Publications by authors named "Ricardo Soares-Dos-Reis"

14 Publications

  • Page 1 of 1

Cerebral Venous Thrombosis after BNT162b2 mRNA SARS-CoV-2 vaccine.

J Stroke Cerebrovasc Dis 2021 May 25;30(8):105906. Epub 2021 May 25.

Department of Neurology, Centro Hospitalar Universitário de São João, E.P.E., Porto, Portugal; Clinical Neurosciences and Mental Health Department, Faculty of Medicine of the University of Porto, Portugal.

The development of SARS-CoV-2 vaccines has raised several concerns regarding venous thromboembolism, namely cerebral venous thrombosis. Although cerebral venous thrombosis has been reported after administration of a viral vector vaccine, due to a possible auto-immune mechanism inducing thrombocytopenia, the same has not happened in mRNA vaccines. We report two cases of cerebral venous thrombosis, shortly after administration of mRNA vaccine. In both patients, there was no evidence of thrombocytopenia or antiplatelet antibodies, and alternative causes for cerebral venous thrombosis were found. As such, despite the temporal relation of both cases to vaccine administration, these types of cerebral venous thrombosis do not seem to be pathophysiological different from cerebral venous thrombosis not associated to SARS-CoV-2 vaccination. Continuous pharmacovigilance is necessary to monitor possible new events and clarify this association.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105906DOI Listing
May 2021

State of the Art and Future Challenges in Multiple Sclerosis Research and Medical Management: An Insight into the 5th International Porto Congress of Multiple Sclerosis.

Neurol Ther 2020 Dec 14;9(2):281-300. Epub 2020 Jul 14.

Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.

The 5th International Porto Congress of Multiple Sclerosis took place between the 14th and 16th of February 2019 in Porto, Portugal. Its intensive programme covered a wide-range of themes-including many of the hot topics, challenges, pitfalls and yet unmet needs in the field of multiple sclerosis (MS)-led by a number of well-acknowledged world experts. This meeting review summarizes the talks that took place during the congress, which focussed on issues in MS as diverse as the development and challenges of progressive MS, epidemiology, differential diagnosis, medical management, molecular research and imaging tools.
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http://dx.doi.org/10.1007/s40120-020-00202-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606370PMC
December 2020

Intensive Blood Pressure Treatment Reduced Stroke Risk in Patients With Albuminuria in the SPRINT Trial.

Stroke 2019 12 22;50(12):3639-3642. Epub 2019 Oct 22.

Renal Division, Department of Medicine, Brigham and Women's Hospital; and Harvard Medical School (F.R.M.C.).

Background and Purpose- Albuminuria is associated with stroke risk among individuals with diabetes. However, the association of albuminuria with incident stroke among nondiabetic patients is less clear. Methods- We performed a post hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial), which examined the effect of higher versus lower intensity blood pressure management on mortality in 8913 participants without diabetes. We fit unadjusted and adjusted Cox proportional hazards models to estimate the association of baseline albuminuria (urinary albumin-to-creatinine ratio ≥30 mg/g versus<30 mg/g) with stroke risk. We also assessed effect modification according to treatment arms. Results- Mean age was 68±9 years, 35% were female, and 30% were black. Median follow-up was 3.2 years, and 19% patients had baseline albuminuria. Incident stroke occurred in 129 individuals during follow-up. Albuminuria was associated with increased stroke risk (unadjusted hazard ratio, 2.24; 95% CI, 1.55-3.23; adjusted hazard ratio 1.73; 95% CI, 1.17-2.56). The association of albuminuria with incident stroke differed according to the randomized treatment arm ( interaction=0.03). In the intensive treatment arm, the association of albuminuria and stroke was nonsignificant (unadjusted hazard ratio, 1.25; 95% CI, 0.69-2.28), whereas, in the standard treatment arm, it was significant (unadjusted hazard ratio, 3.44; 95% CI, 2.11-5.61). Conclusions- In a post hoc analysis of SPRINT, baseline albuminuria (versus not) was associated with a higher risk of incident stroke, but this relationship appeared to be restricted to those in the standard treatment arm. Further studies are required to conclusively determine if reduction of albuminuria in itself is beneficial in reducing stroke risk. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.
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http://dx.doi.org/10.1161/STROKEAHA.119.026316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878195PMC
December 2019

Cautious Interpretation of Observational Data.

JAMA Neurol 2019 Oct 14. Epub 2019 Oct 14.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, England.

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http://dx.doi.org/10.1001/jamaneurol.2019.3456DOI Listing
October 2019

Automated and objective measures of gait dynamics in camptocormia Parkinson's Disease subthalamic deep brain stimulation.

Clin Neurol Neurosurg 2019 Nov 26;186:105537. Epub 2019 Sep 26.

Department of Neurology, Centro Hospitalar Universitário de São João, Porto, Portugal; Department of Neurosurgery, Centro Hospitalar Universitário de São João, Porto, Portugal.

Objective: Axial motor features are common in Parkinson's disease (PD). These include gait impairment and postural abnormalities, such as camptocormia. The response of these symptoms to deep brain stimulation (DBS) is variable and difficult to assess objectively. For the first time, this study analyzes the treatment outcomes of two PD patients with camptocormia that underwent bilateral subthalamic nucleus (STN)-DBS evaluated with disruptive technologies.

Patients And Methods: Two patients with PD and camptocormia who underwent STN-DBS were included. Gait parameters were quantitatively assessed before and after surgery by using the NeuroKinect system and the camptocormia angle was measured using the camptoapp.

Results: After surgery, patient 1 improved 29 points in the UPDRS-III. His camptocormia angle was 68° before and 38° after surgery. Arm and knee angular amplitudes (117.32 ± 7.47 vs 134.77 ± 2.70°; 144.51 ± 7.47 vs 169.08 ± 3.27°) and arm swing (3.59 ± 2.66 vs 5.40 ± 1.76 cm) improved when compared with his preoperative measurements. Patient 2 improved 22 points in the UPDRS-III after surgery. Her camptocormia mostly resolved (47° before to 9° after surgery). Gait analysis revealed improvement of stride length (0.29 ± 0.03 vs 0.35 ± 0.03 m), stride width (18.25 ± 1.16 vs 17.9 ± 0.84 cm), step velocity (0.91 ± 0.57 vs 1.33 ± 0.48 m/s), arm swing (4.51 ± 1.01 vs 7.38 ± 2.71 cm) and arm and hip angular amplitudes (131.57 ± 2.45° vs 137.75 ± 3.18; 100.51 ± 1.56 vs 102.18 ± 1.77°) compared with her preoperative results.

Conclusion: The gait parameters and camptocormia of both patients objectively improved after surgery, as assessed by the two quantitative measurement systems. STN-DBS might have a beneficial effect on controlling axial posturing and gait, being a potential surgical treatment for camptocormia in patients with PD. However, further studies are needed to derive adequate selection criteria for this patient population.
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http://dx.doi.org/10.1016/j.clineuro.2019.105537DOI Listing
November 2019

Intraoperative microelectrode recording in Parkinson's disease subthalamic deep brain stimulation: Analysis of clinical utility.

J Clin Neurosci 2019 Nov 12;69:104-108. Epub 2019 Aug 12.

Department of Clinical Neurosciences and Mental Health, Faculty of Medicine University of Porto, Porto, Portugal; Movement Disorders and Functional Surgery Unit, Centro Hospitalar Universitário de São João, Porto, Portugal; Department of Neurology, Centro Hospitalar Universitário de São João, Porto, Portugal. Electronic address:

This retrospective study aims to explore the clinical utility of microelectrode recording (MER) during subthalamic deep brain stimulation (DBS) surgery in patients with Parkinson's disease (PD). We analyzed the data from 103 PD patients, who consecutively received bilateral subthalamic nucleus (STN) DBS at an experienced academic medical center. We collected demographic, clinical, and DBS related data, including intraoperative microelectrode recording data, electrode positioning, and clinical effects provided by intraoperative microstimulation. The 2 brain sides were independently analyzed and are described as first and second side (to be operated on); the first side is contralateral to motor symptoms onset. Patients were mostly men (64.1%). In both sides of the brain, percentage of agreement with the electrode final position was higher with clinical results than with intraoperative microelectrode recordings (98% vs 57% on the first implantation side, and 97% vs 58% on the second implantation side, respectively). Regarding electrode final implantation depth, 86% of electrodes were implanted between 0 mm and +2 mm in relation to anatomical target, and 95% of electrodes were implanted from -2 mm to +2 mm. Our study suggests that MER might not be necessary to achieve good clinical outcomes in PD patients undergoing STN DBS. These results support and inform the design of future prospective controlled research studies.
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http://dx.doi.org/10.1016/j.jocn.2019.08.021DOI Listing
November 2019

Brody disease: when myotonia is not myotonia.

Pract Neurol 2019 Oct 17;19(5):417-419. Epub 2019 Apr 17.

Neurology Department, Centro Hospitalar Universitário de São João, Porto, Portugal.

A 56-year-old man presented with painless impairment of muscle relaxation on vigorous contraction (eg, eyelid closure, hand grip, running). There were no episodes of paralysis, symptom progression, weakness or extramuscular symptoms. Five of his fifteen siblings had similar complaints. His serum creatine kinase was normal. Electromyography showed electrical silence on muscle relaxation, without myotonic discharges. , and genetic testing was normal, but he had a homozygous pathogenic variant of (c.1315G>A; pGlu439Lys). Brody disease is a rare autosomal recessive myopathy due to mutations that reduce sarcoplasmic reticulum calcium-ATPase1 activity, hence delaying muscle relaxation.
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http://dx.doi.org/10.1136/practneurol-2019-002224DOI Listing
October 2019

Electrochemical Immunosensor for TNFα-Mediated Inflammatory Disease Screening.

ACS Chem Neurosci 2019 06 18;10(6):2676-2682. Epub 2019 Apr 18.

International Iberian Nanotechnology Laboratory , Braga 4715-330 , Portugal.

Inflammation associated with cancer, neurodegenerative, ocular, and autoimmune diseases has a considerable impact on public health. Tumor necrosis factor alpha (TNFα) is a key mediator of inflammatory responses, responsible for many of the systemic manifestations during the inflammatory process. Thus, inhibition of TNFα is a commonplace practice in the treatment of these disorders. Successful therapy requires the ability to determine the appropriate dose of anti-TNFα drugs to be administered in a timely manner, based on circulating TNFα levels. In this Letter, we report the development of an immunosensor technology able to quantify TNFα at the picogram level in relevant human body fluids, holding the potential to early detect inflammation  and monitor TNFα levels during treatment, enabling TNFα-targeted treatments to be tailored according to the immune status of an individual patient. This immunosensor technology is significantly more rapid and sensitive than conventional enzyme linked immunosorbent assays, maintaining high specificity and requiring small sample volumes. These features might also be advantageous in the context of personalized medicine, as this analytical platform can deliver advanced diagnostics and reduce clinical burden.
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http://dx.doi.org/10.1021/acschemneuro.9b00036DOI Listing
June 2019

MicroRNA-155 Amplifies Nitric Oxide/cGMP Signaling and Impairs Vascular Angiotensin II Reactivity in Septic Shock.

Crit Care Med 2018 09;46(9):e945-e954

Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal.

Objectives: Septic shock is a life-threatening clinical situation associated with acute myocardial and vascular dysfunction, whose pathophysiology is still poorly understood. Herein, we investigated microRNA-155-dependent mechanisms of myocardial and vascular dysfunction in septic shock.

Design: Prospective, randomized controlled experimental murine study and clinical cohort analysis.

Setting: University research laboratory and ICU at a tertiary-care center.

Patients: Septic patients, ICU controls, and healthy controls. Postmortem myocardial samples from septic and nonseptic patients. Ex vivo evaluation of arterial rings from patients undergoing coronary artery bypass grafting.

Subjects: C57Bl/6J and genetic background-matched microRNA-155 knockout mice.

Interventions: Two mouse models of septic shock were used. Genetic deletion and pharmacologic inhibition of microRNA-155 were performed. Ex vivo myographic studies were performed using mouse and human arterial rings.

Measurements And Main Results: We identified microRNA-155 as a highly up-regulated multifunctional mediator of sepsis-associated cardiovascular dysfunction. In humans, plasma and myocardial microRNA-155 levels correlate with sepsis-related mortality and cardiac injury, respectively, whereas in murine models, microRNA-155 deletion and pharmacologic inhibition attenuate sepsis-associated cardiovascular dysfunction and mortality. MicroRNA-155 up-regulation in septic myocardium was found to be mostly supported by microvascular endothelial cells. This promoted myocardial microvascular permeability and edema, bioenergetic deterioration, contractile dysfunction, proinflammatory, and nitric oxide-cGMP-protein kinase G signaling overactivation. In isolate cardiac microvascular endothelial cells, microRNA-155 up-regulation significantly contributes to LPS-induced proinflammatory cytokine up-regulation, leukocyte adhesion, and nitric oxide overproduction. Furthermore, we identified direct targeting of CD47 by microRNA-155 as a novel mechanism of myocardial and vascular contractile depression in sepsis, promoting microvascular endothelial cell and vascular insensitivity to thrombospondin-1-mediated inhibition of nitric oxide production and nitric oxide-mediated vasorelaxation, respectively. Additionally, microRNA-155 directly targets angiotensin type 1 receptor, decreasing vascular angiotensin II reactivity. Deletion of microRNA-155 restored angiotensin II and thrombospondin-1 vascular reactivity in LPS-exposed arterial rings.

Conclusions: Our study demonstrates multiple new microRNA-155-mediated mechanisms of sepsis-associated cardiovascular dysfunction, supporting the translational potential of microRNA-155 inhibition in human septic shock.
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http://dx.doi.org/10.1097/CCM.0000000000003296DOI Listing
September 2018

Emerging Biosensing Technologies for Neuroinflammatory and Neurodegenerative Disease Diagnostics.

Front Mol Neurosci 2018 16;11:164. Epub 2018 May 16.

International Iberian Nanotechnology Laboratory, Braga, Portugal.

Neuroinflammation plays a critical role in the onset and progression of many neurological disorders, including Multiple Sclerosis, Alzheimer's and Parkinson's diseases. In these clinical conditions the underlying neuroinflammatory processes are significantly heterogeneous. Nevertheless, a common link is the chronic activation of innate immune responses and imbalanced secretion of pro and anti-inflammatory mediators. In light of this, the discovery of robust biomarkers is crucial for screening, early diagnosis, and monitoring of neurological diseases. However, the difficulty to investigate biochemical processes directly in the central nervous system (CNS) is challenging. In recent years, biomarkers of CNS inflammatory responses have been identified in different body fluids, such as blood, cerebrospinal fluid, and tears. In addition, progress in micro and nanotechnology has enabled the development of biosensing platforms capable of detecting in real-time, multiple biomarkers in clinically relevant samples. Biosensing technologies are approaching maturity where they will become deployed in community settings, at which point screening programs and personalized medicine will become a reality. In this multidisciplinary review, our goal is to highlight both clinical and recent technological advances toward the development of multiplex-based solutions for effective neuroinflammatory and neurodegenerative disease diagnostics and monitoring.
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http://dx.doi.org/10.3389/fnmol.2018.00164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964192PMC
May 2018

Ocular neuromyotonia.

Pract Neurol 2018 Oct 21;18(5):389-390. Epub 2018 Feb 21.

Neurology Department, Coimbra University Hospital Centre, Coimbra, Portugal.

Ocular neuromyotonia is a rare, albeit treatable, ocular motor disorder, characterised by recurrent brief episodes of diplopia due to tonic extraocular muscle contraction. Ephaptic transmission in a chronically damaged ocular motor nerve is the possible underlying mechanism. It usually improves with carbamazepine. A 53-year-old woman presented with a 4-month history of recurrent episodes of binocular vertical diplopia (up to 40/day), either spontaneously or after sustained downward gaze. Between episodes she had a mild left fourth nerve palsy. Sustained downward gaze consistently triggered downward left eye tonic deviation, lasting around 1 min. MR scan of the brain was normal. She improved on starting carbamazepine but developed a rash that necessitated stopping the drug. Switching to lacosamide controlled her symptoms.
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http://dx.doi.org/10.1136/practneurol-2017-001866DOI Listing
October 2018

A role for prolyl isomerase PIN1 in the phosphorylation-dependent modulation of PRRXL1 function.

Biochem J 2017 02 20;474(5):683-697. Epub 2017 Feb 20.

Departamento de Biomedicina, Unidade de Biologia Experimental, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.

encodes for a paired-like homeodomain transcription factor essential for the correct establishment of the dorsal root ganglion - spinal cord nociceptive circuitry during development. -null mice display gross anatomical disruption of this circuitry, which translates to a markedly diminished sensitivity to noxious stimuli. Here, by the use of an immunoprecipitation and mass spectrometry approach, we identify five highly conserved phosphorylation sites (T110, S119, S231, S233 and S251) in PRRXL1 primary structure. Four are phospho-S/T-P sites, which suggest a role for the prolyl isomerase PIN1 in regulating PRRXL1. Accordingly, PRRXL1 physically interacts with PIN1 and displays diminished transcriptional activity in a -null cell line. Additionally, these S/T-P sites seem to be important for PRRXL1 conformation, and their point mutation to alanine or aspartate down-regulates PRRXL1 transcriptional activity. Altogether, our findings provide evidence for a putative novel role of PIN1 in the development of the nociceptive system and indicate phosphorylation-mediated conformational changes as a mechanism for regulating the PRRXL1 role in the process.
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http://dx.doi.org/10.1042/BCJ20160560DOI Listing
February 2017

Dual role of Tlx3 as modulator of Prrxl1 transcription and phosphorylation.

Biochim Biophys Acta 2014 Nov 17;1839(11):1121-31. Epub 2014 Aug 17.

Departamento de Biologia Experimental, Faculdade de Medicina, Universidade do Porto Porto, 4200-319, Portugal; Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4150, Portugal. Electronic address:

The proper establishment of the dorsal root ganglion/spinal cord nociceptive circuitry depends on a group of homeodomain transcription factors that includes Prrxl1, Brn3a and Tlx3. By the use of epistatic analysis, it was suggested that Tlx3 and Brn3a, which highly co-localize with Prrxl1 in these tissues, are required to maintain Prrxl1 expression. Here, we report two Tlx3-dependent transcriptional mechanisms acting on Prrxl1 alternative promoters, referred to as P3 and P1/P2 promoters. We demonstrate that (i) Tlx3 induces the transcriptional activity of the TATA-containing promoter P3 by directly binding to a bipartite DNA motif and (ii) it synergistically interacts with Prrxl1 by indirectly activating the Prrxl1 TATA-less promoters P1/P2 via the action of Brn3a. The Tlx3 N-terminal domain 1-38 was shown to have a major role on the overall Tlx3 transcriptional activity and the C-terminus domain (amino acids 256-291) to mediate the Tlx3 effect on promoters P1/P2. On the other hand, the 76-111 domain was shown to decrease Tlx3 activity on the TATA-promoter P3. In addition to its action on Prrxl1 alternative promoters, Tlx3 proved to have the ability to induce Prrxl1 phosphorylation. The Tlx3 domain responsible for Prrxl1 hyperphosphorylation was mapped and encompasses amino acid residues 76 to 111. Altogether, our results suggest that Tlx3 uses distinct mechanisms to tightly modulate Prrxl1 activity, either by controlling its transcriptional levels or by increasing Prrxl1 phosphorylation state.
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http://dx.doi.org/10.1016/j.bbagrm.2014.08.007DOI Listing
November 2014

Ser¹¹⁹ phosphorylation modulates the activity and conformation of PRRXL1, a homeodomain transcription factor.

Biochem J 2014 May;459(3):441-53

‡Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.

PRRXL1 [paired related homeobox-like 1; also known as DRG11 (dorsal root ganglia 11)] is a paired-like homeodomain transcription factor expressed in DRG and dSC (dorsal spinal cord) nociceptive neurons. PRRXL1 is crucial for the establishment and maintenance of nociceptive circuitry, as Prrxl1(-/-) mice present neuronal loss, reduced pain sensitivity and failure to thrive. In the present study, we show that PRRXL1 is highly phosphorylated in vivo, and that its multiple band pattern on electrophoretic analysis is the result of different phosphorylation states. PRRXL1 phosphorylation appears to be differentially regulated along the dSC and DRG development and it is mapped to two functional domains. One region comprises amino acids 107-143, whereas the other one encompasses amino acids 227-263 and displays repressor activity. Using an immunoprecipitation-MS approach, two phosphorylation sites were identified, Ser¹¹⁹ and Ser²³⁸. Phosphorylation at Ser¹¹⁹ is shown to be determinant for PRRXL1 conformation and transcriptional activity. Ser¹¹⁹ phosphorylation is thus proposed as a mechanism for regulating PRRXL1 function and conformation during nociceptive system development.
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http://dx.doi.org/10.1042/BJ20131014DOI Listing
May 2014