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1. On the Blueprint of the Long Primary Afferent Axons and the Dichotomous Axon Trajectory of Clarke’s Nucleus. A Morphological Tracing Study on the Effect of Hypoxia during Development

Author

Frits C. de Beer and Harry W. Steinbusch

Subjects
Clarke’s nucleus, development, DRG neurons, fetal hyposaturation, HRP, injury, Human anatomy, QM1-695
Abstract

The primary afferent system in the rat’s spinal cord starts to develop in the third last week of gestation. First, the pseudounipolar DRG neurons extend their centripetal long primary axons, targeting rostral supra-segmental nuclei in the spinal cord. Meanwhile, the subsequent innervation of the juxta- and intra-segmental spinal levels enables the three subdivisions to commence integrating a complex network with the body periphery. This process may continue to refine and adapt the system life-long. The experimental data elucidated the steps involved in developing the cytoarchitecture by separating the axons of the long and intermediate subdivisions from the short subdivision. Here, we present a blueprint of the features of the long primary afferent axons developing in sequential waves. The pioneering long afferent axons targeted the dorsal gracile nuclei at spring tide and Clarke’s nuclei at neap tide in ventrally bent trajectories. The paradigm’s myelotomy blocked these pioneering fibers from stepping down the developmental cascade, rendering an unknown phenotype. This reflected a hypothetical transition hub stationed on the assembly line, delineating a critical period. The paradigm also affected the neuropil’s ripening independently from the long primary afferent system. The data disclosed that fetal hyposaturation yielded an in vivo genomic engineering capability. Fetal tissue was susceptible to hyposaturation, showing remarkable versatility early in fetal life. The translational impact may favor research into the elusive etiology of clinical syndromes concerning the afferent system relating to fetal hyposaturation.

Published
2023
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2. Ultra-Early and Short-Term Tranexamic Acid Treatment in Patients With Good- and Poor-Grade Aneurysmal Subarachnoid Hemorrhage

Author

Neurologen, Brain, Circulatory Health, Projectafdeling CVZ, Tjerkstra, Maud A., Post, René, Germans, Menno R., Vergouwen, Mervyn D.I., Jellema, Korne, Koot, Radboud W., Kruyt, Nyika D., Wolfs, Jasper F.C., De Beer, Frits C., Kieft, Hans H., Nanda, Dharmin, Van Der Pol, Bram, Roks, Gerwin, De Beer, Frank, Reichman, Loes J.A., Brouwers, Paul J.A.M., Kwa, Vincent I.H., Van Der Ree, Taco C., Bienfait, Henri P., Boogaarts, Hieronymus D., Klijn, Catharina J., Visser, Victoria, van den Berg, René, Coert, Bert A., Horn, Janneke, Majoie, Charles B.L.M., Rinkel, Gabriël J.E., Roos, Yvo B.W.E.M., Vandertop, W. Peter, Verbaan, Dagmar, ULTRA trial study group, Neurologen, Brain, Circulatory Health, Projectafdeling CVZ, Tjerkstra, Maud A., Post, René, Germans, Menno R., Vergouwen, Mervyn D.I., Jellema, Korne, Koot, Radboud W., Kruyt, Nyika D., Wolfs, Jasper F.C., De Beer, Frits C., Kieft, Hans H., Nanda, Dharmin, Van Der Pol, Bram, Roks, Gerwin, De Beer, Frank, Reichman, Loes J.A., Brouwers, Paul J.A.M., Kwa, Vincent I.H., Van Der Ree, Taco C., Bienfait, Henri P., Boogaarts, Hieronymus D., Klijn, Catharina J., Visser, Victoria, van den Berg, René, Coert, Bert A., Horn, Janneke, Majoie, Charles B.L.M., Rinkel, Gabriël J.E., Roos, Yvo B.W.E.M., Vandertop, W. Peter, Verbaan, Dagmar, and ULTRA trial study group

Published
2024

3. Ultra-Early and Short-Term Tranexamic Acid Treatment in Patients With Good- and Poor-Grade Aneurysmal Subarachnoid Hemorrhage

Author

Tjerkstra, Maud A; https://orcid.org/0000-0001-9060-3435, Post, René; https://orcid.org/0000-0001-7844-6262, Germans, Menno R; https://orcid.org/0000-0003-2185-4526, Vergouwen, Mervyn D I; https://orcid.org/0000-0002-6823-1628, Jellema, Korne, Koot, Radboud W, Kruyt, Nyika D; https://orcid.org/0000-0002-2320-0932, Wolfs, Jasper F C, De Beer, Frits C; https://orcid.org/0000-0003-4725-7156, Kieft, Hans H; https://orcid.org/0000-0003-2083-710X, Nanda, Dharmin, Van Der Pol, Bram; https://orcid.org/0000-0001-5173-9989, Roks, Gerwin; https://orcid.org/0000-0002-1393-9848, De Beer, Frank, Reichman, Loes J A, Brouwers, Paul J A M, Kwa, Vincent I H; https://orcid.org/0000-0002-0942-6206, Van Der Ree, Taco C, Bienfait, Henri P; https://orcid.org/0000-0002-5698-0031, Boogaarts, Hieronymus D; https://orcid.org/0000-0001-5855-2447, Klijn, Catharina J; https://orcid.org/0000-0002-8495-4578, Visser, Victoria, van den Berg, René, Coert, Bert A, Horn, Janneke; https://orcid.org/0000-0002-3788-7675, Majoie, Charles B L M; https://orcid.org/0000-0002-7600-9568, Rinkel, Gabriël J E, Roos, Yvo B W E M; https://orcid.org/0000-0001-9205-5882, Vandertop, W Peter; https://orcid.org/0000-0001-5417-0265, Verbaan, Dagmar; https://orcid.org/0000-0002-9212-5470, Tjerkstra, Maud A; https://orcid.org/0000-0001-9060-3435, Post, René; https://orcid.org/0000-0001-7844-6262, Germans, Menno R; https://orcid.org/0000-0003-2185-4526, Vergouwen, Mervyn D I; https://orcid.org/0000-0002-6823-1628, Jellema, Korne, Koot, Radboud W, Kruyt, Nyika D; https://orcid.org/0000-0002-2320-0932, Wolfs, Jasper F C, De Beer, Frits C; https://orcid.org/0000-0003-4725-7156, Kieft, Hans H; https://orcid.org/0000-0003-2083-710X, Nanda, Dharmin, Van Der Pol, Bram; https://orcid.org/0000-0001-5173-9989, Roks, Gerwin; https://orcid.org/0000-0002-1393-9848, De Beer, Frank, Reichman, Loes J A, Brouwers, Paul J A M, Kwa, Vincent I H; https://orcid.org/0000-0002-0942-6206, Van Der Ree, Taco C, Bienfait, Henri P; https://orcid.org/0000-0002-5698-0031, Boogaarts, Hieronymus D; https://orcid.org/0000-0001-5855-2447, Klijn, Catharina J; https://orcid.org/0000-0002-8495-4578, Visser, Victoria, van den Berg, René, Coert, Bert A, Horn, Janneke; https://orcid.org/0000-0002-3788-7675, Majoie, Charles B L M; https://orcid.org/0000-0002-7600-9568, Rinkel, Gabriël J E, Roos, Yvo B W E M; https://orcid.org/0000-0001-9205-5882, Vandertop, W Peter; https://orcid.org/0000-0001-5417-0265, and Verbaan, Dagmar; https://orcid.org/0000-0002-9212-5470

Abstract

The results of the ULTRA trial showed that ultra-early and short-term treatment with tranexamic acid (TXA) does not improve clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). Possibly, the lack of a beneficial effect in all patients with aSAH is masked by antagonistic effects of TXA in certain subgroups. In this post hoc subgroup analysis, we investigated the effect of TXA on clinical outcome in patients with good-grade and poor-grade aSAH.

Published
2024

5. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial

Author

René Post, Menno R Germans, Maud A Tjerkstra, Mervyn D I Vergouwen, Korné Jellema, Radboud W Koot, Nyika D Kruyt, Peter W A Willems, Jasper F C Wolfs, Frits C de Beer, Hans Kieft, Dharmin Nanda, Bram van der Pol, Gerwin Roks, Frank de Beer, Patricia H A Halkes, Loes J A Reichman, Paul J A M Brouwers, Renske M van den Berg-Vos, Vincent I H Kwa, Taco C van der Ree, Irene Bronner, Janneke van de Vlekkert, Henri P Bienfait, Hieronymus D Boogaarts, Catharina J M Klijn, René van den Berg, Bert A Coert, Janneke Horn, Charles B L M Majoie, Gabriël J E Rinkel, Yvo B W E M Roos, W Peter Vandertop, Dagmar Verbaan, Menno R. Germans, Maud A. Tjerkstra, Mervyn D.I. Vergouwen, Radboud W. Koot, Nyika D. Kruyt, Peter W.A. Willems, Jasper F.C. Wolfs, Frits C. de Beer, Patricia H.A. Halkes, Loes J.A. Reichman, Paul J.A.M. Brouwers, Renske M. van den Berg-Vos, Vincent I.H. Kwa, Taco C. van der Ree, Henri P. Bienfait, Hieronymus D. Boogaarts, Catharina J.M. Klijn, Martine van Bilzen, H.J.G. Dieks, Koen de Gans, J.B.M. ten Holter, Jelle R. de Kruijk, Charlie T.J.M. Leijzer, Delmar Molenaar, Robbert J. van Oostenbrugge, Jeske van Pamelen, Fianne H.M. Spaander, Sarah E. Vermeer, J. Manuela Voorend, Bert A. Coert, Charles B.L.M. Majoie, Gabriël J.E. Rinkel, Yvo B.W.E.M. Roos, W. Peter Vandertop, Neurosurgery, Amsterdam Neuroscience - Neurovascular Disorders, Neurology, Radiology and nuclear medicine, VU University medical center, ACS - Atherosclerosis & ischemic syndromes, Graduate School, ANS - Systems & Network Neuroscience, ANS - Neurovascular Disorders, Experimental Vascular Medicine, Radiology and Nuclear Medicine, and ACS - Microcirculation

Subjects
Intention-to-treat analysis, Antifibrinolytic, business.industry, medicine.drug_class, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], General Medicine, Odds ratio, 030204 cardiovascular system & hematology, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], law.invention, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Randomized controlled trial, law, Modified Rankin Scale, Anesthesia, Clinical endpoint, Medicine, 030212 general & internal medicine, Prospective cohort study, business, Tranexamic acid, medicine.drug
Abstract

BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months.METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812.FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups.INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale.FUNDING: Fonds NutsOhra.

Published
2021
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6. Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage Post Hoc Analysis of the ULTRA Trial

Author

Tjerkstra, M., Post, R., Germans, Menno R., Vergouwen, M.D., Jellema, K., Koot, Radboud W., Beer, Frits C. de, Pol, Bram van der, Boogaarts, H.D., Klijn, C.J.M., Peter Vandertop, W., Verbaan, D., Tjerkstra, M., Post, R., Germans, Menno R., Vergouwen, M.D., Jellema, K., Koot, Radboud W., Beer, Frits C. de, Pol, Bram van der, Boogaarts, H.D., Klijn, C.J.M., Peter Vandertop, W., and Verbaan, D.

Abstract

Item does not contain fulltext

Published
2022

7. Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial

Author

Neurologen, Brain, Circulatory Health, Neurochirurgen, Tjerkstra, Maud A, Post, Rene, Germans, Menno R, Vergouwen, Mervyn D I, Jellema, Korné, Koot, Radboud W, Kruyt, Nyika D, Willems, Peter W A, Wolfs, Jasper F C, de Beer, Frits C, Kieft, Hans, Nanda, Dharmin, van der Pol, Bram, Roks, Gerwin, de Beer, Frank, Halkes, Patricia H A, Reichman, Loes J A, Brouwers, Paul J A M, Van den Berg-Vos, Renske M, Kwa, Vincent I H, van der Ree, Taco C, Bronner, Irene, Bienfait, Henri P, Boogaarts, Hieronymus, Klijn, Catharina Jm, van den Berg, René, Coert, Bert A, Horn, Janneke, Majoie, Charles B L M, Rinkel, Gabriël J E, Roos, Yvo B W M, Vandertop, William, Verbaan, Dagmar, Neurologen, Brain, Circulatory Health, Neurochirurgen, Tjerkstra, Maud A, Post, Rene, Germans, Menno R, Vergouwen, Mervyn D I, Jellema, Korné, Koot, Radboud W, Kruyt, Nyika D, Willems, Peter W A, Wolfs, Jasper F C, de Beer, Frits C, Kieft, Hans, Nanda, Dharmin, van der Pol, Bram, Roks, Gerwin, de Beer, Frank, Halkes, Patricia H A, Reichman, Loes J A, Brouwers, Paul J A M, Van den Berg-Vos, Renske M, Kwa, Vincent I H, van der Ree, Taco C, Bronner, Irene, Bienfait, Henri P, Boogaarts, Hieronymus, Klijn, Catharina Jm, van den Berg, René, Coert, Bert A, Horn, Janneke, Majoie, Charles B L M, Rinkel, Gabriël J E, Roos, Yvo B W M, Vandertop, William, and Verbaan, Dagmar

Published
2022

8. Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial

Author

Maud A, Tjerkstra, Rene, Post, Menno R, Germans, Mervyn D I, Vergouwen, Korné, Jellema, Radboud W, Koot, Nyika D, Kruyt, Peter W A, Willems, Jasper F C, Wolfs, Frits C, de Beer, Hans, Kieft, Dharmin, Nanda, Bram, van der Pol, Gerwin, Roks, Frank, de Beer, Patricia H A, Halkes, Loes J A, Reichman, Paul J A M, Brouwers, Renske M, Van den Berg-Vos, Vincent I H, Kwa, Taco C, van der Ree, Irene, Bronner, Henri P, Bienfait, Hieronymus, Boogaarts, Catharina Jm, Klijn, René, van den Berg, Bert A, Coert, Janneke, Horn, Charles B L M, Majoie, Gabriël J E, Rinkel, Yvo B W M, Roos, William, Vandertop, Dagmar, Verbaan, Neurosurgery, Neurology, Radiology and nuclear medicine, Intensive care medicine, VU University medical center, Amsterdam Neuroscience - Neurovascular Disorders, and ACS - Atherosclerosis & ischemic syndromes

Subjects
Neurology (clinical)
Abstract

Background and ObjectivesThe ULTRA trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at 6 months. An expected proportion of the included patients experienced nonaneurysmal subarachnoid hemorrhage. In this post hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at 6 months.MethodsThe ULTRA trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013, and January 20, 2020. After confirmation of subarachnoid hemorrhage on noncontrast CT, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care or usual care only. In this post hoc analysis, we included all ULTRA participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin scale (mRS), dichotomized into good (0–3) and poor (4–6) outcomes.ResultsOf the 813 ULTRA trial patients who experienced an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio [aOR] 0.92; 95% CI 0.69–1.24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0–2) (aOR 0.76; 95% CI 0.57–1.03), all-cause mortality at 30 days (aOR 0.91; 95% CI 0.65–1.28), and all-cause mortality at 6 months (aOR 1.10; 95% CI 0.80–1.52).DiscussionUltra-early and short-term tranexamic acid treatment did not improve clinical outcomes at 6 months in patients with aneurysmal subarachnoid hemorrhage and therefore cannot be recommended.Trial Registration InformationClinicalTrials.gov(NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013).Classification of EvidenceThis study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage.

Published
2021
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9. Dorsal myelotomy in E15-E16 fetal rat: A promising paradigm in regeneration research, with serendipitous transcriptomic effects on development, of the primary afferent system

Author

Frits C. de Beer

Subjects
Dorsum, Neurons, Fetus, Fetal surgery, General Neuroscience, Regeneration (biology), medicine.medical_treatment, Central nervous system, Biology, Axons, Nerve Regeneration, Rats, Transcriptome, Fetal Experimentation, medicine.anatomical_structure, Spinal Cord, Afferent, Ganglia, Spinal, medicine, Animals, Neurons, Afferent, Neuroscience
Abstract

Background Using a multidisciplinary approach in neuroscience has tackled the regeneration enigma in the central nervous system for decades. Reported regeneration potential in mammals is lacking confirmation without a suitable paradigm. In vivo fetal experimentation offers an almost insurmountable drawback, though its feasibility has been shown long ago. New method: Following two former technical papers on fetal surgery, here we present dorsal myelotomy in fetal rat and antegrade HRP-tracing as a suitable paradigm to reveal the intrinsic regenerative program in DRG neurons. Moreover, disclosing the spatio-temporal development of the primary afferent system appeared as an unexpected feature of the design. Conclusion this paper underlines the feasibility that fetal experimentation may offer a new venue for research into the rat transcriptome.

Published
2021

10. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial

Author

Post, R., Germans, Menno R., Tjerkstra, M., Vergouwen, M.D., Jellema, K., Koot, Radboud W., Willems, Peter W.A., Beer, Frits C. de, Boogaarts, H.D., Klijn, C.J.M., Vandertop, W.P., Verbaan, D., Post, R., Germans, Menno R., Tjerkstra, M., Vergouwen, M.D., Jellema, K., Koot, Radboud W., Willems, Peter W.A., Beer, Frits C. de, Boogaarts, H.D., Klijn, C.J.M., Vandertop, W.P., and Verbaan, D.

Abstract

Contains fulltext : 230384.pdf (Publisher’s version ) (Closed access)

Published
2021

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