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Background and Objectives: The aim of this study was to evaluate the impact of medications on oxidative stress, inflammatory biomarkers and semen characteristics in males with idiopathic infertility. Materials and Methods: In this observational case-control clinical study, 50 men with idiopathic infertility were enrolled, of whom 38 (the study group) were on pharmacological treatment and 12 made up the control group. The study group was clustered according to the medications (Group A: anti-hypertensive, n = 10; Group B: thyroxine, n = 6; Group C: non-steroidal anti-inflammatory drugs, n = 13; Group D: miscellaneous, n = 6; Group E: lipid-lowering drugs, n = 4). Semen analyses were performed according to WHO 2010 guidelines. Interleukins (IL)-10, IL-1 beta, IL-4, IL-6, Tumor Necrosis Factor- alpha (TNF-alpha) and IL-1 alpha were determined using a solid-phase sandwich immunoassay. The diacron reactive oxygen metabolites, d-ROMs test, was performed by means of a colorimetric determination of reactive oxygen metabolites and measured with a spectrophotometer. Beta-2-microglobulin and cystatin-C were measured with an immunoturbidimetric analyzer. Results: No differences between the study and control groups for age and macroscopic and microscopic semen characteristics were found, nor were any differences found after clustering according to the drug categories. IL-1 alpha and IL-10 were significantly lower in the study group compared with the control group; IL-10 was significantly lower in groups A, B, C and D compared with the control group. Furthermore, a direct correlation between IL-1 alpha, IL-10 and TNF-alpha and leukocytes was found. Conclusions: Despite the sample size limitations, the data suggest a correlation between drug use and activation of the inflammatory response. This could clarify the pathogenic mechanism of action for several pharmacological classes on male infertility.
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Infertilidade Masculina , Sêmen , Masculino , Humanos , Interleucina-1alfa/metabolismo , Fator de Necrose Tumoral alfa/análise , Interleucina-10/metabolismo , Infertilidade Masculina/tratamento farmacológico , Estresse Oxidativo , Oxigênio/metabolismoRESUMO
Activation of glial cells (reactive gliosis) and the purinergic pathway, together with metalloproteinase (MMP)-induced remodeling of the neural extracellular matrix (nECM), drive maladaptive changes in the spinal cord following peripheral nerve injury (PNI). We evaluated the effects on spinal maladaptive plasticity through administration of oxidized ATP (oxATP), an antagonist of P2X receptors (P2XR), and/or GM6001, an inhibitor of MMPs, in rats following spared nerve injury (SNI) of the sciatic nerve. With morpho-molecular techniques, we demonstrated a reduction in spinal reactive gliosis and changes in the neuro-glial-nECM crosstalk via expression remodeling of P2XR, nerve growth factor (NGF) receptors (TrkA and p75), and histone deacetylase 2 (HDAC2) after treatments with oxATP/GM6001. Altogether, our data suggest that MMPs and purinergic inhibition have a modulatory impact on key proteins in the neuro-glial-nECM network, acting at different levels from intracellular signaling to epigenetic modifications.
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Traumatismos dos Nervos Periféricos , Animais , Gliose/metabolismo , Metaloproteinases da Matriz/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Medula Espinal/metabolismoRESUMO
Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.
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Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Microambiente Tumoral , Animais , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Humanos , Hipóxia Tumoral , Efeito Warburg em OncologiaRESUMO
The bioactive form of vitamin D, 1,25-dihydroxyvitamin D (1,25D3), exerts immunomodulatory actions resulting in neuroprotective effects potentially useful against neurodegenerative and autoimmune diseases. In fact, vitamin D deficiency status has been correlated with painful manifestations associated with different pathological conditions. In this study, we have investigated the effects of vitamin D deficiency on microglia cells, as they represent the main immune cells responsible for early defense at central nervous system (CNS), including chronic pain states. For this purpose, we have employed a model of low vitamin D intake during gestation to evaluate possible changes in primary microglia cells obtained from postnatal day(P)2-3 pups. Afterwards, pain measurement and microglia morphological analysis in the spinal cord level and in brain regions involved in the integration of pain perception were performed in the parents subjected to vitamin D restriction. In cultured microglia, we detected a reactive-activated and proliferative-phenotype associated with intracellular reactive oxygen species (ROS) generation. Oxidative stress was closely correlated with the extent of DNA damage and increased ß-galactosidase (B-gal) activity. Interestingly, the incubation with 25D3 or 1,25D3 or palmitoylethanolamide, an endogenous ligand of peroxisome proliferator-activated-receptor-alpha (PPAR-α), reduced most of these effects. Morphological analysis of ex-vivo microglia obtained from vitamin-D-deficient adult mice revealed an increased number of activated microglia in the spinal cord, while in the brain microglia appeared in a dystrophic phenotype. Remarkably, activated (spinal) or dystrophic (brain) microglia were detected in a prominent manner in females. Our data indicate that vitamin D deficiency produces profound modifications in microglia, suggesting a possible role of these cells in the sensorial dysfunctions associated with hypovitaminosis D.
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Dor Crônica/etiologia , Microglia/efeitos dos fármacos , Deficiência de Vitamina D/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Células Cultivadas , Dor Crônica/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Vitamina D/metabolismo , Vitamina D/farmacologia , Deficiência de Vitamina D/fisiopatologiaRESUMO
BACKGROUND: Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target. Siponimod (BAF312), a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients. We investigated whether siponimod, in addition to its peripheral immune modulation, may exert direct neuroprotective effects in the central nervous system (CNS) of mice with chronic progressive EAE. METHODS: Minipumps allowing continuous intracerebroventricular (icv) infusion of siponimod for 4 weeks were implanted into C57BL/6 mice subjected to MOG35-55-induced EAE. Electrophysiology, immunohistochemistry, western blot, qPCR experiments, and peripheral lymphocyte counts were performed. In addition, the effect of siponimod on activated microglia was assessed in vitro to confirm the direct effect of the drug on CNS-resident immune cells. RESULTS: Siponimod administration (0.45 µg/day) induced a significant beneficial effect on EAE clinical scores with minimal effect on peripheral lymphocyte counts. Siponimod rescued defective GABAergic transmission in the striatum of EAE, without correcting the EAE-induced alterations of glutamatergic transmission. We observed a significant attenuation of astrogliosis and microgliosis together with reduced lymphocyte infiltration in the striatum of EAE mice treated with siponimod. Interestingly, siponimod reduced the release of IL-6 and RANTES from activated microglial cells in vitro, which might explain the reduced lymphocyte infiltration. Furthermore, the loss of parvalbumin-positive (PV+) GABAergic interneurons typical of EAE brains was rescued by siponimod treatment, providing a plausible explanation of the selective effects of this drug on inhibitory synaptic transmission. CONCLUSIONS: Altogether, our results show that siponimod has neuroprotective effects in the CNS of EAE mice, which are likely independent of its peripheral immune effect, suggesting that this drug could be effective in limiting neurodegenerative pathological processes in MS.
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Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Encefalomielite Autoimune Experimental/complicações , Degeneração Neural , Fármacos Neuroprotetores/uso terapêutico , Sinapses/fisiologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Transformada , Córtex Cerebral/citologia , Citocinas/farmacologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Adjuvante de Freund/imunologia , Adjuvante de Freund/toxicidade , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Degeneração Neural/etiologia , Degeneração Neural/patologia , Degeneração Neural/prevenção & controle , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Sinapses/efeitos dos fármacos , Potenciais Sinápticos/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T/patologia , Substância Branca/efeitos dos fármacos , Substância Branca/patologiaRESUMO
Background: Pericapsular nerve group (PENG) block, although effective for pain management following total hip arthroplasty (THA), does not cover skin analgesia. In this randomized controlled trial, we compared the effectiveness of PENG block combined with lateral femoral cutaneous nerve (LFCN) block or wound infiltration (WI) on postoperative analgesia and functional outcomes. Methods: Fifty patients undergoing posterior-approached THA under spinal anesthesia were randomly allocated to receive LFCN block with 10 mL of 0.5% ropivacaine or WI with 20 mL of 0.5% ropivacaine. In both groups, PENG block was performed by injecting 20 mL of 0.5% ropivacaine. Primary outcomes were static and dynamic pain scores (0-10 numeric rating scale) measured in the first 24 h after surgery. Secondary outcomes included postoperative opioid consumption, functional assessment and length of hospital stay. Results: Postoperative static NRS of patients receiving LFCN was higher than that of patients receiving WI at 6 h but lower at 24 h, with a median (IQR) of 3 (2-4) vs. 2 (1-2) (p < 0.001) and 2 (2-3) vs. 3 (3-4) (p = 0.02), respectively. Static pain scores at 12 h did not show significant differences, with an NRS of 3 (2-4) for WI vs. 3 (3-4) for LFCN (p = 0.94). Dynamic pain and range of movement followed a similar trend. No significant differences were detected in other outcomes. Conclusions: LFCN block was not inferior to WI for postoperative analgesia and functional recovery in association with PENG block during the first postoperative day, although it had worse short-term pain scores. Based on these results, it is reasonable to consider LFCN block as a valid alternative to WI or even a complementary technique added to WI to enhance skin analgesia during the first 24 h after THA. Future studies are expected to confirm this hypothesis and find the best combination between PENG block and other techniques to enhance analgesia after THA.
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(1) Background: In the last few years, many randomized controlled trials (RCTs) have compared direct Macintosh laryngoscopy with McGrath videolaryngoscopy in order to assess the potential benefits of the latter; the results were sometimes controversial. (2) Methods: We conducted a comprehensive literature search to identify our articles according to inclusion and exclusion criteria: to be included, each study had to be a prospective randomized trial or comparison between the McGrath videolaryngoscope and the Macintosh laryngoscope in an adult population. We did not include manikin trials or studies involving double-lumen tubes. (3) Results: 10 studies met the inclusion criteria necessary. In total, 655 patients were intubated with the McGrath and 629 with the Macintosh. In total, 1268 of 1284 patients were successfully intubated, showing equivalent results for the two devices: 648 of 655 patients with the McGrath videolaryngoscope and 620 of 629 patients with the Macintosh laryngoscope. No differences were noted in terms of hemodynamic changes or the incidence of adverse events. (4) Conclusions: We can assert that the McGrath videolaryngoscope and Macintosh laryngoscope, even if with equivalent tracheal intubation results, supplement each other.
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During pre-approval clinical trials, the safety of axi-cel, a second-generation CAR-T-cell therapy directed against CD19, which dramatically improved the prognosis of intractable B-cell lymphomas, has been investigated only in about 400 patients. Therefore, additional information on this issue is urgently needed. In the present paper, we evaluated the 2905 ICSRs with axi-cel as the suspected drug that had been uploaded in the EudraVigilance database from 1 January 2018 to 31 December 2022. About 80% of the reported adverse events were serious, and about 20% of them did not fully resolve or caused death. The adverse events most-frequently reported were Nervous system disorders (25.6%) and, among them, immune-effector-cell-associated neurotoxicity syndrome, followed by Immune system disorders (23.1%), General disorders and administration site conditions (12.0%), Blood and lymphatic system disorders (7.2%), and Infections and infestations (5.8%). Disproportionality analysis showed that the frequency of reported adverse events related to the nervous system was higher with axi-cel than with the other approved CAR-T-cells, except brexu-cel. In conclusion, real-world pharmacovigilance data showed that nervous system and immune system disorders are the adverse events most reported in axi-cel-related ICSRs and suggest that axi-cel could be more neurotoxic than other CAR-T-cells.
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Following insults or injury, microglia cells are activated contributing to the cytotoxic response or by promoting an immune-mediated damage resolution. Microglia cells express HCA2R, a hydroxy carboxylic acid (HCA) receptor, which has been shown to mediate neuroprotective and anti-inflammatory effects. In this study we found that HCAR2 expression levels were increased in cultured rat microglia cells after Lipopolysaccharide (LPS) exposure. In a similar fashion, the treatment with MK 1903, a potent full agonist of HCAR2, increased the receptor protein levels. Moreover, HCAR2 stimulation prevented i) cells viability ii) morphological activation iii) pro/anti-inflammatory mediators production in LPS-treated cells. Likewise, HCAR2 stimulation reduced the proinflammatory mediators mRNA expression induced by neuronal chemokine fractalkine (FKN), a neuronal derived chemokine activating its unique receptor, chemokine receptor 1 (CX3CR1) on microglia surface. Interestingly, electrophysiological recordings in vivo revealed that MK1903 was able to prevent the increase of the nociceptive neurons (NS) firing activity mediated by the spinal FKN application in healthy rats. Collectively, our data demonstrate that HCAR2 is functionally expressed in microglia, by showing its capability to shift microglia toward an anti-inflammatory phenotype. Moreover, we indicated the contribute of HCAR2 in the FKN signaling and suggested a possible HCAR2/CX3CR1 functional interaction. This study paves the way for further investigations aimed at understanding the role HCAR2 as potential target in neuroinflammation-based CNS disorders. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".
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Quimiocinas CXC , Microglia , Ratos , Animais , Quimiocinas CXC/metabolismo , Quimiocinas CXC/farmacologia , Lipopolissacarídeos/farmacologia , Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismoRESUMO
Multisystem inflammatory syndrome in children (MIS-c) is an uncommon, but serious, inflammatory response that occurs after SARS-CoV-2 infection. As time went by, MIS-c was also reported as a potential adverse event following COVID-19 vaccination. A descriptive analysis was performed of Individual Case Safety Reports (ICSRs) associated with anti COVID-19 vaccines and related to the pediatric population from 2020 to 2022. The present pharmacovigilance study aimed to describe cases of MIS-c following COVID-19 vaccination, stratified by sex, reported in the Vaccine Adverse Events Reporting System (VAERS) and meeting the Brighton Collaboration criteria for case definition. We assessed all suspected cases through the case definition and classification of the Brighton Collaboration Group, and only definitive, probable, and possible cases were included in the analysis. The Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI) was computed to assess if males have a lower/higher probability of reporting ICSRs with MIS-c compared with females. Overall, we found 79 cases of potentially reported MIS-c following vaccination. This study demonstrated that MIS-c following vaccination was more commonly reported for male subjects with a median age of 10 years (IQR 10.0-11.4), especially after the first dose of anti COVID-19 vaccines with a median time to onset of 27 days. Even so, the rate of occurrence of MIS-c following anti COVID-19 vaccines is lower (0.12/100,000 vaccinated subjects; 95% CI, 0.12-0.13). Overall, all ICSRs were serious and caused or prolonged hospitalization. Finally, disproportionality analysis showed that males had a higher reporting probability of MIS-c compared with females following immunization with mRNA COVID-19 vaccines. Since only a few years of marketing are available, further data from real-life contexts are needed.
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The maladaptive response of the central nervous system (CNS) following nerve injury is primarily linked to the activation of glial cells (reactive gliosis) that produce an inflammatory reaction and a wide cellular morpho-structural and functional/metabolic remodeling. Glial acidic fibrillary protein (GFAP), a major protein constituent of astrocyte intermediate filaments (IFs), is the hallmark of the reactive astrocytes, has pleiotropic functions and is significantly upregulated in the spinal cord after nerve injury. Here, we investigated the specific role of GFAP in glial reaction and maladaptive spinal cord plasticity following sciatic nerve spared nerve injury (SNI) in GFAP KO and wild-type (WT) animals. We evaluated the neuropathic behavior (thermal hyperalgesia, allodynia) and the expression of glial (vimentin, Iba1) and glutamate/GABA system markers (GLAST, GLT1, EAAC1, vGLUT, vGAT, GAD) in lumbar spinal cord sections of KO/WT animals. SNI induced neuropathic behavior in both GFAP KO and WT mice, paralleled by intense microglial reaction (Iba1 expression more pronounced in KO mice), reactive astrocytosis (vimentin increase) and expression remodeling of glial/neuronal glutamate/GABA transporters. In conclusion, it is conceivable that the lack of GFAP could be detrimental to the CNS as it lacks a critical sensor for neuroinflammation and morpho-functional-metabolic rewiring after nerve injury. Understanding the maladaptive morpho-functional changes of glial cells could represent the first step for a new glial-based targeted approach for mechanisms of disease in the CNS.
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Traumatismos dos Nervos Periféricos , Animais , Gliose/metabolismo , Ácido Glutâmico/metabolismo , Homeostase , Hiperalgesia , Camundongos , Camundongos Knockout , Neuroglia/metabolismo , VimentinaRESUMO
Relevance of blood-based biomarkers is increasing into the neurodegenerative diseases field, but data on Parkinson's disease (PD) remain still scarce. In this study, we used the SiMoA technique to measure serum content of total tau protein and amyloid-ß peptides (Aß-42, Aß-40) in 22 PD patients and ten control subjects. Serum levels of each biomarker were correlated with the respective CSF levels in both the groups; in PD patients, also the correlations between serum biomarkers and main clinical parameters were tested (motor, non-motor, cognitive scores and levodopa equivalent daily dose). Serum biomarkers did not exhibit quantitative differences between patients and controls; however, only PD patients had inter-fluids (serum-CSF) associations in tau and amyloid-ß-42 levels. Moreover, serum content of tau protein was inversely correlated with cognitive performances (MoCA score). These findings, albeit preliminary, indicate that brain-derived peptides may change in parallel in both peripheral blood and CSF of PD patients, eventually even in association with some clinical features. Further studies are now needed to validate the use of blood-based biomarkers in PD.
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The composition of the intestinal microbiota plays a critical role in shaping the immune system. Modern lifestyle, the inappropriate use of antibiotics, and exposure to pollution have significantly affected the composition of commensal microorganisms. The intestinal microbiota has been shown to sustain inappropriate autoimmune responses at distant sites in animal models of disease, and may also have a role in immune-mediated central nervous system (CNS) diseases such as multiple sclerosis (MS). We studied the composition of the gut mycobiota in fecal samples from 27 persons with MS (pwMS) and in 18 healthy donors (HD), including 5 pairs of homozygous twins discordant for MS. We found a tendency towards higher fungal abundance and richness in the MS group, and we observed that MS twins showed a higher rate of food-associated strains, such as Saccharomyces cerevisiae. We then found that in pwMS, a distinct population of cells with antibacterial and antifungal activity is expanded during the remitting phase and markedly decreases during clinically and/or radiologically active disease. These cells, named MAIT (mucosal-associated invariant T cells) lymphocytes, were significantly more activated in pwMS compared to HD in response to S. cerevisiae and Candida albicans strains isolated from fecal samples. This activation was also mediated by fungal-induced IL-23 secretion by innate immune cells. Finally, immunofluorescent stainings of MS post-mortem brain tissues from persons with the secondary progressive form of the disease showed that MAIT cells cross the blood-brain barrier (BBB) and produce pro-inflammatory cytokines in the brain. These results were in agreement with the hypothesis that dysbiosis of the gut microbiota might determine the inappropriate response of a subset of pathogenic mucosal T cells and favor the development of systemic inflammatory and autoimmune diseases.
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Microbioma Gastrointestinal , Células T Invariantes Associadas à Mucosa , Esclerose Múltipla , Animais , Encéfalo , Linfócitos T CD8-Positivos/patologia , Saccharomyces cerevisiaeRESUMO
Prognostic determination of patients in coma after resuscitation from cardiac arrest is a common and difficult requirement with significant ethical, social and legal implications. We set out to seek markers that can be used for the early detection of patients with a poor prognosis, so as to reduce uncertainty over treatment and non-treatment decisions, and to improve relationships with families. We reviewed the medical literature from 1991 to 2010, using key words such as post-anoxic coma, post-anoxic vegetative state, vegetative state prognosis, recovery after cardiac arrest. Neurological examination, electrophysiology, imaging, and biochemical markers are all useful tools for estimating patients' chances of recovery from cardiac arrest. It seems unlikely that any single test will prove to have 100% predictive value for outcome; but the combination of various prognostic markers, as shown in some articles, could increase the reliability of outcome prediction. However, further research is needed.
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Parada Cardíaca/complicações , Estado Vegetativo Persistente/diagnóstico , Recuperação de Função Fisiológica , Biomarcadores , Parada Cardíaca/fisiopatologia , Humanos , Hipóxia/complicações , Hipóxia/fisiopatologia , Exame Neurológico/normas , Estado Vegetativo Persistente/etiologia , Estado Vegetativo Persistente/fisiopatologia , Valor Preditivo dos Testes , PrognósticoRESUMO
BACKGROUND: Ceftolozane/tazobactam (C/T) is a ß-lactam/ß-lactamase inhibitor combination that mainly targets Gram-negative bacteria. The current international guidelines recommend including C/T treatment in the empirical therapy for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). Pseudomonas aeruginosa (PA) is one of the most challenging Gram-negative bacteria. We conducted a systematic review of all cases reported in the literature to summarize the existing evidence. METHODS: The main electronic databases were screened to identify case reports of patients with drug-resistant PA respiratory infections treated with C/T. RESULTS: A total of 22 publications were included for a total of 84 infective episodes. The clinical success rate was 72.6% across a wide range of comorbidities. The 45.8% of patients treated with C/T presented colonization by PA. C/T was well tolerated. Only six patients presented adverse events, but none had to stop treatment. The most common therapeutic regimens were 1.5 g every 8 h and 3 g every 8 h. CONCLUSION: C/T may be a valid therapeutic option to treat multidrug-resistant (MDR), extensively drug-resistant (XDR), pandrug-resistant (PDR), and carbapenem-resistant (CR) PA infections. However, further data are necessary to define the optimal treatment dosage and duration.
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The animal models of neuropathic pain that faithfully reproduce the symptoms that occur in humans are a fundamental tool for understanding the mechanisms underlying the disease, identifying new targets, and developing effective drugs. So far, the studies aimed at describing the animal models of neuropathic pain have been focused mainly on the sensory symptoms associated with the disease consisting of mechanical allodynia and hyperalgesia, cold allodynia and hyperalgesia, and heat hyperalgesia. However, affective and cognitive comorbidities occur in patients suffering from neuropathic pain, arising in a closely associated and dependent manner on the sensory symptoms. The same occurs in animal models of neuropathic pain in which anxiety- and depressive- like behaviors and cognitive disorders are observable at different time points from the induction of neuropathy. Today there are several tests available that exploit different paradigms in rodents for measuring sensorial, affective, and cognitive behavior. This review will describe those mainly used in the scientific community. The tests mainly used are based on the motor activity of the animals tested, so it is fundamental that it remains unaffected in the model used for inducing neuropathic pain. We hope that this review will be useful to the scientific community to direct the choice towards the best, most suitable, and simplest tests for the study of the sensory, affective, and cognitive symptoms associated with neuropathic pain.
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Neuralgia , Roedores , Animais , Cognição , Modelos Animais de Doenças , Humanos , HiperalgesiaRESUMO
Remdesivir was recommended for hospitalized patients with COVID-19. As already reported in the Summary of Product Characteristics, most of remdesivir's safety concerns are hepatoxicity and nephrotoxicity related. However, some cases have raised concerns regarding the potential cardiac events associated with remdesivir; therefore, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency requested to investigate all available data. Therefore, we analyzed all Individual Case Safety Reports (ICSRs) collected in the EudraVigilance database focusing on cardiac adverse events. From April to December 2020, 1375 ICSRs related to remdesivir were retrieved from EudraVigilance, of which 863 (62.8%) were related to male and (43.3%) adult patients. A total of 82.2% of all AEs (N = 2604) was serious and one third of the total ICSRs (N = 416, 30.3%) had a fatal outcome. The most frequently reported events referred to hepatic/hepatobiliary disorders (19.4%,), renal and urinary disorders (11.1%) and cardiac events (8.4%). Among 221 cardiac ICSRs, 69 reported fatal outcomes. Other drugs for cardiovascular disorders were reported as suspected/concomitant together with remdesivir in 166 ICSRs (75.1%), 62 of which were fatal. Moreover, the mean time to overall cardiac event was 3.3 days (±2.2). Finally, disproportionality analysis showed a two-fold increased risk of reporting a cardiac adverse event associated with remdesivir compared to both hydroxychloroquine and azithromycin. This study showed that remdesivir could be associated to risk of cardiac events, suggesting a potential safety signal which has not been completely evaluated yet. Further studies are needed to confirm these findings.
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BACKGROUND: General and local anaesthetics are widely used during surgery. These drugs have peculiar safety profiles, being commonly associated with mild and reversible local adverse drug reactions (ADRs), but also with more severe and systemic ADRs, including respiratory and cardiovascular depression and anaphylaxis. METHODS AND OBJECTIVES: We carried out a descriptive analysis of Individual Case Safety Reports (ICSRs) sent to the Campania Regional Centre of Pharmacovigilance (Southern Italy) from 2001 to 2021 that reported general or local anaesthetics as suspected drugs, with the aim of describing their overall characteristics, focussing on the ADRs' seriousness and distribution by System Organ Class (SOC) and Preferred Term (PT). RESULTS: A total of 110 ICSRs documenting general or local anaesthetics were sent to the Italian pharmacovigilance database during 20 years of spontaneous reporting activities in the Campania region. ADRs mainly occurred in patients with a median age of 48 years and in a slightly higher percentage of men. ADRs were more commonly classified as not serious and had a favourable outcome. In terms of ADRs' distribution by SOC and PT, both general and local anaesthetics were associated with general and cutaneous disorders, with common ADRs that included lack of efficacy, rash, and erythema. In addition, general anaesthetics were associated with the occurrence of respiratory ADRs, while local anaesthetics were associated with the occurrence of nervous ADRs. CONCLUSION: Even though a limited number of ICSRs documenting anaesthetics-induced ADRs were retrieved from the Italian spontaneous reporting database in the Campania region, we believe that the continuous monitoring of these drugs is highly recommended, especially among the frail population.
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Low back pain represents a significant socioeconomic burden. Several nonsurgical medical treatments have been proposed for the treatment of this disabling condition. Epidural steroid injections (ESIs) are commonly used to treat lumbosacral radicular pain and to avoid surgery. Even though it is still not clear which type of conservative intervention is superior, several studies have proved that ESIs are able to increase patients' quality of life, relieve lumbosacral radicular pain and finally, reduce or delay more invasive interventions, such as spinal surgery. The aim of this narrative review is to analyze the mechanism of action of ESIs in patients affected by low back pain and investigate their current application in treating this widespread pathology.