Immunology of Kidney Disease.

The immune system and the kidneys are closely related. Immune components mediate acute kidney disease and are crucial to the progression of chronic kidney disease. Beyond its pathogenic functions, the immune system supports immunological homeostasis in healthy kidneys. The kidneys help maintain immune equilibrium by removing metabolic waste products and toxins, thereby limiting local and systemic inflammation. In this review, we describe the close relationship between the immune system and the kidneys. We discuss how the imbalance in the immune response can be deleterious to the kidneys and how immunomodulation can be important in preventing end-stage renal disease. In addition, recent tools such as in silico platforms and kidney organoids can help unveil the relationship between immune cells and kidney homeostasis.

PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine.

Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving anti-PD-1 had more robust circulating Tfh responses than adults not receiving immunotherapy. PD-1 pathway blockade resulted in transcriptional signatures of increased cellular proliferation in circulating Tfh and responding B cells compared with controls. These latter observations suggest an underlying change in the Tfh-B cell and germinal centre axis in a subset of immunotherapy patients. Together, these results demonstrate dynamic effects of anti-PD-1 therapy on influenza vaccine responses and highlight analytical vaccination as an approach that may reveal underlying immune predisposition to adverse events.

Sepsis expands a CD39+ plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity.

Sepsis results in elevated adenosine in circulation. Extracellular adenosine triggers immunosuppressive signaling via the A2a receptor (A2aR). Sepsis survivors develop persistent immunosuppression with increased risk of recurrent infections. We utilized the cecal ligation and puncture (CLP) model of sepsis and subsequent infection to assess the role of adenosine in post-sepsis immune suppression. A2aR-deficient mice showed improved resistance to post-sepsis infections. Sepsis expanded a subset of CD39hi B cells and elevated extracellular adenosine, which was absent in mice lacking CD39-expressing B cells. Sepsis-surviving B cell-deficient mice were more resistant to secondary infections. Mechanistically, metabolic reprogramming of septic B cells increased production of ATP, which was converted into adenosine by CD39 on plasmablasts. Adenosine signaling via A2aR impaired macrophage bactericidal activity and enhanced interleukin-10 production. Septic individuals exhibited expanded CD39hi plasmablasts and adenosine accumulation. Our study reveals CD39hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease.

Infection-elicited microbiota promotes host adaptation to nutrient restriction.

The microbiota performs multiple functions vital to host fitness, including defense against pathogens and adaptation to dietary changes. Yet, how environmental challenges shape microbiota resilience to nutrient fluctuation remains largely unexplored. Here, we show that transient gut infection can optimize host metabolism toward the usage of carbohydrates. Following acute infection and clearance of the pathogen, mice gained more weight as a result of white adipose tissue expansion. Concomitantly, previously infected mice exhibited enhanced carbohydrate (glucose) disposal and insulin sensitivity. This metabolic remodeling depended on alterations to the gut microbiota, with infection-elicited Betaproteobacteria being sufficient to enhance host carbohydrate metabolism. Further, infection-induced metabolic alteration protected mice against stunting in the context of limited nutrient availability. Together, these results propose that alterations to the microbiota imposed by acute infection may enhance host fitness and survival in the face of nutrient restriction, a phenomenon that may be adaptive in settings where both infection burden and food precarity are prevalent.

Highly divergent and diverse viral community infecting sylvatic mosquitoes from Northeast Brazil.

Mosquitoes can transmit several pathogenic viruses to humans, but their natural viral community is also composed of a myriad of other viruses such as insect-specific viruses (ISVs) and those that infect symbiotic microorganisms. Besides a growing number of studies investigating the mosquito virome, the majority are focused on few urban species, and relatively little is known about the virome of sylvatic mosquitoes, particularly in high biodiverse biomes such as the Brazilian biomes. Here, we characterized the RNA virome of 10 sylvatic mosquito species from Atlantic forest remains at a sylvatic-urban interface in Northeast Brazil employing a metatranscriptomic approach. A total of 16 viral families were detected. The phylogenetic reconstructions of 14 viral families revealed that the majority of the sequences are putative ISVs. The phylogenetic positioning and, in most cases, the association with a high RNA-dependent RNA polymerase amino acid divergence from other known viruses suggests that the viruses characterized here represent at least 34 new viral species. Therefore, the sylvatic mosquito viral community is predominantly composed of highly divergent viruses highlighting the limited knowledge we still have about the natural virome of mosquitoes in general. Moreover, we found that none of the viruses recovered were shared between the species investigated, and only one showed high identity to a virus detected in a mosquito sampled in Peru, South America. These findings add further in-depth understanding about the interactions and coevolution between mosquitoes and viruses in natural environments. IMPORTANCE: Mosquitoes are medically important insects as they transmit pathogenic viruses to humans and animals during blood feeding. However, their natural microbiota is also composed of a diverse set of viruses that cause no harm to the insect and other hosts, such as insect-specific viruses. In this study, we characterized the RNA virome of sylvatic mosquitoes from Northeast Brazil using unbiased metatranscriptomic sequencing and in-depth bioinformatic approaches. Our analysis revealed that these mosquitoes species harbor a diverse set of highly divergent viruses, and the majority comprises new viral species. Our findings revealed many new virus lineages characterized for the first time broadening our understanding about the natural interaction between mosquitoes and viruses. Finally, it also provided several complete genomes that warrant further assessment for mosquito and vertebrate host pathogenicity and their potential interference with pathogenic arboviruses.

Are silymarin and N-acetylcysteine able to prevent liver damage mediated by multiple factors? Findings against ethanol plus LPS-induced liver injury in mice.

This study investigated the effect of N-acetylcysteine (NAC) and silymarin (SIL) in the liver of mice exposed to ethanol and lipopolysaccharides (LPS). Mice were divided into four groups (n = 6): naive, vehicle, NAC (200 mg/kg), and SIL (200 mg/kg). Treatments were given orally (po) once daily for 10 days. Liver injury was induced by administration of ethanol (30%, po) for 10 days, once daily, followed by a single administration of LPS (2 mg/kg, ip) 24 h before euthanasia. After the treatment period, animals were euthanized, and liver and blood samples were collected. NAC, but not SIL, prevented the increase in oxalacetic glutamic transaminase (OGT) and pyruvic glutamic transaminase (PGT) serum levels. NAC and SIL did not restore levels of reduced glutathione or hepatic malonaldehyde. The treatments with NAC or SIL showed no difference in the activity of glutathione S-transferase, superoxide dismutase, and catalase compared to vehicle group. Myeloperoxidase and N-acetylglucosaminidase activities are increased, as well as the IL-6 and IL-10 levels in the liver. The treatment with NAC, but not SIL, reduced the N-acetylglucosamines activity and the IL-6 and IL-10 amount in the liver. Histological findings revealed microsteatosis in the vehicle group, which was not prevented by SIL but was partially reduced in animals receiving NAC. Unlike other liver injury models, NAC (200 mg/kg) or SIL (200 mg/kg) did not positively affect antioxidant patterns in liver tissue of animals exposed to ethanol plus LPS, but NAC treatment displays anti-inflammatory properties in this model.

Artificial intelligence algorithms and 3D volumetric rendering for basal cell carcinoma detection and tumor depth assessment in RCM-OCT images: a pilot study.

The Reflectance Confocal Microscopy - Optical Coherence Tomography (RCM-OCT) device has shown utility in detecting and assessing depth of basal cell carcinoma (BCC) in vivo but is challenging for novices to interpret. Artificial intelligence (AI) applied to RCM-OCT could aid readers. We trained artificial intelligence (AI) models, using OCT rasters of biopsy-confirmed BCC, to detect and create 3D BCC rendering and automatically measure tumor depth. Trained AI models were applied to a separate test set containing rasters of BCC, benign lesions, and normal skin. Blinded reader analysis and tumor depth correlation with histopathology were conducted. BCC detection improved from viewing OCT rasters only (sensitivity 73.3%, specificity 45.5%) to viewing rasters with AI-generated BCC rendering (sensitivity 86.7%, specificity 48.5%). A Pearson Correlation r2 = 0.59 (p=0.02) was achieved for the tumor depth measurement between AI and histologic measured depths. Thus, addition of AI to the RCM-OCT device may expand its utility widely.

Longitudinal impact of leisure-time physical activity on pain intensity and daily activity limitation in people with low back pain. Findings from the PAMPA cohort.

OBJECTIVE: We aimed to prospectively evaluate the association between leisure-time physical activity and outcomes related to low back pain (LBP), such as pain intensity and daily activity limitation. METHODS: We analyzed data from the PAMPA (Prospective Study about Mental and Physical Health) cohort, a longitudinal study with adults residing in Southern Brazil. Participants answered an online-based, self-administered questionnaire. Physical activity was assessed as minutes per week, and those who reported engaging in 150 min/week or more were considered active. We also assessed the types of activities participants engaged. Pain intensity was assessed with a numeric pain rating scale (from 0 to 10), and participants reported whether their pain restricted their daily activities. Generalized linear models were used to investigate the association between physical activity and LBP outcomes. RESULTS: Data from 991 individuals (82.7% women) aged 38.9 ± 13.9 were analyzed. Pain intensity was higher in those inactive in waves one (ß: 0.54; 95 % CI 0.23, 0.86), three (ß: 0.38; 95% CI 0.02, 0.75), and four (ß: 0.48; 95% CI 0.06, 0.90). Also, being physically inactive at wave one was associated with a higher probability of daily activity limitation at waves two (IRR 1.77; 95% CI 1.27; 2.46), three (IRR 1.63; 95% CI 1.17, 2.29), and four (IRR 1.73; 95% CI 1.20, 2.50). CONCLUSION: Not practicing at least 150 min/week of physical activity resulted in higher levels of pain and an increased risk of daily activity limitation in individuals with LBP. Moreover, various forms of activities have shown to be advantageous in alleviating pain among this group.

Cisplatin Toxicity Causes Neutrophil-Mediated Inflammation in Zebrafish Larvae.

Cisplatin is an antineoplastic agent used to treat various tumors. In mammals, it can cause nephrotoxicity, tissue damage, and inflammation. The release of inflammatory mediators leads to the recruitment and infiltration of immune cells, particularly neutrophils, at the site of inflammation. Cisplatin is often used as an inducer of acute kidney injury (AKI) in experimental models, including zebrafish (Danio rerio), due to its accumulation in kidney cells. Current protocols in larval zebrafish focus on studying its effect as an AKI inducer but ignore other systematic outcomes. In this study, cisplatin was added directly to the embryonic medium to assess its toxicity and impact on systemic inflammation using locomotor activity analysis, qPCR, microscopy, and flow cytometry. Our data showed that larvae exposed to cisplatin at 7 days post-fertilization (dpf) displayed dose-dependent mortality and morphological changes, leading to a decrease in locomotion speed at 9 dpf. The expression of pro-inflammatory cytokines such as interleukin (il)-12, il6, and il8 increased after 48 h of cisplatin exposure. Furthermore, while a decrease in the number of neutrophils was observed in the glomerular region of the pronephros, there was an increase in neutrophils throughout the entire animal after 48 h of cisplatin exposure. We demonstrate that cisplatin can have systemic effects in zebrafish larvae, including morphological and locomotory defects, increased inflammatory cytokines, and migration of neutrophils from the hematopoietic niche to other parts of the body. Therefore, this protocol can be used to induce systemic inflammation in zebrafish larvae for studying new therapies or mechanisms of action involving neutrophils.

Chikungunya virus infection in the southernmost state of Brazil was characterised by self-limited transmission (2017-2019) and a larger 2021 outbreak.

BACKGROUND: Chikungunya is a mosquito-borne virus that has been causing large outbreaks in the Americas since 2014. In Brazil, Asian-Caribbean (AC) and East-Central-South-African (ECSA) genotypes have been detected and lead to large outbreaks in several Brazilian states. In Rio Grande do Sul (RS), the southernmost state of Brazil, the first cases were reported in 2016. OBJECTIVES AND METHODS: We employed genome sequencing and epidemiological investigation to characterise the Chikungunya fever (CHIKF) burden in RS between 2017-2021. FINDINGS: We detected an increasing CHIKF burden linked to travel associated introductions and communitary transmission of distinct lineages of the ECSA genotype during this period. MAIN CONCLUSIONS: Until 2020, CHIKV introductions were most travel associated and transmission was limited. Then, in 2021, the largest outbreak occurred in the state associated with the introduction of a new ECSA lineage. CHIKV outbreaks are likely to occur in the near future due to abundant competent vectors and a susceptible population, exposing more than 11 million inhabitants to an increasing infection risk.

Antiulcer mechanisms of the hydroalcoholic extract from Aztec marigolds' medicinal and edible flowers (Tagetes erecta L.).

The antiulcer mechanisms of the dry extract of T. erecta flowers (DETe) were studied here. The acute ulcers induced by acidified ethanol or indomethacin were reproduced in mice pretreated with DETe (3 - 300 mg/kg). The antiulcer activity of DETe was also verified in mice pretreated with NEM, L-NAME, indomethacin, or yohimbine. The antisecretory effect of DETe was verified in rats, and its anti-Helicobacter pylori activity was determined in vitro. DETe (300 mg/kg, p.o) reduced the ethanol- or indomethacin-induced ulcer by 49 and 93%, respectively. The pre-treatment with L-NAME, NEM or yohimbine abolished the gastroprotective effect of DETe. However, DETe did not change the volume, acidity, or peptic activity in rats and did not affect H. pylori. This study expands knowledge about the antiulcerogenic potential of DETe, evidencing the role of nitric oxide, non-protein sulfhydryl groups, α2 adrenergic receptors, and prostaglandins, but not antisecretory or anti-H. pylori properties.

Traditional Plants Used in Southern Brazil as a Source to Wound Healing Therapies.

In southern Brazil, the biodiversity is great and the traditional use of medicinal plants for wound healing has been documented in ethnobotanical studies and pharmacological studies have assessed their wound properties and phytochemistry. Therefore, this study evaluated ethnobotanical surveys regarding medicinal plants used in southern Brazil for wound healing and studies about the healing properties of these plants published between 2000 and 2022. To retrieve articles related to the study, Web of Science, PubMed (NLM), Open Access Journals, Scielo, Lilacs, and Google Scholar, with keywords including medicinal plants, wound healing, and South of Brazil, have been used. As a result, 73 medicinal plants belonging to 39 families were found in ethnobotanical surveys as a traditional resource used for wound healing in southern Brazil, 15 of which were cited more than once. Besides, 14 of these 15 plants were also used as healing agents worldwide. The most cited plant with healing actions in southern Brazil was Symphytum officinale L. (comfrey). From 2000 to date, 44 articles scientifically demonstrated the wound-healing effects of the southern Brazilian plants found in ethnobotanical surveys reviewed. The folk medicine of southern Brazil presents a variety of medicinal plants for wound-healing purposes, and scientific data were found for some of those plants. However, the wound-healing properties of many plants have yet to be investigated, and the current literature still needs more phytochemical information about the plants studied. Aside from this, the future focus should be on the standardization of herbal extracts, and further research is required to investigate the pharmacological mechanisms. Clinical research in this area remains in its infancy and warrants more robust further clinical studies.

Brazilian Red Propolis Accelerates Gastric Healing and Reduces Gastric Submucosal Layer Inflammation in Ultrasound-Monitored Rats.

Propolis has been used for the treatment of gastric disturbances in folk medicine, nevertheless, the gastric healing effects of Brazilian red propolis have not been unveiled. This study aimed to assess the gastric healing effect of the hydroalcoholic extract of red propolis (HERP) in the acetic acid-induced ulcer model. Rats under acetic acid-induced-ulcer were treated with HERP (100 mg/kg, p.o.) twice a day for seven days. Histological changes, oxidative stress, and inflammatory parameters were analyzed in the gastric tissue. Moreover, the gastric wall thickness was measured by ultrasound. The in vitro cytotoxicity of HERP and cellular migration of fibroblasts were evaluated. The treatment with HERP promoted gastric healing, reducing gastric wall thickness, macroscopic lesion area, and histopathological damages compared to the vehicle. Moreover, HERP reduced oxidative stress and inflammation in the gastric tissue but did not change mucin or collagen levels. HERP did not show signs of toxicity either in vivo or in vitro. HERP displayed a healing effect in vivo by reducing oxidative stress and inflammation. These data contribute to validating the popular use of this product in the treatment of gastric disorders and advance scientific knowledge in the search for new drugs for the management of gastric ulcers.

Systematic review and meta-analysis on population attributable fraction for physical inactivity to dementia.

INTRODUCTION: The number of cases of dementia attributable to physical inactivity remains unclear due to heterogeneity in physical inactivity definitions and statistical approaches used. METHODS: Studies that used population-based samples to estimate the population attributable fraction (PAF) of physical inactivity for dementia were included in this review. Weighted PAFs were adjusted for communality among the risk factors (i.e., inactive persons may also share other risk factors) analyzed. Values were reported as percentage (%) of cases of dementia attributable to physical inactivity. RESULTS: We included 22 studies. The overall impact of physical inactivity, defined by any criteria, on dementia ranged from 6.6% (95% CI: 3.6%, 9.6%; weighted) to 16.6% (95% CI: 14.4%, 18.9%; unweighted). Studies using the WHO criterion for physical inactivity estimated a higher unweighted impact (ß = 7.3%; 95% CI: 2.0%, 12.6%) than studies using other criteria. DISCUSSION: Conservatively, one in 15 cases of dementia may be attributable to physical inactivity, defined by any criteria.

Random forest of perfect trees: concept, performance, applications and perspectives.

MOTIVATION: The principle of Breiman's random forest (RF) is to build and assemble complementary classification trees in a way that maximizes their variability. We propose a new type of random forest that disobeys Breiman's principles and involves building trees with no classification errors in very large quantities. We used a new type of decision tree that uses a neuron at each node as well as an in-innovative half Christmas tree structure. With these new RFs, we developed a score, based on a family of ten new statistical information criteria, called Nguyen information criteria (NICs), to evaluate the predictive qualities of features in three dimensions. RESULTS: The first NIC allowed the Akaike information criterion to be minimized more quickly than data obtained with the Gini index when the features were introduced in a logistic regression model. The selected features based on the NICScore showed a slight advantage compared to the support vector machines-recursive feature elimination (SVM-RFE) method. We demonstrate that the inclusion of artificial neurons in tree nodes allows a large number of classifiers in the same node to be taken into account simultaneously and results in perfect trees without classification errors. AVAILABILITY AND IMPLEMENTATION: The methods used to build the perfect trees in this article were implemented in the 'ROP' R package, archived at https://cran.r-project.org/web/packages/ROP/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Neuroprotective effects of strength training in a neuroinflammatory animal model.

BACKGROUND: The preventive role of muscular strength on diminishing neuroinflammation is yet unknown. In this study, the role of the prophylactic muscular strength exercise was investigated in order to verify whether it would diminish cognitive alterations and modify the antioxidant intracellular scenery in an animal neuroinflammatory model in of the CA1 region of the hippocampus. METHODS: The animals received muscular strength training (SE) three times a week for eight weeks. Subsequently, the stereotaxic surgery was performed with an intra-hippocampal infusion of either saline solution (SAL) or lipopolysaccharide (LPS). Next, we performed the behavioral tests: object recognition and social recognition. Then, the animals were euthanized, and their hippocampus and prefrontal cortex were collected. In another moment, we performed the dosage of the antioxidant activity and histological analysis. RESULTS: The results showed that the muscular strength exercises could show a beneficial prophylactic effect in the cognitive deficiencies caused by acute neuroinflammation. Regarding oxidative stress, there was an increase in catalase enzyme activity (CAT) in the group (SE + LPS) compared to the control groups (p < 0.05). As for the cognitive alterations, there were found in the (SE + LPS) group, diminishing the mnemonic hazard of the discriminative and social memories compared to the control groups (p < 0.05). CONCLUSION: We concluded, therefore, that the exercise performed prophylactically presents a protective effect capable of minimizing such mnemonic deficits and increasing catalase enzyme activity in rats that suffered a local neuroinflammatory process in the hippocampus.

Dengue fever presenting as acute cerebellar ataxia: Case report and literature review.

Dengue fever has been associated with several neurological complications, cerebellar involvement being among the rarest of them. Here, we describe the case of a 70-year-old female who presented a cerebellar syndrome during the first day of an arboviral infection, posteriorly confirmed as dengue fever. Among the seven other cases in which the relationship between dengue virus and ataxia was reported, only in one cerebellar presentation occurred as early. Onset, course, and prognosis, as well as the adequate investigation and management of these patients, are discussed. While the disease pattern is not better characterized by future studies, differential diagnosis and close follow-up are essential tools for guaranteeing good outcomes.

Point-of-care testing allows successful simultaneous screening of sickle cell disease, HIV, and tuberculosis for households in rural Guinea-Bissau, West Africa.

Diagnosis of noncommunicable genetic diseases like sickle cell disease (SCD) and communicable diseases such as human immunodeficiency virus (HIV) or tuberculosis (TB) is often difficult in rural areas of Africa due to the lack of infrastructures, trained staff, or capacity to involve families living in remote areas. The availability of point-of-care (POC) tests for the above diseases offers the opportunity to build joint programs to tackle all conditions. We report successful simultaneous screening of SCD, HIV, and TB utilizing POC tests in 898 subjects in Fanhe, in rural Guinea-Bissau. Adherence was 100% and all diagnosed subjects were enrolled in care programs.

Herbal Medicines in the Treatment of Dyspepsia: An Overview.

This review focuses on the efficacy of herbal medicines for managing dyspepsia in humans and animals. Searches were conducted on the PubMed, Science Direct, and Medline databases, for publications in the last 3 years. In each database, the search terms used consisted of the 2 key terms describing the disorder and subtypes plus each of the terms relating to the therapy. The key terms used were "natural product" and "medicinal plant" in a cross-over with "dyspepsia" and "functional dyspepsia" (i.e., gastroprotection, Helicobacter pylori infection, prokinetic). We included all human and animal studies on the effects of herbal medicines reporting the key outcome of dyspepsia symptoms. Preclinical studies using critically validated models showed that most medicinal plants with gastroprotective action had antioxidant, anti-inflammatory, anti-apoptotic, and antisecretory effects. Moreover, several species displayed anti Helicobacter pylori and prokinetic efficacy. The data availability of controlled clinical studies is currently minimal. The use of different methodologies and the minimal number of patients raise doubts about the effects of these preparations. Only adequate clinical trials with scientifically validated methods can determine whether different herbal medicines can be used as viable alternatives to the conventional pharmacological treatments used to control dyspepsia symptoms.

Cytotoxicity, antinociceptive and gastroproiltective potential of the Abuta selloana Eichler: a fruit plant from Catarinense flora, Brazil.

This study evaluated some biological activities of extracts from Abuta selloana. The gastroprotective potential was determined against ethanol/HCl- and indomethacin-induced gastric ulcers, whereas the antinociceptive effect was evaluated by acetic acid-induced abdominal contortions in mice. The cytotoxicity activity was measured against human cancer cell lines: U251 (glioma), MCF-7 (breast cancer) and NCI-H460 (lung cancer). The radical scavenger potential was verified; and preliminary phytochemical analyses were performed. The phytochemical screening revealed higher levels of phenolic compounds in all extracts. Moreover, the methanolic extract from pulp fruit (MEPu), peel fruit (MEPe), branches (MEB) and leaves (MEL) scavenged the DPPH radical at 100 µg/mL. Besides, only MEL presented GI50 < 30 µg/mL in all tested cells. Besides, MEPu, MEPe, MEB or MEL at 10 mg/kg (i.p) reduced the abdominal contortions at 47.22%, 63.31%, 84.59% and 37.76%, respectively. The MEPu, MEPe, MEB and MEL reduced the ethanol/HCl- and indomethacin- induced ulcer at 250 mg/kg (p.o). In conclusion, A. selloana had interesting biological activities; presenting the leaves as a promising source for compounds with cytotoxic potential, however, further studies should be performed to confirm its antitumoral activity. Besides, the whole plant can be an important source of bioactive compounds associated with gastroprotective and antinociceptive properties.