inflammation in underweight patients (p=0.044) than in patients of normal weight. No significant difference in the frequency of different drug or surgical treatments was observed among the groups. Conclusion: Despite the predominance of overweight and obesity in patients with IBD, no differences in the patterns of disease were seen between the overweight and normal-weight groups; however, obesity was associated with IBD onset in older adults and a higher frequency compatible symptom with axial joint inflammation. These data reinforce the importance of monitoring the nutritional status of IBD patients and the need for a multidisciplinary approach, as recommended in the current guidelines.

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RATIONALE: In the context of a major health crisis, health professionals must first compare patients' recovery prospects, thus giving priority to the goal of saving the greatest number of lives. AIMS AND OBJECTIVES: Critically evaluate a protocol for allocation of scarce intensive care units (ICU), which the authors proposed at the onset of the COVID-19 pandemic and originally published in two Brazilian newspapers; and compare that protocol with similar proposals, particularly with 2 successive protocols issued by the Brazilian Critical Care Association. The main objective is to highlight the advantages of the authors' approach and discuss some criticisms that has been levelled against the proposed protocol after its original publication in 2020. METHOD: Comparative analysis of 3 different protocols (the authors' proposed protocol and 2 successive protocols issued by the Brazilian Critical Care Association) with regard to ethical principles. RESULTS: The main objective of a healthcare system is to ensure a fair patient triage process when it is impossible to grant admission to all patients in need of treatment. Decision-making regarding the impartial prioritization of ICU admissions must be based primarily on clinical criteria. The Sequential Organ Failure Assessment (SOFA) is, for ethical and technical reasons, a useful tool for clinical assessments of patients. Based on three ranges of SOFA scores, patients can be classified into a "high", a "medium", and a "low" priority group. In the case of ties, the life cycle principle must be the tiebreaker. If the tie persists, a draw must be used. CONCLUSION: The authors' proposed protocol has advantages over the other two protocols due to its greater practicality and capacity to account for egalitarian and consequentialist principles simultaneously. It aims at saving as many lives as possible within the constraints of fairness. Furthermore, the proposed protocol avoids discrimination against people with disabilities without, at the same time, promoting discrimination against the elderly.

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OBJECTIVE: To determine the minimum alveolar concentration (MAC) of sevoflurane in Holstein steers using electric stimulation. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of 15 Holstein steers aged 7.3 ± 1.2 months and weighing 121 ± 25 kg. METHODS: Animals were anesthetized with sevoflurane at 8% in oxygen at 5 L minute-1 via facemask and were intubated with an orotracheal tube of a compatible size. After 15 minutes of stabilization of the initial expired concentration of sevoflurane (Fe'Sevo) at 2.6%, electrical stimulation on the thoracic limb was initiated with a sequence of 2 × 10 ms followed by 2 × 3 second electrical currents of 50 V and 50 Hz, 5 seconds apart. Following each stimulus with a negative response, the Fe'Sevo was decreased by 0.2% and a 15 minute interval was awaited before the next stimulus. The procedure was repeated until the first Fe'Sevo value with a positive motor response was obtained. The Fe'Sevo was then increased by 0.1%, followed by a new stimulus, until a negative response was obtained. The value of MAC was calculated as the arithmetic mean between the lowest Fe'Sevo associated with a negative motor response and the highest Fe'Sevo associated with a positive response. RESULTS: The mean MAC for the 15 steers was 2.0 ± 0.3%, which corresponds to 2.1 ± 0.3% at sea level. CONCLUSIONS: Based on the proposed methodology, the MAC of sevoflurane for healthy Holstein steers is 2.1 ± 0.3% at sea level. CLINICAL RELEVANCE: This Fe'Sevo value can be used to guide depth of anesthesia in steers weighing approximately 120 kg in clinical practice.

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Purpose: Ulcerative colitis (UC) and Crohn's disease (CD) are inflammatory bowel diseases (IBDs) with multifactorial causes. They are becoming more prevalent in developing countries such as Brazil; however, relevant studies in poorer regions of the country are limited. Here, we report the clinical-epidemiological profile of patients with IBD treated at reference centers in three states of Northeast Brazil. Patients and Methods: This was a prospective cohort study involving patients at referral outpatient clinics for IBD from January 2020 through December 2021. Results: Of 571 patients with IBD, 355 (62%) had UC, and 216 (38%) had CD. The patients were predominantly women (355, 62%) for both UC and CD. Extensive colitis was the pattern present in 39% of the UC cases. For CD, ileocolonic disease was the predominant manifestation (38%), with 67% of cases showing penetrating and/or stenosing behavior. The majority of patients were diagnosed between the ages of 17 and 40, corresponding to 60.2% in CD and 52.7% in UC. The median time between symptom onset and diagnosis was 12 months for CD and 8 months for UC (p=0.042). Joint involvement was the most frequent extraintestinal manifestation, with arthralgia and arthritis present in 41.9% and 18.6% of the patients, respectively. Biological therapy was prescribed to 73% of CD patients and 26% of UC patients. A progressive increase in new cases was observed in every 5-year interval over the last five decades, with 58.6% being diagnosed in the last 10 years. Conclusion: More extensive disease behavior patterns predominated in UC, while forms associated with complications were prevalent in CD. A prolonged time to diagnosis may have contributed to these findings. A progressive increase in IBD incidence was observed and may be related to greater urbanization and better access to specialized outpatient clinics, resulting in improvements in diagnosis.

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Miconazole-loaded nanoparticles coated with hyaluronic acid (miconazole-loaded nanoparticles/HA) were developed to overcome the limitations of the conventional therapy of the vulvovaginal candidiasis (VVC). They were synthesized by emulsification and solvent evaporation techniques, characterized by diameter, polydispersity index, zeta potential, encapsulation efficiency, atomic force microscopy (AFM), evaluated in terms of efficacy against C. albicans in vitro, and tested in a murine VVC model. Nanoparticles showed 211nm of diameter with a 0.32 polydispersity index, -53mV of zeta potential, and 90% miconazole encapsulation efficiency. AFM evidenced nanoparticles with a spherical shape. They inhibited the proliferation of C. albicans in vitro and in vivo after a single administration. Nanoparticles released the miconazole directly in the site of action at low therapeutic doses, which was enough to eliminate the fungal burden in the murine VVC model. These systems were rationally designed since the existence of the HA induces their adhesion on the vaginal mucus and their internalization via CD44 receptors, inhibiting the C. albicans. Therefore, miconazole-loaded nanoparticles/HA represent an innovative non-conventional pharmaceutical dosage form to treat the VVC and recurrent VVC.

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OBJECTIVE: To describe the development of a virtual educational booklet for self-care promotion of postmenopausal women with osteoporosis during the COVID-19 pandemics. METHOD: This methodological study was conducted in three steps: bibliographic search, development of virtual educational booklet by 12 evaluators and ten representatives of the target audience. A questionnaire adapted from the literature was used to evaluate the educational booklet. The questionnaire consisted of seven items: scientific accuracy, content, language, illustrations, specificity and comprehension, readability, and quality of information. A minimum score of 0.75 in the content validity index (CVI) of each questionnaire item and minimum agreement of 75% among positive responses of postmenopausal women were required to validate the virtual booklet. RESULTS: Health professionals and representatives of the target audience suggested changes regarding layout, illustrations, and content of the virtual booklet. CVI of the final version was 0.84 between health professionals and agreement among the target audience was 90%. CONCLUSION: The virtual educational booklet with exercises and instructions for postmenopausal women with osteoporosis was valid and should be used by health professionals for advice on self-care and health promotion during the COVID-19 pandemic.

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ETNOPHARMACOLOGICAL RELEVANCE: Traditional uses of Annona muricata L. (soursop) include treatment for cancer, fungal infections, and inflammatory diseases. Its phytoconstituents, mainly acetogenins and alkaloids, are associated with therapeutic activity and clinical application is currently under investigation. However, the application of phytotherapy to treat diseases caused by fungal biofilms, such as vulvovaginal candidiasis (VVC), is still limited. AIM OF THE STUDY: To investigate the activity of the ethanolic extract of A. muricata leaves (AML) against biofilms formed by multiresistant Candida albicans (ATCC® 10231) both in vitro and in a VVC experimental model. MATERIAL AND METHODS: C. albicans biofilms were grown and their adhesion, proliferation, development, and matrix composition studied by spectrophotometry, scanning electron microscopy (SEM), whole slide imaging (WSI), and biochemical assays without or with AML treatment. In parallel, in vivo experiments were conducted using a murine model of infection treated with different concentrations of the extract and nystatin. Fungal burden and histological changes were investigated. RESULTS: The proliferation and adhesion of C. albicans biofilms were significantly reduced as confirmed by SEM and WSI quantitative analyses. Furthermore, the concentration of carbohydrates, proteins and DNA was reduced in the biofilm matrix. In vivo assays demonstrated that AML was able to reduce the fungal burden and the inflammatory process. CONCLUSIONS: The findings further emphasized the therapeutic and scientific potential of AML, thus encouraging its future use in the treatment of VVC.

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Although the beneficial effect of biostimulation on reproduction has been reported, the influence of selectivity and social factors on the response to biostimulation has not received sufficient research attention in both Bos indicus and Bos indicus influenced cattle. Furthermore, 'green and cheap' strategies to improve cattle reproduction are currently in demand while Bos indicus influenced cattle with inferior reproductive performance, and farmers with economic limitations are common in tropical zones. Hence, to assess the reproductive response of crossbred taurus × indicus cows to biostimulation by pre-pubertal (PPM) or pubertal (PM) teasers males, two trials of 2 years each were conducted. Trial 1 n = 187 cows (Year 1:85 cows exposed to PPM and Year 2:102 cows exposed to PM). Trial 2 n = 196 cows (Year 1:101 cows exposed to PPM and Year 2:95 cows exposed to PM). The effect of exposing cows to PPM and PM on the intervals calving to first service (ICFS), calving to conception (ICC) and economic cost of days open (ECDO) was analysed using Kruskal-Wallis ANOVA and the effect of exposing cows to PPM and to PM on reproductive status at 90 days (RS90) and proportion of cows requiring hormonal protocols (PRH) was compared using χ2 analysis. Both ICFS and ICC were shorter (p < .0001) for PM-exposed females (96.12 ± 4.1 and 110.93 ± 2.9 days; respectively) compared with those PPM-exposed (134.41 ± 3.3 and 135.64 ± 2.4 days; respectively). With RS90, more (p < .0001) PM-exposed cows (50.7%) were pregnant compared with PPM-exposed cows (16.1%). The PRH was greater (p < .0001) in PPM-exposed cows (79.0%) compared with PM-exposed (27.9%). The ECDO was less (p < .0001) in PM-exposed cows (US$ 142.9 ± 3.8) compared with PPM-exposed (US$ 176.3 ± 2.9). In conclusion, cows exposed to PM had shorter ICFS and ICC compared with cows exposed to PPM. More cows exposed to PM were pregnant after 90 days, and PRH was less than cows exposed to PPM. Cows exposed to PM had a reduced ECDO than those exposed to PPM.

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OBJECTIVES: To develop alginate nanoparticles functionalized with polysorbate 80 (P80) as miltefosine carriers for brain targeting in the oral treatment of cryptococcal meningitis. METHODS: Miltefosine-loaded alginate nanoparticles functionalized or not with P80 were produced by an emulsification/external gelation method and the physicochemical characteristics were determined. The haemolytic activity and cytotoxic and antifungal effects of nanoparticles were assessed in an in vitro model of the blood-brain barrier (BBB). A murine model of disseminated cryptococcosis was used for testing the efficacy of oral treatment with the nanoparticles. In addition, serum biomarkers were measured for toxicity evaluation and the nanoparticle biodistribution was analysed. RESULTS: P80-functionalized nanoparticles had a mean size of ∼300 nm, a polydispersity index of ∼0.4 and zeta potential around -50 mV, and they promoted a sustained drug release. Both nanoparticles were effective in decreasing the infection process across the BBB model and reduced drug cytotoxicity and haemolysis. In in vivo cryptococcosis, the oral treatment with two doses of P80 nanoparticles reduced the fungal burden in the brain and lungs, while the non-functionalized nanoparticles reduced fungal amount only in the lungs, and the free miltefosine was not effective. In addition, the P80-functionalization improved the nanoparticle distribution in several organs, especially in the brain. Finally, treatment with nanoparticles did not cause any toxicity in animals. CONCLUSIONS: These results support the potential use of P80-functionalized alginate nanoparticles as miltefosine carriers for non-toxic and effective alternative oral treatment, enabling BBB translocation and reduction of fungal infection in the brain.

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