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Type I interferon signaling (IFN-I) perturbations are major drivers of COVID-19. Dysregulated IFN-I in the brain, however, has been linked to both reduced cognitive resilience and neurodegenerative diseases such as Alzheimer's. Previous works from our group have proposed a model where peripheral induction of IFN-I may be relayed to the CNS, even in the absence of fulminant infection. The aim of our study was to identify significantly enriched IFN-I signatures and genes along the transolfactory route, utilizing published datasets of the nasal mucosa and olfactory bulb amygdala transcriptomes of COVID-19 patients. We furthermore sought to identify these IFN-I signature gene networks associated with Alzheimer's disease pathology and risk. Gene expression data involving the nasal epithelium, olfactory bulb, and amygdala of COVID-19 patients and transcriptomic data from Alzheimer's disease patients were scrutinized for enriched Type I interferon pathways. Gene set enrichment analyses and gene-Venn approaches were used to determine genes in IFN-I enriched signatures. The Agora web resource was used to identify genes in IFN-I signatures associated with Alzheimer's disease risk based on its aggregated multi-omic data. For all analyses, false discovery rates (FDR) <0.05 were considered statistically significant. Pathways associated with type I interferon signaling were found in all samples tested. Each type I interferon signature was enriched by IFITM and OAS family genes. A 14-gene signature was associated with COVID-19 CNS and the response to Alzheimer's disease pathology, whereas nine genes were associated with increased risk for Alzheimer's disease based on Agora. Our study provides further support to a type I interferon signaling dysregulation along the extended olfactory network as reconstructed herein, ranging from the nasal epithelium and extending to the amygdala. We furthermore identify the 14 genes implicated in this dysregulated pathway with Alzheimer's disease pathology, among which HLA-C, HLA-B, HLA-A, PSMB8, IFITM3, HLA-E, IFITM1, OAS2, and MX1 as genes with associated conferring increased risk for the latter. Further research into its druggability by IFNb therapeutics may be warranted.
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BACKGROUND: Spinal cord injury (SCI) presents a major global health challenge, with rising incidence rates and substantial disability. Although progress has been made in understanding SCI's pathophysiology and early management, there is still a lack of effective treatments to mitigate long-term consequences. This study investigates the potential of sovateltide, a selective endothelin B receptor agonist, in improving clinical outcomes in an acute SCI rat model. METHODS: Thirty male Sprague-Dawley rats underwent sham surgery (group A) or SCI and treated with vehicle (group B) or sovateltide (group C). Clinical tests, including Basso, Beattie, and Bresnahan scoring, inclined plane, and allodynia testing with von Frey hair, were performed at various time points. Statistical analyses assessed treatment effects. RESULTS: Sovateltide administration significantly improved motor function, reducing neurological deficits and enhancing locomotor recovery compared with vehicle-treated rats, starting from day 7 post injury. Additionally, the allodynic threshold improved, suggesting antinociceptive properties. Notably, the sovateltide group demonstrated sustained recovery, and even reached preinjury performance levels, whereas the vehicle group plateaued. CONCLUSIONS: This study suggests that sovateltide may offer neuroprotective effects, enhancing neurogenesis and angiogenesis. Furthermore, it may possess anti-inflammatory and antinociceptive properties. Future clinical trials are needed to validate these findings, but sovateltide shows promise as a potential therapeutic strategy to improve functional outcomes in SCI. Sovateltide, an endothelin B receptor agonist, exhibits neuroprotective properties, enhancing motor recovery and ameliorating hyperalgesia in a rat SCI model. These findings could pave the way for innovative pharmacological interventions for SCI in clinical settings.
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Modelos Animais de Doenças , Hiperalgesia , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal , Animais , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/complicações , Masculino , Ratos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Receptor de Endotelina B/efeitos dos fármacos , Endotelinas/farmacologia , Fragmentos de PeptídeosRESUMO
Background: Real-world, observational studies have investigated the safety profile of Direct Oral Anticoagulants (DOACs) on Major Hemorrhage (MH) used for stroke prevention in Non-Valvular Atrial Fibrillation (NVAF). We performed a systematic review and meta-analysis to investigate the comparative safety of DOACs versus other DOACs and versus Vitamin K Antagonists (VKAs) adhering to PRISMA guidelines. We defined MH according to the International Society on Thrombosis and Haemostasis statement or as the composite outcome of intracranial, gastrointestinal, genitourinary, respiratory, cavitary and musculoskeletal bleeding in case of studies using International Statistical Classification of Diseases codes for patient selection. Methods: We systematically investigated two databases (Medline, Embase) until April of 2021, gathered observational studies and extracted hazard ratios (HRs) with 95% confidence intervals (CI) on our outcome of interest. Additional subgroup analyses according to DOAC dosing, prior diagnosis of chronic kidney disease, prior diagnosis of stroke, history of previous use of VKA, the users' age, the users' gender and study population geographic region were conducted. All analyses were performed with a random-effects model. Results: From this search, 55 studies were included and 76 comparisons were performed. The MH risk associated with Rivaroxaban use was higher than the risk with Dabigatran use (HR: 1.32, 95% CI: 1.21-1.45, I 2 : 12.39%) but similar to VKA use (HR: 0.94, 95% CI: 0.87-1.02, I 2 : 76.57%). The MH risk associated with Dabigatran use was lower than the risk with VKA use (HR: 0.75, 95% CI: 0.64-0.90, I 2 : 87.57%). The MH risk associated with Apixaban use was lower than the risk with Dabigatran use (HR: 0.75, 95% CI: 0.64-0.88, I 2 : 58.66%), with Rivaroxaban use (HR: 0.58, 95% CI: 0.50-0.68, I 2 : 74.16%) and with VKA use (HR: 0.60, 95% CI: 0.55-0.65, I 2 : 58.83%). Our aforementioned subgroup analyses revealed similar results. Conclusions: All in all, Apixaban was associated with a reduced MH risk compared to Dabigatran, Rivaroxaban and VKA. Dabigatran was associated with a reduced MH risk compared to both Rivaroxaban and VKA.
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BACKGROUND: Visual Snow Syndrome is a recently recognized neurological condition presenting, continuous, tiny dots across the entire visual field, accompanied by nyctalopia, photophobia and palinopsia that persist for months. It may be part of migraine aura spectrum, yet its definition is still questionable. Diagnostic criteria for Visual Snow Syndrome are included in the supplemental material of ICHD-3. We aimed to summarize recent data to improve the understanding of Visual Snow Syndrome. METHODS: After presenting four new cases, we conducted a PRISMA systematic search in PubMed/MEDLINE and Embase databases using the keyword "visual snow" with specific inclusion and exclusion criteria. RESULTS: From the 855 articles identified 30 were included for the qualitative analysis. These reports covered five aspects related to Visual Snow Syndrome: epidemiology, clinical features, comorbidities, pathophysiology, and treatment. We found limited data concerning Visual Snow Syndrome's epidemiology (one study). Clinical presentation (22 articles) and the comorbidities (migraine with aura and tinnitus most often, five reports) are described in detail. The pathophysiology of Visual Snow Syndrome is only approached with hypotheses, but several neuroimaging studies have been identified (seven articles). Treatment is based on single case reports only. CONCLUSION: Data for Visual Snow Syndrome are few and not strong enough to support Visual Snow Syndrome as a medical identity. Further investigation is needed.
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Transtornos de Enxaqueca , Enxaqueca com Aura , Humanos , Transtornos de Enxaqueca/epidemiologia , Enxaqueca com Aura/diagnóstico , Neuroimagem , Fotofobia , Transtornos da Visão/epidemiologia , Transtornos da Visão/diagnósticoRESUMO
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development.
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COVID-19 , Doenças Neurodegenerativas , Doença de Parkinson , Transtornos Parkinsonianos , COVID-19/complicações , Comunicação Celular , Humanos , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/etiologia , Transtornos Parkinsonianos/patologia , RNA Viral , SARS-CoV-2 , alfa-Sinucleína/metabolismoRESUMO
BACKGROUND: Perioperative cardiac arrest is a rare complication with an incidence of around 1 in 1400 cases, but it carries a high burden of mortality reaching up to 70% at 30 days. Despite its specificities, guidelines for treatment of perioperative cardiac arrest are lacking. Gathering the available literature may improve quality of care and outcome of patients. METHODS: The PERIOPCA Task Force identified major clinical questions about the management of perioperative cardiac arrest and framed them into the therapy population [P], intervention [I], comparator [C], and outcome [O] (PICO) format. Systematic searches of PubMed, Embase, and the Cochrane Library for articles published until September 2020 were performed. Consensus-based treatment recommendations were created using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The strength of consensus among the Task Force members about the recommendations was assessed through a modified Delphi consensus process. RESULTS: Twenty-two PICO questions were addressed, and the recommendations were validated in two Delphi rounds. A summary of evidence for each outcome is reported and accompanied by an overall assessment of the evidence to guide healthcare providers. CONCLUSIONS: The main limitations of our work lie in the scarcity of good quality evidence on this topic. Still, these recommendations provide a basis for decision making, as well as a guide for future research on perioperative cardiac arrest.
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Parada Cardíaca/terapia , Período Perioperatório/tendências , Consenso , Técnica Delphi , Parada Cardíaca/etiologia , HumanosRESUMO
BACKGROUND: Knowing the kinetics of endogenous stress hormones during cardiac arrest and cardiopulmonary resuscitation (CRP) will help to optimize personalized physiology-guided treatment. The aim of this study was to examine the dynamic changes in stress hormones in a swine model of ventricular fibrillation (VF) cardiac arrest. METHODS: Ventricular fibrillation was induced in 10 healthy Landrace/Large White piglets, which were subsequently left untreated for 8 min. All animals were resuscitated according to the 2015 European Resuscitation Council guidelines. The concentration of adrenalin, noradrenalin, and cortisol was measured at baseline and at the 4th and 8th minute of VF-cardiac arrest, as well as at 30-min, 60-min, 24 h and 48 h post-ROSC. RESULTS: By the end of the 4th min of VF, the animals of the ROSC group exhibited significantly higher adrenaline levels compared to those of the no-ROSC group (7264 pg/ml vs. 1648 pg/ml, p = 0.03). Noradrenaline was higher in the ROSC group at the 4th min of VF (3021 pg/ml vs. 1626 pg/ml, p = 0.02). Cortisol levels in the ROSC group were significantly lower by the end of the 8th min of VF [16.25 ng/ml vs. 92.82 ng/ml, p = 0.03]. With a cut-off point of 5970 pg/ml, adrenaline at the 4th min of VF exhibited 100% sensitivity and 80% specificity for predicting ROSC. CONCLUSION: Higher endogenous adrenaline and lower endogenous cortisol levels were associated with ROSC.
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Epinefrina/farmacocinética , Parada Cardíaca/metabolismo , Hidrocortisona/farmacocinética , Norepinefrina/farmacocinética , Fibrilação Ventricular/metabolismo , Animais , Reanimação Cardiopulmonar , Modelos Animais de Doenças , Parada Cardíaca/terapia , Masculino , Estudos Prospectivos , Suínos , Fibrilação Ventricular/terapiaRESUMO
BACKGROUND: Listeria monocytogenes is an opportunistic pathogen of the central nervous system commonly associated with impaired cell-mediated immunity. We hereby present a case of adult neurolisteriosis where the only immunological feature persistently present was serum IgM deficiency, suggesting that non-specific humoral immunity may also play a central role in the control of neuroinvasion by Listeria monocytogenes. CASE PRESENTATION: A 62-year-old male who had never experienced severe infections presented with headache, nuchal rigidity and confusion. Neuroimaging was normal and lumbar puncture revealed pleiocytosis (760 leukocytes/mm3) and hypoglycorrhachia (34 mg/dL). The patient was treated empirically for bacterial meningitis. Indeed, further analysis of the CSF showed infection by Listeria monocytogenes, which was accompanied by reduced serum IgM levels that persisted well beyond the period of acute bacterial infection. Levels of IgG and IgA isotypes, along with peripheral blood counts of major leukocyte subsets, were at the same time largely preserved. Intriguingly, the absence of membrane-bound IgM on B cells was essentially complete in the acute post-infection period leading to a remarkable recovery after 12 months, suggesting that mechanisms other than defective membrane expression are underlying serum deficiency. CONCLUSIONS: As far as we know, this is the first reported case of neurolisteriosis associated with IgM deficiency in an adult individual without a history of severe infections or other underlying conditions. A possible role of circulating IgM against invasive disease caused by Listeria monocytogenes, particularly in the early course of host-pathogen interaction, is discussed.
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Hospedeiro Imunocomprometido , Imunoglobulina M/deficiência , Meningite por Listeria/imunologia , Humanos , Síndromes de Imunodeficiência/complicações , Masculino , Pessoa de Meia-IdadeRESUMO
Calcitonin gene-related peptide (CGRP) is a neuropeptide with a pivotal role in the pathophysiology of migraine. Blockade of CGRP is a new therapeutic target for patients with migraine. CGRP and its receptors are distributed not only in the central and peripheral nervous system but also in the cardiovascular system, both in blood vessels and in the heart. We reviewed the current evidence on the role of CGRP in the cardiovascular system in order to understand the possible short- and long-term effect of CGRP blockade with monoclonal antibodies in migraineurs.In physiological conditions, CGRP has important vasodilating effects and is thought to protect organs from ischemia. Despite the aforementioned cardiovascular implication, preventive treatment with CGRP antibodies has shown no relevant cardiovascular side effects. Results from long-term trials and from real life are now needed.
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Anticorpos Monoclonais/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos de Enxaqueca/tratamento farmacológico , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Sistema Cardiovascular/fisiopatologia , Humanos , Transtornos de Enxaqueca/etiologia , Transtornos de Enxaqueca/fisiopatologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Fatores Sexuais , Vasodilatação/fisiologiaRESUMO
Cerebral vasospasm and delayed cerebral ischemia represent a very challenging aspect of cerebrovascular pathophysiology, most commonly subarachnoid hemorrhage, with significantly high mortality if left untreated. Considerable advances have been made in medical treatment and prompt diagnosis, while newer endovascular modalities have recently been proposed for cases of resistant cerebral vasospasm. However, there is still paucity of data regarding which and whether a single endovascular technique is non inferior to the pharmacological standard of care. In this review, we aim to summarize the current funds of knowledge concerning cerebral vasospasm and the emerging role of the endovascular techniques for its treatment.
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Isquemia Encefálica , Procedimentos Endovasculares , Vasoespasmo Intracraniano , Humanos , Procedimentos Endovasculares/métodos , Isquemia Encefálica/terapia , Vasoespasmo Intracraniano/terapia , Vasoespasmo Intracraniano/etiologiaRESUMO
Perioperative stroke is a devastating complication that occurs during surgery or within 30 days following the surgical procedure. Its prevalence ranges from 0.08 to 10% although it is most likely an underestimation, as sedatives and narcotics can substantially mask symptomatology and clinical presentation. Understanding the underlying pathophysiology and identifying potential therapeutic targets are of paramount importance. Protease-activated receptors (PARs), a unique family of G-protein-coupled receptors, are widely expressed throughout the human body and play essential roles in various physiological and pathological processes. This review elucidates the biology and significance of PARs, outlining their diverse functions in health and disease, and their intricate involvement in cerebrovascular (patho)physiology and neuroprotection. PARs exhibit a dual role in cerebral ischemia, which underscores their potential as therapeutic targets to mitigate the devastating effects of stroke in surgical patients.
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Migraine is a leading cause of disability worldwide, yet it remains underrecognized and undertreated, especially in the pediatric and adolescent population. Chronic migraine occurs approximately in 1% of children and adolescents requiring preventive treatment. Topiramate is the only FDA-approved preventative treatment for children older than 12 years of age, but there is conflicting evidence regarding its efficacy. OnabotulinumtoxinA is a known and approved treatment for the management of chronic migraine in people older than 18 years. Several studies examine its role in the pediatric population with positive results; however, the clear-cut benefit is still unclear. OnabotulinumtoxinA seems not only to improve disability scores (PedMIDAS) but also to improve the quality, characteristics, and frequency of migraines in the said population. This systematic review aims to summarize the evidence on the efficacy, dosing, administration, long-term outcomes, and safety of onabotulinumtoxinA in pediatric and adolescent migraine. Eighteen studies met the eligibility criteria and were included in this review. The mean monthly migraine days (MMDs), decreased from of 21.2 days per month to 10.7 after treatment. The reported treatment-related adverse effects were mild and primarily injection site related and ranged from 0% to 47.0%. Thus, this review provides compelling evidence suggesting that OnabotulinumtoxinA may represent a safe and effective preventive treatment option for pediatric migraine.
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Toxinas Botulínicas Tipo A , Transtornos de Enxaqueca , Humanos , Transtornos de Enxaqueca/prevenção & controle , Transtornos de Enxaqueca/tratamento farmacológico , Toxinas Botulínicas Tipo A/uso terapêutico , Toxinas Botulínicas Tipo A/efeitos adversos , Criança , Adolescente , Fármacos Neuromusculares/uso terapêutico , Fármacos Neuromusculares/efeitos adversos , Resultado do TratamentoRESUMO
INTRODUCTION: Loss of dorsolateral nigral hyperintensity (DNH) on iron-sensitive brain MRI is useful for Parkinson's disease detection. DNH loss could also be of diagnostic value in dementia with Lewy bodies (DLB), an a-synuclein-related pathology. We aim to quantitatively synthesize evidence, investigating the role of MRI, a first-line imaging modality, in early DLB detection and differentiation from other dementias. METHODS: Our study was conducted according to the PRISMA statement. MEDLINE, Scopus, Web of Science, and Cochrane Library were searched using the terms like "dementia with Lewy bodies", "dorsolateral nigral hyperintensity", and "MRI". Only English-written peer-reviewed diagnostic accuracy studies were included. We used QUADAS-2 for quality assessment. RESULTS: Our search yielded 363 search results. Three studies were eligible, all with satisfying, high quality. The total population of 227 patients included 63 with DLB and 164 with other diseases (Alzheimer disease, frontotemporal dementia, mild cognitive impairment). Using a univariate random-effects logistic regression model, our meta-analysis resulted in pooled sensitivity, specificity and DOR of 0.82 [0.62; 0.92], 0.79 [0.70; 0.86] and 16.26 ([3.3276; 79.4702], p = 0.0006), respectively, for scans with mixed field strength (1.5 and 3 T). Subgroup analysis of 3 T scans showed pooled sensitivity, specificity and DOR of 0.82 [0.61; 0.93], 0.82 [0.72; 0.89] and 18.36 ([4.24; 79.46], p < 0.0001), respectively. DISCUSSION: DNH loss on iron-sensitive MRI might comprise a supportive biomarker for DLB detection, that could augment the value of the DLB diagnostic criteria. Further evaluation using standardized protocols is needed, as well as direct comparison to other supportive and indicative biomarkers.
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Doença por Corpos de Lewy , Imageamento por Ressonância Magnética , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/diagnóstico , Imageamento por Ressonância Magnética/normas , Substância Negra/diagnóstico por imagem , Substância Negra/patologiaRESUMO
INTRODUCTION: Intraoperative hemodynamic and metabolic optimization of both the high-risk surgical patients and critically ill patients remains challenging. Reductions in oxygen delivery or increases in oxygen consumption can initiate complex cellular processes precipitating oxygen debt (OXD). METHODS: This study tested the hypothesis that intraoperative changes in sublingual microcirculatory flow reflect clinically relevant transitions from aerobic to anaerobic metabolism (TRANAM). We included patients undergoing elective major and emergency non-cardiac surgery. Macro- and microcirculatory variables, oxygen extraction, and transitions of metabolism were assessed in both cohorts. RESULTS: In the elective group, OXD was progressively increased over time, with an estimated 2.24 unit increase every 30 min (adjusted p < 0.001). Also, OXD was negatively correlated with central venous pressure (ρ = -0.247, adjusted p = 0.006) and positively correlated with stroke volume variation (ρ = 0.185, adjusted p = 0.041). However, it was not significantly correlated with sublingual microcirculation variables. In the emergency surgery group, OXD increased during the first two intraoperative hours and then gradually decreased until the end of surgery. In that cohort, OXD was positively correlated with diastolic arterial pressure (ρ = 0.338, adjpatients and the critically ill patients remains challengingsted p = 0.015). Also, OXD was negatively correlated with cardiac index (ρ = -0.352, adjusted p = 0.003), Consensus Proportion of Perfused Vessels (PPV) (ρ = -0.438, adjusted p < 0.001), and Consensus PPV (small) (ρ = -0.434, adjusted p < 0.001). CONCLUSIONS: TRANAM were evident in both the elective major and emergency non-cardiac surgery cohorts independent of underlying alterations in the sublingual microcirculation.
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Current treatment options for acute ischemic stroke, including intravenous thrombolysis (IVT) and mechanical thrombectomy, have undoubtedly revolutionized stroke care. The need for additional treatment options has brought into the light direct thrombin inhibitors (DTIs) and, specifically, argatroban as a promising candidate. However, there is uncertainty regarding the safety of adding argatroban to IVT, mainly due to the increased hemorrhagic risk. In this study, we performed a systematic review and meta-analysis examining the safety and efficacy of argatroban as an add-on treatment for IVT. The following databases were searched from inception until the 14th of May 2023: Pubmed/MEDLINE, ClinicalTrials.gov, the EU Clinical Trials Register, EMBASE/Scopus, and the Cochrane Library. Only randomized clinical trials (RCTs) enrolling patients with acute ischemic stroke who underwent IVT evaluating the add-on use of any DTIs were selected for the systematic review and further meta-analysis. The PRISMA guidelines were followed at all stages. Four studies with argatroban were included in the final analysis. Analysis of risk ratio and relative risk shows that the add-on therapy with argatroban seems to be effective and favors a good clinical outcome (mRS 0-2) at 90 days, similar to that of alteplase. All studies showed a low pooled incidence of symptomatic intracerebral hemorrhage (5%), parenchymal hematoma (3%), and other major bleeding (1%). Argatroban as an add-on treatment to IVT seems not to be associated with excessive bleeding risk; however, its efficacy remains unproven. According to this synopsis of the currently available evidence, it is premature to use argatroban as an add-on to IVT treatment outside the current clinical trial setting.
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BACKGROUND: several blood-based biomarkers have been proposed for predicting vancomycin-associated kidney injury (VIKI). However, no systematic analysis has compared their prognostic value. OBJECTIVE: this systematic review and meta-analysis was designed to investigate the role of blood biomarkers and metabolomic profiling as diagnostic and prognostic predictors in pre-clinical studies of VIKI. METHODS: a systematic search of PubMed was conducted for relevant articles from January 2000 to May 2022. Animal studies that administered vancomycin and studied VIKI were eligible for inclusion. Clinical studies, reviews, and non-English literature were excluded. The primary outcome was to investigate the relationship between the extent of VIKI as measured by blood biomarkers and metabolomic profiling. Risk of bias was assessed with the CAMARADES checklist the SYRCLE's risk of bias tool. Standard meta-analysis methods (random-effects models) were used. RESULTS: there were four studies for the same species, dosage, duration of vancomycin administration and measurement only for serum creatine and blood urea nitrogen in rats. A statistically significant increase was observed between serum creatinine in the vancomycin group compared to controls (pooled p = 0.037; Standardized Mean Difference: 2.93; 95% CI: 0.17 to 5.69; I2 = 92.11%). Serum BUN levels were not significantly different between control and vancomycin groups (pooled p = 0.11; SMD: 3.05; 95% CI: 0.69 to 6.8; I2 = 94.84%). We did not identify experimental studies using metabolomic analyses in animals with VIKI. CONCLUSIONS: a total of four studies in rodents only described outcomes of kidney injury as defined by blood biomarkers. Blood biomarkers represented included serum creatinine and BUN. Novel blood biomarkers have not been explored.
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BACKGROUND: Multiple Sclerosis treatment with B-cell targeted therapies may be associated with an increased incidence of headache. We aimed to find and compare the association of B-cell targeted therapies with the incidence of headache in patients with Multiple Sclerosis. METHODS: In a systematic based approach, the following databases were searched from inception until the 6th of June 2020: Pubmed/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. Only randomized clinical trials (RCTs) enrolling patients with Multiple Sclerosis comparing B-cell targeted therapies (Rituximab, Ocrelizumab, Ofatumumab, Ublituximab or Cladribine) with placebo were selected for the systematic review and further meta-analysis. PRISMA guidelines were followed at all stages of the systematic review. The primary outcome was an all-cause headache of B-cell targeting therapy in patients with Multiple Sclerosis. RESULTS: Nine RCTs were included. Compared with placebo, treatment with B-cell targeting therapies revealed a trend in headache risk, but it was not statistically significant (Relative Risk 1.12 [95% Confidence Interval 0.96-1.30]; p = 0.15; I2 = 9.32%). Surprisingly, in a sub-group analysis, Cladribine was statistically significant for an increase in headache risk (RR 1.20 [95% CI 1.006-1.42]; p = 0.042; I2 = 0%; 3 studies with 2107 participants). CONCLUSIONS: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Sub-analyses revealed a significant association between Cladribine alone and an increased incidence of headache. Whereas a purinergic signaling cascade is proposed as a mechanism of action, further research is needed to unravel the underlying pathogenetic mechanism of headache induction and establish headache prevention strategies.
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Introduction: Cluster headache (CH) is probably the most severe idiopathic pain condition, yet its current medical management remains poor.Areas covered: Only repurpose medicines are currently in use for the prevention of CH, partially because the pathophysiology of the condition is still elusive. In this article we performed a systematic review to evaluate the evidence for efficacy of the currently available or emerging treatments for CH.Expert opinion: We found several ongoing randomized clinical trials testing prophylactic treatments for CH and only few for the standard ones. Recent data from randomized trials with monoclonal antibodies targeting the calcitonin gene related peptide pathway (anti-CGRP mAbs) are controversial, although its role in the pathogenesis of the condition is well documented. This inconsistency may depict inadequacies in clinical trial designing. Anti-CGRP mAbs and antagonists of pituitary adenylate cyclase-activating polypeptide (PACAP) along with neuromodulation techniques, are curing the necessary valuable evidence that could illuminate the therapeutical future for cluster headache. Orexin pathway is another attractive target for CH treatment. To improve the evidence for efficacy, we further propose that the design of the clinical trials for CH needs to be radically reviewed to allow more patients to participate.
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Antineoplásicos Imunológicos , Cefaleia Histamínica , Transtornos de Enxaqueca , Anticorpos Monoclonais/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/uso terapêutico , Cefaleia Histamínica/tratamento farmacológico , Humanos , Transtornos de Enxaqueca/tratamento farmacológicoRESUMO
Now more than ever is the time of monoclonal antibody use in neurology. In headaches, disease-specific and mechanism-based treatments existed only for symptomatic management of migraines (i.e., triptans), while the standard prophylactic anti-migraine treatments consist of non-specific and repurposed drugs that share limited safety profiles and high risk for interactions with other medications, resulting in rundown adherence rates. Recent advances in headache science have increased our understanding of the role of calcitonin gene relate peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) pathways in cephalic pain neurotransmission and peripheral or central sensitization, leading to the development of monoclonal antibodies (mAbs) or small molecules targeting these neuropeptides or their receptors. Large scale randomized clinical trials confirmed that inhibition of the CGRP system attenuates migraine, while the PACAP mediated nociception is still under scientific and clinical investigation. In this review, we provide the latest clinical evidence for the use of anti-CGRP in migraine prevention with emphasis on efficacy and safety outcomes from Phase III and real-world studies.