Bacteremia and Mortality among Patients with Nontunneled and Tunneled Catheters for Hemodialysis.

Introduction: Central venous catheters for hemodialysis (HD) can be nontunneled catheters (NTC) or tunneled catheters (TC). Bacteremia and dysfunction are complications that can impact morbidity and mortality. We decided to compare the rates of bacteremia and dysfunction between NTC and TC and patient survival 90 days after catheter insertion. Methods: Retrospective cohort to evaluate catheters inserted between January 2011 and December 2020 in a tertiary hospital. Catheters in patients with end-stage chronic kidney disease were included. Patients with acute kidney injury, catheters that lasted less than three HD sessions, and patients who died within one week after insertion were excluded. Bacteremia and dysfunction rates, bacteremia-free survival, and dysfunction-free survival were investigated. Multivariable analysis was performed using a Cox proportional hazards regression model for patient survival at 90 days. Results: 670 catheters were analyzed in 287 patients, 422 NTC (63%), and 248 TC (37%). The rates of confirmed bacteremia per 1,000 catheter-days were 1.19 for NTC and 0.20 for TC (p < 0.0001). The confirmed or possible bacteremia rates were 2.27 and 0.37 per 1,000 catheter-days for NTC and TC, respectively (p < 0.0001). The dysfunction rates were 3.96 and 0.86 for NTC and TC, respectively (p < 0.0001). Patient survival at 90 days was higher in the TC group than the NTC group (96.8% vs. 89.1%; p < 0.0001). Conclusion: We found lower rates of bacteremia and dysfunction for TC and demonstrated that using NTC affects patient mortality.

Systemic and local complement activation in peritoneal dialysis patients via conceivably distinct pathways.

BACKGROUND: Despite several advantages compared to haemodialysis (HD), peritoneal dialysis (PD) remains an underused dialysis technique due to its high technique failure rate related to membrane fibrosis and peritonitis events. Previous work has suggested a harmful role for the complement system in these processes, highlighting the need for a more comprehensive examination in PD. METHODS: Plasma levels of C1q, mannose-binding lectin (MBL), Properdin, Factor D, C3d/C3-ratio and soluble membrane attack complex (sC5b-9) were determined in PD patients (n = 55), HD patients (n = 41), non-dialysis chronic kidney disease (CKD) patients (n = 15) and healthy controls (n = 14). Additionally, C1q, MBL, Properdin, Factor D and sC5b-9 levels were assessed in the peritoneal dialysis fluid (PDF). In a subgroup, interleukin-6, matrix metalloproteinase-2 (MMP-2), myeloperoxidase (MPO) and elastase were measured in the PDF. RESULTS: PD patients had significantly higher systemic levels of sC5b-9 compared to healthy controls, CKD and HD patients (p < 0.001). Plasma levels of C1q and C3d/C3-ratios were significantly associated with systemic sC5b-9 levels (p < 0.001). Locally, sC5b-9 was detected in the PDF of all PD patients, and levels were approximately 33% of those in matched plasma, but they did not correlate. In the PDF, only Properdin levels remained significantly associated with PDF sC5b-9 levels in multivariate analysis (p < 0.001). Additionally, PDF levels of sC5b-9 positively correlated with elastase, MPO and MMP-2 levels in the PDF (p < 0.01). CONCLUSIONS: Our data reveal both systemic and local complement activation in PD patients. Furthermore, these two processes seem independent considering the involvement of different pathways and the lack of correlation.

Effect of aquatic exercise programs according to the International Classification of Functionality, Disability and Health domains in individuals with Parkinson's disease: a systematic review and meta-analysis with GRADE quality assessment.

PURPOSE: To investigate the effects of aquatic exercise programs (AEP) in body structure and function, activity, and participation outcomes in individuals with Parkinson's disease (PD) with mild to moderate disability levels. METHODS: Six databases were searched from inception until November 2022. Randomized clinical trials that used AEP alone, AEP combined and/or compared two types of AEP were included. The quality of evidence was assessed by the GRADE approach and the standardized mean differences (SMD) were calculated the meta-analysis. RESULTS: Twelve studies (n = 380) were included. AEP alone was superior to active control in improving body structure and function outcome: postural balance (low evidence, SMD = 0.47, p = 0.02). No statistically significant differences were found for the other body structure and function outcomes: lower limb muscle strength (p = 0.14) and depressive symptoms (p = 0.79), activity outcomes: mobility (p = 0.32) and participation outcomes: quality of life (p = 0.05). AEP combined showed no statistically significant difference for the outcomes of body structure and function: postural balance (p = 0.11) and activity: mobility (p = 0.21) when compared to active control. CONCLUSION: AEP showed positive effects on body structure and function outcome (postural balance) in individuals with PD with mild to moderate disability levels while, no significant improvements were noticed for activity and participation outcomes.IMPLICATIONS FOR REHABILITATIONOur findings indicate that aquatic exercise programs (AEP) lead to significant improvements on body structure and function (i.e., postural balance) in individuals with Parkinson's disease (PD).The AEP evaluated in this study implemented postural balance, gait, single and double training, as well as aerobic exercises, trunk mobility exercises, and Ai Chi.The average duration, frequency, and total time implemented were 50 minutes, three times a week, for seven weeks, respectively.Considering the potential benefits identified in this study, AEP can be recommended as an adjunct treatment strategy for individuals with PD.Additionally, the use of the International Classification of Functionality, Disability and Health on the development of rehabilitation treatment plans is advised.

Pesticide-Induced Inflammation at a Glance.

The increasing number of studies reporting the risks of the exposure to pesticides aligned with the intensified use of such hazardous chemicals has emerged as a pressing contemporary issue, notably due to the potential effects to both the environment and human health. Pesticides, while broadly applied in modern agriculture for pest control and crop protection, have raised concerns due to their unintended effects on non-target organisms. The immune system exerts a key role in the protection against the exposome, which could result in cellular imbalances and tissue damage through the inflammatory response. Pesticides, which encompass a diverse array of chemicals, have been linked to inflammation in experimental models. Therefore, the aim of this review is to discuss the increasing concern over the risks of pesticide exposure focusing on the effects of various chemical classes on inflammation by covering, as broadly as possible, different experimental approaches as well as the multiple or co-exposure of pesticides. Overall, pesticides potentially induce inflammation in different experimental models, manifested through skin irritation, respiratory impairment, or systemic effects. The connection between pesticides and inflammation highlights the importance of proper handling and regulation of these substances and underscores the need for research into safer and sustainable practices to reduce our reliance on synthetic pesticides and fertilizers.

Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives.

Visual impairment and blindness are a growing public health problem as they reduce the life quality of millions of people. The management and treatment of these diseases represent scientific and therapeutic challenges because different cellular and molecular actors involved in the pathophysiology are still being identified. Visual system components, particularly retinal cells, are extremely sensitive to genetic or metabolic alterations, and immune responses activated by local insults contribute to biological events, culminating in vision loss and irreversible blindness. Several ocular diseases are linked to retinal cell loss, and some of them, such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and diabetic retinopathy, are characterized by pathophysiological hallmarks that represent possibilities to study and develop novel treatments for retinal cell degeneration. Here, we present a compilation of revisited information on retinal degeneration, including pathophysiological and molecular features and biochemical hallmarks, and possible research directions for novel treatments to assist as a guide for innovative research. The knowledge expansion upon the mechanistic bases of the pathobiology of eye diseases, including information on complex interactions of genetic predisposition, chronic inflammation, and environmental and aging-related factors, will prompt the identification of new therapeutic strategies.

Evolution of the Bacillus Calmette-Guérin scar Russia and Moreau strains in newborns: A brazilian cohort.

Background: In Brazil, in 1925, the Moreau strain was introduced, and since its implementation, it has been the routine vaccine for health services. Since 2013, many countries, including Brazil, have been experiencing problems with the production of vaccines. As of January 2018, the country started to use the BCG vaccine with Russia strain, developed by the Serum Institute India. Objective: To describe the evolution of the vaccine scar in neonates vaccinated by BCG-Russia compared to BCG-Moreau. Methods: This was a cohort study was conducted in Salvador city, northeast Brazil. The study population consisted of newborns from the reference maternity hospital, who were vaccinated with BCG-ID strains Moreau or Russia, followed up to assess vaccine lesion evolution. Results: It was observed that regardless of the vaccine strains, the evolution of the lesion was the same: wheal, reddish macula, induration, pustule, ulcer, and scar. The proportion of vaccine scar in the group vaccinated with BCG Russia was lower than that of BCG Moreau, 62.5 % and 90.9 %, respectively, with a statistically significant difference. Conclusion: The evolution of the scar by BCG-Russia was similar to the Moreau scar, however different proportions were observed in different stages of lesion between the groups.

Detection of Abnormal Prion Protein by Immunohistochemistry.

Abnormal prion proteins (PrPSc) are the disease-associated isoform of cellular prion protein and diagnostic markers of transmissible spongiform encephalopathies (TSEs). These neurodegenerative diseases affect humans and several animal species and include scrapie, zoonotic bovine spongiform encephalopathy (BSE), chronic wasting disease of cervids (CWD), and the newly identified camel prion disease (CPD). Diagnosis of TSEs relies on immunodetection of PrPSc by application of both immunohistochemistry (IHC) and western immunoblot methods (WB) on encephalon tissues, namely, the brainstem (obex level). IHC is a widely used method that uses primary antibodies (monoclonal or polyclonal) against antigens of interest in cells of a tissue section. The antibody-antigen binding can be visualized by a color reaction that remains localized in the area of the tissue or cell where the antibody was targeted. As such, in prion diseases, as in other fields of research, the immunohistochemistry techniques are not solely used for diagnostic purposes but also in pathogenesis studies. Such studies involve detecting the PrPSc patterns and types from those previously described to identify the new prion strains. As BSE can infect humans, it is recommended that biosafety laboratory level-3 (BSL-3) facilities and/or practices are used to handle cattle, small ruminants, and cervid samples included in the TSE surveillance. Additionally, containment and prion-dedicated equipment are recommended, whenever possible, to limit contamination. The PrPSc IHC procedure consists of a formic acid epitope-demasking step also acting as a prion inactivation measure, as formalin-fixed and paraffin-embedded tissues used in this technique remain infectious. When interpreting the results, care must be taken to distinguish non-specific immunolabeling from target labeling. For this purpose, it is important to recognize artifacts of immunolabeling obtained in known TSE-negative control animals to differentiate those from specific PrPSc immunolabeling types, which can vary between TSE strains, host species, and prnp genotype, further described herein.

Effective Pre-Clinical Treatment of Fish Envenoming with Polyclonal Antiserum.

Envenomation by venomous fish, although not always fatal, is capable of causing damage to homeostasis by activating the inflammatory process, with the formation of edema, excruciating pain, necrosis that is difficult to heal, as well as hemodynamic and cardiorespiratory changes. Despite the wide variety of pharmacological treatments used to manage acute symptoms, none are effective in controlling envenomation. Knowing the essential role of neutralizing polyclonal antibodies in the treatment of envenoming for other species, such as snakes, this work aimed to produce a polyclonal antiserum in mice and test its ability to neutralize the main toxic effects induced by the venoms of the main venomous Brazilian fish. We found that the antiserum recognizes the main toxins present in the different venoms of Thalassophryne nattereri, Scorpaena plumieri, Potamotrygon gr. Orbignyi, and Cathorops spixii and was effective in pre-incubation trials. In an independent test, the antiserum applied immediately to the topical application of T. nattereri, P. gr orbygnyi, and C. spixii venoms completely abolished the toxic effects on the microcirculation, preventing alterations such as arteriolar contraction, slowing of blood flow in postcapillary venules, venular stasis, myofibrillar hypercontraction, and increased leukocyte rolling and adherence. The edematogenic and nociceptive activities induced by these venoms were also neutralized by the immediate application of the antiserum. Importantly, the antiserum prevented the acute inflammatory response in the lungs induced by the S. plumieri venom. The success of antiserum containing neutralizing polyclonal antibodies in controlling the toxic effects induced by different venoms offers a new strategy for the treatment of fish envenomation in Brazil.

Inflammasome Coordinates Senescent Chronic Wound Induced by Thalassophryne nattereri Venom.

Thalassophryne nattereri toadfish (niquim) envenomation, common in the hands and feet of bathers and fishermen in the north and northeast regions of Brazil, is characterized by local symptoms such as immediate edema and intense pain. These symptoms progress to necrosis that lasts for an extended period of time, with delayed healing. Wound healing is a complex process characterized by the interdependent role of keratinocytes, fibroblasts, and endothelial and innate cells such as neutrophils and macrophages. Macrophages and neutrophils are actively recruited to clear debris during the inflammatory phase of wound repair, promoting the production of pro-inflammatory mediators, and in the late stage, macrophages promote tissue repair. Our hypothesis is that injury caused by T. nattereri venom (VTn) leads to senescent wounds. In this study, we provide valuable information about the mechanism(s) behind the dysregulated inflammation in wound healing induced by VTn. We demonstrate in mouse paws injected with the venom the installation of γH2AX/p16Ink4a-dependent senescence with persistent neutrophilic inflammation in the proliferation and remodeling phases. VTn induced an imbalance of M1/M2 macrophages by maintaining a high number of TNF-α-producing M1 macrophages in the wound but without the ability to eliminate the persistent neutrophils. Chronic neutrophilic inflammation and senescence were mediated by cytokines such as IL-1α and IL-1ß in a caspase-1- and caspase-11-dependent manner. In addition, previous blocking with anti-IL-1α and anti-IL-ß neutralizing antibodies and caspase-1 (Ac YVAD-CMK) and caspase-11 (Wedelolactone) inhibitors was essential to control the pro-inflammatory activity of M1 macrophages induced by VTn injection, skewing towards an anti-inflammatory state, and was sufficient to block neutrophil recruitment and senescence.

The impact of the COVID-19 pandemic on neuropsychiatric and sleep disorders, and quality of life in individuals with neurodegenerative and demyelinating diseases: a systematic review and meta-analysis of observational studies.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has affected the mental health, sleep and quality of life, especially in individuals with chronic disease. Therefore, the purpose of this systematic review and meta-analysis was to investigate the impact of the COVID-19 pandemic on neuropsychiatric disorders (depression, anxiety, stress), sleep disorders (sleep quality, insomnia) and quality of life in individuals with Parkinson's disease (PD), Multiple Sclerosis (MS) and Alzheimer's disease (AD) compared to healthy controls. METHODS: Seven databases (Medline, Embase, ScienceDirect, Web of Science, The Cochrane Library, Scielo and Lilacs) were searched between March 2020 and December 2022. Observational studies (i.e., cross-sectional, case-control, cohort) were included. GRADE approach was used to assess the quality of evidence and strength of the recommendation. Effect size was calculated using standardized mean differences (SMD; random effects model). A customized Downs and Black checklist was used to assess the risk of bias. RESULTS: Eighteen studies (PD = 7, MS = 11) were included. A total of 627 individuals with PD (healthy controls = 857) and 3923 individuals with MS (healthy controls = 2432) were analyzed. Twelve studies (PD = 4, MS = 8) were included in the meta-analysis. Individuals with PD had significantly elevated levels of depression (very low evidence, SMD = 0.40, p = 0.04) and stress (very low evidence, SMD = 0.60, p < 0.0001). There was no difference in anxiety (p = 0.08). Individuals with MS had significantly higher levels of depression (very low evidence, SMD = 0.73, p = 0.007) and stress (low evidence, SMD = 0.69, p = 0.03) and low quality of life (very low evidence, SMD = 0.77, p = 0.006). There was no difference in anxiety (p = 0.05) and sleep quality (p = 0.13). It was not possible to synthesize evidence in individuals with AD and sleep disorder (insomnia). CONCLUSION: In general, the COVID-19 pandemic negatively impacted individuals with PD and MS. Individuals with PD showed significantly higher levels of depression and stress; and individuals with MS presented significantly higher depression and stress levels, as well as significantly lower quality of life when compared to healthy controls. Further studies are needed to investigate the impact of the COVID-19 pandemic in individuals with AD.

Previous BCG vaccination is associated with less severe clinical progression of COVID-19.

BACKGROUND: BCG vaccination, originally used to prevent tuberculosis, is known to "train" the immune system to improve defence against viral respiratory infections. We investigated whether a previous BCG vaccination is associated with less severe clinical progression of COVID-19 METHODS: A case-control study comparing the proportion with a BCG vaccine scar (indicating previous vaccination) in cases and controls presenting with COVID-19 to health units in Brazil. Cases were subjects with severe COVID-19 (O2 saturation < 90%, severe respiratory effort, severe pneumonia, severe acute respiratory syndrome, sepsis, and septic shock). Controls had COVID-19 not meeting the definition of "severe" above. Unconditional regression was used to estimate vaccine protection against clinical progression to severe disease, with strict control for age, comorbidity, sex, educational level, race/colour, and municipality. Internal matching and conditional regression were used for sensitivity analysis. RESULTS: BCG was associated with high protection against COVID-19 clinical progression, over 87% (95% CI 74-93%) in subjects aged 60 or less and 35% (95% CI - 44-71%) in older subjects. CONCLUSIONS: This protection may be relevant for public health in settings where COVID-19 vaccine coverage is still low and may have implications for research to identify vaccine candidates for COVID-19 that are broadly protective against mortality from future variants. Further research into the immunomodulatory effects of BCG may inform COVID-19 therapeutic research.

Would Cutibacterium acnes Be the Villain for the Chronicity of Low Back Pain in Degenerative Disc Disease? Preliminary Results of an Analytical Cohort.

In the last decade, several studies have demonstrated Cutibacterium acnes colonization in intervertebral discs (IVDs) in patients with lumbar disc degeneration (LDD) and low back pain (LBP), but the meaning of these findings remains unclear. Being aware of this knowledge gap, we are currently conducting a prospective analytical cohort study with LBP and LDD patients undergoing lumbar microdiscectomy and posterior fusion. The IVDs samples collected during the surgeries are subjected to a stringent analytical protocol using microbiological, phenotypic, genotypic, and multiomic techniques. Additionally, pain-related scores and quality-of-life indexes are monitored during patient follow-up. Our preliminary results for 265 samples (53 discs from 23 patients) revealed a C. acnes prevalence of 34.8%, among which the phylotypes IB and II were the most commonly isolated. The incidence of neuropathic pain was significantly higher in the colonized patients, especially between the third and sixth postoperative months, which strongly suggests that the pathogen plays an important role in the chronicity of LBP. The future results of our protocol will help us to understand how C. acnes contributes to transforming inflammatory/nociceptive pain into neuropathic pain and, hopefully, will help us to find a biomarker capable of predicting the risk of chronic LBP in this scenario.

An Overview towards Zebrafish Larvae as a Model for Ocular Diseases.

Despite the obvious morphological differences in the visual system, zebrafish share a similar architecture and components of the same embryonic origin as humans. The zebrafish retina has the same layered structure and cell types with similar metabolic and phototransduction support as humans, and is functional 72 h after fertilization, allowing tests of visual function to be performed. The zebrafish genomic database supports genetic mapping studies as well as gene editing, both of which are useful in the ophthalmological field. It is possible to model ocular disorders in zebrafish, as well as inherited retinal diseases or congenital or acquired malformations. Several approaches allow the evaluation of local pathological processes derived from systemic disorders, such as chemical exposure to produce retinal hypoxia or glucose exposure to produce hyperglycemia, mimicking retinopathy of prematurity or diabetic retinopathy, respectively. The pathogenesis of ocular infections, autoimmune diseases, or aging can also be assessed in zebrafish larvae, and the preserved cellular and molecular immune mechanisms can be assessed. Finally, the zebrafish model for the study of the pathologies of the visual system complements certain deficiencies in experimental models of mammals since the regeneration of the zebrafish retina is a valuable tool for the study of degenerative processes and the discovery of new drugs and therapies.

Estimating sequence diversity of prion protein gene (PRNP) in Portuguese populations of two cervid species: red deer and fallow deer.

Among the transmissible spongiform encephalopathies (TSEs), chronic wasting disease (CWD) in cervids is now a rising concern in wildlife within Europe, after the detection of the first case in Norway in 2016, in a wild reindeer and until June 2022 a total of 34 cases were described in Norway, Sweden and Finland. The definite diagnosis is post-mortem, performed in target areas of the brain and lymph nodes. Samples are first screened using a rapid test and, if positive, confirmed by immunohistochemistry and Western immunoblotting. The study of the genetics of the prion protein gene, PRNP, has been proved to be a valuable tool for determining the relative susceptibility to TSEs. In the present study, the exon 3 of PRNP gene of 143 samples from red deer (Cervus elaphus) and fallow deer (Dama dama) of Portugal was analysed. Three single nucleotide polymorphisms (SNPs) were found in red deer - codon A136A, codon T98A, codon Q226E - and no sequence variation was detected in fallow deer. The low genetic diversity found in our samples is compatible with previous studies in Europe. The comparison with results from North America suggests that the free-ranging deer from our study may present susceptibility to CWD, although lack of experimental data and the necessity of continuous survey are necessary to evaluate these populations.

The Anti-Inflammatory Peptide TnP Is a Candidate Molecule for Asthma Treatment.

Asthma is the most common chronic lung disease, with increasing morbidity and mortality worldwide. Accumulation of peribronchial leukocytes is the hallmark of asthma, in particular, eosinophils, which have been reported as the primary cell associated with the induction of airway hyperresponsiveness. Continued exacerbation and accumulation of other leukocytes, such as neutrophils, Th1, and Th17 cells correlate with many of the long-term effects of asthma, such as airway remodeling. We have patented the TnP family of synthetic cyclic peptides, which is in the preclinical phase of developmental studies for chronic inflammatory diseases. The aim of this work was to investigate whether TnP could show anti-inflammatory activity in a murine model of asthma that includes a mixed phenotype of eosinophilic and neutrophilic inflammation. For this, Balb/c mice, sensitized with OVA and exposed to 1% challenge with OVA aerosol, were submitted to prophylactic treatment, receiving TnP at 0.3 mg/kg orally, 1 h before each challenge. We found that sensitized mice challenged with OVA and treated with TnP showed no airway hyperreactivity or lung remodeling. TnP acts systemically in secondary lymphoid organs and locally in the lung, inhibiting the production of Th2/Th17 cytokines. Furthermore, TnP prevented the infiltration of eosinophils and neutrophils in the BAL and lung tissue, inhibited the production of IgE/IgG1, prevented hyperplasia of mucus-producing cells, and decreased the thickening and deposition of sub-epithelial collagen. Our results showed TnP as a candidate molecule for the treatment of airway remodeling associated with inflammatory diseases, such as asthma.

Colonization of intervertebral discs by Cutibacterium acnes in patients with low back pain: Protocol for an analytical study with microbiological, phenotypic, genotypic, and multiomic techniques.

Lumbar disc degeneration (LDD) and low back pain (LBP) are two conditions that are closely related. Several studies have shown Cutibacterium acnes colonization of degenerated discs, but whether and how these finding correlates with LBP is unknown. A prospective study was planned to identify molecules present in lumbar intervertebral discs (LLIVD) colonized by C. acnes in patients with LDD and LBP and correlate them with their clinical, radiological, and demographic profiles. The clinical manifestations, risk factors, and demographic characteristics of participants undergoing surgical microdiscectomy will be tracked. Samples will be isolated and pathogens found in LLIVD will be characterized phenotypically and genotypically. Whole genome sequencing (WGS) of isolated species will be used to phylotype and detect genes associated with virulence, resistance, and oxidative stress. Multiomic analyses of LLIVD colonized and non-colonized will be carried out to explain not only the pathogen's role in LDD, but also its involvement in the pathophysiology of LBP. This study was approved by the Institutional Review Board (CAAE 50077521.0.0000.5258). All patients who agree to participate in the study will sign an informed consent form. Regardless of the study's findings, the results will be published in a peer-reviewed medical journal. Trials registration number NCT05090553; pre-results.

Interim FDG18-PET SUVmax Variation Adds Prognostic Value to Deauville 5-Point Scale in the Identification of Patients with Ultra-High-Risk Diffuse Large B Cell Lymphoma.

INTRODUCTION: Interim response evaluation by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (iPET) in diffuse large B cell lymphoma (DLBCL) could be important to rule out disease progression and has been suggested to be predictive of survival. However, treatment guidance by iPET is not yet recommended for DLBCL in clinical practice. We aimed to compare the predictive value of iPET when utilizing the visual Deauville 5-point scale (DS) and the semiquantitative variation of maximum standardized uptake value (ΔSUVmax). MATERIALS AND METHODS: We included 85 patients diagnosed with DLBCL and uniformly treated with standard protocols. iPET with DS of 1-3 and/or ΔSUVmax ≥66% was defined as negative. Univariable and multivariable Cox regression analyses were performed to determine the independent factors affecting progression free survival (PFS) or overall survival (OS) and to estimate PFS and OS. RESULTS: iPET positivity, measured by DS or ΔSUVmax, showed predictive value of disease refractoriness, improved by combining DS and ΔSUVmax. After a median follow-up of 50.1 months, iPET was an independent predictor for both PFS and OS when interpreted by DS, but only for PFS by ΔSUVmax. Combined visual and semiquantitative analysis (D4-5 & ΔSUVmax<66%) was an independent predictor of PFS and OS, and allowed to identify an ultra-high-risk subgroup of patients with very dismal outcome, increasing the discriminating capacity for iPET. CONCLUSION: Our study suggests that combined DS and ΔSUVmax in iPET assessment predicts refractory disease and distinguishes ultra-high-risk DLBCL patients with a very dismal prognosis, who may benefit from PET-guided therapy adjustment.

Revisiting retinal degeneration hallmarks: insights from molecular markers and therapy perspectives

Visual impairment and blindness are a growing public health problem as they reduce the life quality of millions of people. The management and treatment of these diseases represent scientific and therapeutic challenges because different cellular and molecular actors involved in the pathophysiology are still being identified. Visual system components, particularly retinal cells, are extremely sensitive to genetic or metabolic alterations, and immune responses activated by local insults contribute to biological events, culminating in vision loss and irreversible blindness. Several ocular diseases are linked to retinal cell loss, and some of them, such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and diabetic retinopathy, are characterized by pathophysiological hallmarks that represent possibilities to study and develop novel treatments for retinal cell degeneration. Here, we present a compilation of revisited information on retinal degeneration, including pathophysiological and molecular features and biochemical hallmarks, and possible research directions for novel treatments to assist as a guide for innovative research. The knowledge expansion upon the mechanistic bases of the pathobiology of eye diseases, including information on complex interactions of genetic predisposition, chronic inflammation, and environmental and aging-related factors, will prompt the identification of new therapeutic strategies.

Effective pre-clinical treatment of fish envenoming with polyclonal antiserum

Envenomation by venomous fish, although not always fatal, is capable of causing damage to homeostasis by activating the inflammatory process, with the formation of edema, excruciating pain, necrosis that is difficult to heal, as well as hemodynamic and cardiorespiratory changes. Despite the wide variety of pharmacological treatments used to manage acute symptoms, none are effective in controlling envenomation. Knowing the essential role of neutralizing polyclonal antibodies in the treatment of envenoming for other species, such as snakes, this work aimed to produce a polyclonal antiserum in mice and test its ability to neutralize the main toxic effects induced by the venoms of the main venomous Brazilian fish. We found that the antiserum recognizes the main toxins present in the different venoms of Thalassophryne nattereri, Scorpaena plumieri, Potamotrygon gr. Orbignyi, and Cathorops spixii and was effective in pre-incubation trials. In an independent test, the antiserum applied immediately to the topical application of T. nattereri, P. gr orbygnyi, and C. spixii venoms completely abolished the toxic effects on the microcirculation, preventing alterations such as arteriolar contraction, slowing of blood flow in postcapillary venules, venular stasis, myofibrillar hypercontraction, and increased leukocyte rolling and adherence. The edematogenic and nociceptive activities induced by these venoms were also neutralized by the immediate application of the antiserum. Importantly, the antiserum prevented the acute inflammatory response in the lungs induced by the S. plumieri venom. The success of antiserum containing neutralizing polyclonal antibodies in controlling the toxic effects induced by different venoms offers a new strategy for the treatment of fish envenomation in Brazil.

Inflammasome coordinates senescent chronic wound induced by Thalassophryne nattereri venom

Thalassophryne nattereri toadfish (niquim) envenomation, common in the hands and feet of bathers and fishermen in the north and northeast regions of Brazil, is characterized by local symptoms such as immediate edema and intense pain. These symptoms progress to necrosis that lasts for an extended period of time, with delayed healing. Wound healing is a complex process characterized by the interdependent role of keratinocytes, fibroblasts, and endothelial and innate cells such as neutrophils and macrophages. Macrophages and neutrophils are actively recruited to clear debris during the inflammatory phase of wound repair, promoting the production of pro-inflammatory mediators, and in the late stage, macrophages promote tissue repair. Our hypothesis is that injury caused by T. nattereri venom (VTn) leads to senescent wounds. In this study, we provide valuable information about the mechanism(s) behind the dysregulated inflammation in wound healing induced by VTn. We demonstrate in mouse paws injected with the venom the installation of γH2AX/p16Ink4a-dependent senescence with persistent neutrophilic inflammation in the proliferation and remodeling phases. VTn induced an imbalance of M1/M2 macrophages by maintaining a high number of TNF-α-producing M1 macrophages in the wound but without the ability to eliminate the persistent neutrophils. Chronic neutrophilic inflammation and senescence were mediated by cytokines such as IL-1α and IL-1β in a caspase-1- and caspase-11-dependent manner. In addition, previous blocking with anti-IL-1α and anti-IL-β neutralizing antibodies and caspase-1 (Ac YVAD-CMK) and caspase-11 (Wedelolactone) inhibitors was essential to control the pro-inflammatory activity of M1 macrophages induced by VTn injection, skewing towards an anti-inflammatory state, and was sufficient to block neutrophil recruitment and senescence.