Publications by authors named "Sebastian Thilemann"

12 Publications

  • Page 1 of 1

Small vessel disease is associated with an unfavourable outcome in stroke patients on oral anticoagulation.

Eur Stroke J 2020 Mar 12;5(1):63-72. Epub 2019 Nov 12.

Department of Neurology and Stroke Center, University Hospital and University of Basel, Switzerland.

Introduction: Cerebral small vessel disease is an important cause for both ischaemic stroke and intracranial haemorrhage. To date, knowledge on the impact of small vessel disease on the clinical course in stroke patients treated with oral anticoagulation for atrial fibrillation is limited.

Patients And Methods: Registry-based prospective observational study of 320 patients (aged 78.2 ± 9.2 years) treated with anticoagulation following atrial fibrillation stroke. Patients underwent standardised magnetic-resonance-imaging assessing measures of small vessel disease, including cerebral microbleeds and white matter hyperintensities. Median follow-up was 754 (interquartile range = [708-828]) days. Using adjusted logistic and Cox regression, we assessed the association of imaging measures with clinical outcome including recurrent ischaemic stroke, intracranial haemorrhage and death and assessed disability (modified Rankin Scale).

Results: Overall, recurrent ischaemic stroke was more common than intracranial haemorrhage (22 versus 8, respectively). Cerebral microbleeds were related to an increased risk of the composite endpoint (ischaemic stroke, intracranial haemorrhage, death: odds ratio (OR) 2.05, 95% confidence interval (CI) 1.27-3.31;  = 0.003), as were white matter hyperintensities (OR 2.00, 95%CI 1.23-3.27,  = 0.005). This was also true in time-to-event analysis (cerebral microbleeds: HR 2.31, 95%CI 1.39-3.52;  < 0.001; white matter hyperintensities: HR 1.99, 95%CI 1.20-3.17;  = 0.007). Both measures were associated with an increased risk for recurrent ischaemic stroke (cerebral microbleeds: HR 4.42, 95%CI 1.07-18.20;  = 0.04; white matter hyperintensities: HR 5.27, 95%CI 1.08-25.79,  = 0.04) and intracranial haemorrhage (cerebral microbleeds: HR 2.43, 95%CI 1.04-5.69;  = 0.04; white matter hyperintensities: HR 2.57, 95%CI 1.11-5.98,  = 0.03). Furthermore, confluent white matter hyperintensities were associated with increased disability (OR 4.03; 95%CI 2.16-7.52;  < 0.001) and mortality (HR 1.81, 95%CI 1.04-3.14,  = 0.04).

Discussion And Conclusion: In atrial fibrillation stroke patients treated with oral anticoagulation, small vessel disease is associated with an unfavourable outcome. The presence of microbleeds indicated a risk higher for recurrent ischaemic stroke than for intracranial haemorrhage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2396987319888016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092732PMC
March 2020

Outcome of endovascular therapy in stroke with large vessel occlusion and mild symptoms.

Neurology 2019 10 7;93(17):e1618-e1626. Epub 2019 Oct 7.

From the Stroke Center (C.M., G.D., G.B., C.S., A.C., C.W.C.), Neurocenter of Southern Switzerland, Lugano; Stroke Center and Neurology Service (S.N., P.M., C.W.C.), Department of Clinical Neurosciences, Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois); Department of Neurology (M.H., S.J., M.A., U.F.) and Institute of Diagnostic and Interventional Neuroradiology (A.C., J.K.), Institute of Diagnostic, Interventional and Pediatric Radiology, and Department of Neurology, University Hospital Bern and University of Bern, Inselspital; Department of Neurology and Stroke Center (M.M., S.T., H.G., L.H.B.), University Hospital of Basel; Stroke Center (E.C.), Service de Neurologie, HUG, Geneva; Department of Neurology (T.K., K.N.), Cantonal Hospital Aarau; Stroke Center (A.L.), Department of Neurology, University Hospital of Zürich; and Stroke Center (G.K.), Department of Neurology, Cantonal Hospital, St. Gallen, Switzerland.

Objective: To compare outcomes after endovascular therapy (EVT) and IV thrombolysis (IVT) in patients with stroke with emergent large vessel occlusion (LVO) and mild neurologic deficits.

Methods: This was a retrospective analysis of patients from the Swiss Stroke Registry with admission NIH Stroke Scale score ≤5 and LVO treated by EVT (± IVT) vs IVT alone. The primary endpoint was favorable functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months. Secondary outcomes were independence (mRS score 0-2), mRS score (ordinal shift analysis), and survival with high disability (mRS score 4-5). Safety endpoints were mortality and symptomatic hemorrhage.

Results: Of 11,356 patients, 312 met the criteria and propensity score method matched 108 in each group. A comparably large proportion of patients with EVT and IVT had favorable outcome (63% vs 65.7% respectively; odds ratio 0.94, 95% confidence interval 0.51-1.72; = 0.840). Patients with EVT showed a nonsignificant trend toward higher mRS score at 3 months ( = 0.717), while the proportion of surviving patients with high disability was comparably very low in both groups ( = 0.419). Mortality was slightly higher among those with EVT (9.3% vs 2.8%; = 0.06), and symptomatic intracranial hemorrhage was a rare event in both groups (2.8% vs 0%; = 0.997).

Conclusions: In acute ischemic stroke, EVT and IVT appear similarly effective in achieving favorable outcome at 3 months for patients with LVO and mild neurologic symptoms. EVT might be marginally inferior to IVT regarding outcome across all levels of disability and mortality. Further studies are required to determine whether certain subgroups of patients with LVO and mild symptoms benefit from EVT.

Classification Of Evidence: This study provides Class III evidence that patients with LVO and mild symptoms receiving either EVT or IVT had similar favorable functional outcomes at 3 months.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008362DOI Listing
October 2019

Reasons for Prehospital Delay in Acute Ischemic Stroke.

J Am Heart Assoc 2019 10 2;8(20):e013101. Epub 2019 Oct 2.

Department of Neurology University Hospital Basel Basel Switzerland.

Background Prehospital delay reduces the proportion of patients with stroke treated with recanalization therapies. We aimed to identify novel and modifiable risk factors for prehospital delay. Methods and Results We included patients with an ischemic stroke confirmed by diffusion-weighted magnetic resonance imaging, symptom onset within 24 hours and hospitalized in the Stroke Center of the University Hospital Basel, Switzerland. Trained study nurses interviewed patients and proxies along a standardized questionnaire. Prehospital delay was defined as >4.5 hours between stroke onset-or time point of wake-up-and admission. Overall, 336 patients were enrolled. Prehospital delay was observed in 140 patients (42%). The first healthcare professionals to be alarmed were family doctors for 29% of patients (97/336), and a quarter of these patients had a baseline National Institute of Health Stroke Scale score of 4 or higher. The main modifiable risk factor for prehospital delay was a face-to-face visit to the family doctor (adjusted odds ratio, 4.19; 95% CI, 1.85-9.46). Despite transport by emergency medical services being associated with less prehospital delay (adjusted odds ratio, 0.41; 95% CI, 0.24-0.71), a minority of patients (39%) who first called their family doctor were transported by emergency medical services to the hospital. The second risk factor was lack of awareness of stroke symptoms (adjusted odds ratio, 4.14; 95% CI, 2.36-7.24). Conclusions Almost 1 in 3 patients with a diffusion-weighted magnetic resonance imaging-confirmed ischemic stroke first called the family doctor practice. Face-to-face visits to the family doctor quadrupled the odds of prehospital delay. Efforts to reduce prehospital delay should address family doctors and their staffs as important partners in the prehospital pathway. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02798770.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.119.013101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818040PMC
October 2019

Intravenous thrombolysis for suspected ischemic stroke with seizure at onset.

Ann Neurol 2019 11 9;86(5):770-779. Epub 2019 Sep 9.

Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.

Objective: Seizure at onset (SaO) has been considered a relative contraindication for intravenous thrombolysis (IVT) in patients with acute ischemic stroke, although this appraisal is not evidence based. Here, we investigated the prognostic significance of SaO in patients treated with IVT for suspected ischemic stroke.

Methods: In this multicenter, IVT-registry-based study we assessed the association between SaO and symptomatic intracranial hemorrhage (sICH, European Cooperative Acute Stroke Study II definition), 3-month mortality, and 3-month functional outcome on the modified Rankin Scale (mRS) using unadjusted and adjusted logistic regression, coarsened exact matching, and inverse probability weighted analyses.

Results: Among 10,074 IVT-treated patients, 146 (1.5%) had SaO. SaO patients had significantly higher National Institutes of Health Stroke Scale score and glucose on admission, and more often female sex, prior stroke, and prior functional dependence than non-SaO patients. In unadjusted analysis, they had generally less favorable outcomes. After controlling for confounders in adjusted, matched, and weighted analyses, all associations between SaO and any of the outcomes disappeared, including sICH (odds ratio [OR] = 1.53 [95% confidence interval (CI) = 0.74-3.14], OR = 0.52 [95% CI = 0.13-2.16], OR = 0.68 [95% CI = 0.15-3.03], OR = 0.95 [95% CI = 0.39-2.32]), mortality (OR = 1.49 [95% CI = 1.00-2.24], OR = 0.98 [95% CI = 0.5-1.92], OR = 1.13 [95% CI = 0.55-2.33], OR = 1.17 [95% CI = 0.73-1.88]), and functional outcome (mRS ≥ 3/ordinal mRS: OR = 1.33 [95% CI = 0.96-1.84]/1.35 [95% CI = 1.01-1.81], OR = 0.78 [95% CI = 0.45-1.32]/0.78 [95% CI = 0.52-1.16], OR = 0.75 [95% CI = 0.43-1.32]/0.45 [95% CI = 0.10-2.06], OR = 0.87 [95% CI = 0.57-1.34]/1.00 [95% CI = 0.66-1.52]). These results were consistent regardless of whether patients had an eventual diagnosis of ischemic stroke (89/146) or stroke mimic (57/146 SaO patients).

Interpretation: SaO was not an independent predictor of poor prognosis. Withholding IVT from patients with assumed ischemic stroke presenting with SaO seems unjustified. ANN NEUROL 2019;86:770-779.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25582DOI Listing
November 2019

Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation.

Ann Neurol 2019 06 30;85(6):823-834. Epub 2019 Apr 30.

Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy.

Objective: We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia.

Methods: We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (<3 months before starting oral anticoagulation) and a minimum follow-up of 3 months. We analyzed the association between type of anticoagulation (DOAC versus VKA) with the composite primary endpoint (recurrent ischemic stroke [AIS], intracerebral hemorrhage [ICH], or mortality) using mixed-effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs).

Results: We included 4,912 patients (median age, 78 years [interquartile range {IQR}, 71-84]; 2,331 [47.5%] women; median National Institute of Health Stroke Severity Scale at onset, 5 [IQR, 2-12]); 2,256 (45.9%) patients received VKAs and 2,656 (54.1%) DOACs. Median time from index event to starting oral anticoagulation was 5 days (IQR, 2-14) for VKAs and 5 days (IQR, 2-11) for DOACs (p = 0.53). There were 262 acute ischemic strokes (AISs; 4.4%/year), 71 intracranial hemorrrhages (ICHs; 1.2%/year), and 439 deaths (7.4%/year) during the total follow-up of 5,970 patient-years. Compared to VKAs, DOAC treatment was associated with reduced risks of the composite endpoint (HR, 0.82; 95% CI, 0.67-1.00; p = 0.05) and ICH (HR, 0.42; 95% CI, 0.24-0.71; p < 0.01); we found no differences for the risk of recurrent AIS (HR, 0.91; 95% CI, 0.70-1.19; p = 0.5) and mortality (HR, 0.83; 95% CI, 0.68-1.03; p = 0.09).

Interpretation: DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly attributed to lower risks of ICH. ANN NEUROL 2019;85:823-834.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563449PMC
June 2019

Development and Validation of a Prognostic Model of Swallowing Recovery and Enteral Tube Feeding After Ischemic Stroke.

JAMA Neurol 2019 05;76(5):561-570

Department of Neurology, Kantonsspital St Gallen, St Gallen, Switzerland.

Importance: Predicting the duration of poststroke dysphagia is important to guide therapeutic decisions. Guidelines recommend nasogastric tube (NGT) feeding if swallowing impairment persists for 7 days or longer and percutaneous endoscopic gastrostomy (PEG) placement if dysphagia does not recover within 30 days, but, to our knowledge, a systematic prediction method does not exist.

Objective: To develop and validate a prognostic model predicting swallowing recovery and the need for enteral tube feeding.

Design, Setting, And Participants: We enrolled participants with consecutive admissions for acute ischemic stroke and initially severe dysphagia in a prospective single-center derivation (2011-2014) and a multicenter validation (July 2015-March 2018) cohort study in 5 tertiary stroke referral centers in Switzerland.

Exposures: Severely impaired oral intake at admission (Functional Oral Intake Scale score <5).

Main Outcomes And Measures: Recovery of oral intake (primary end point, Functional Oral Intake Scale ≥5) or return to prestroke diet (secondary end point) measured 7 (indication for NGT feeding) and 30 (indication for PEG feeding) days after stroke.

Results: In total, 279 participants (131 women [47.0%]; median age, 77 years [interquartile range, 67-84 years]) were enrolled (153 [54.8%] in the derivation study; 126 [45.2%] in the validation cohort). Overall, 64% (95% CI, 59-71) participants failed to recover functional oral intake within 7 days and 30% (95% CI, 24-37) within 30 days. Prolonged swallowing recovery was independently associated with poor outcomes after stroke. The final prognostic model, the Predictive Swallowing Score, included 5 variables: age, stroke severity on admission, lesion location, initial risk of aspiration, and initial impairment of oral intake. Predictive Swallowing Score prediction estimates ranged from 5% (score, 0) to 96% (score, 10) for a persistent impairment of oral intake on day 7 and from 2% to 62% on day 30. Model performance in the validation cohort showed a discrimination (C statistic) of 0.84 (95% CI, 0.76-0.91; P < .001) for predicting the recovery of oral intake on day 7 and 0.77 (95% CI, 0.67-0.87; P < .001) on day 30, and a discrimination for a return to prestroke diet of 0.94 (day 7; 95% CI, 0.87-1.00; P < .001) and 0.71 (day 30; 95% CI, 0.61-0.82; P < .001). Calibration plots showed high agreement between the predicted and observed outcomes.

Conclusions And Relevance: The Predictive Swallowing Score, available as a smartphone application, is an easily applied prognostic instrument that reliably predicts swallowing recovery. It will support decision making for NGT or PEG insertion after ischemic stroke and is a step toward personalized medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2018.4858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515605PMC
May 2019

Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage.

Ann Neurol 2018 03 3;83(3):451-459. Epub 2018 Mar 3.

Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

Objective: Information about rivaroxaban plasma level (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban.

Methods: In a multicenter registry-based study (Novel Oral Anticoagulants in Stroke Patients collaboration; ClinicalTrials.gov: NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS patients had RivLev ≤ 100ng/ml, indicating possible eligibility for thrombolysis, and how many ICH patients had RivLev ≥ 75ng/ml, making them possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation, regression models) and studied the sensitivity and specificity of international normalized ratio (INR) thresholds to substitute RivLev using cross tables and receiver operating characteristic curves.

Results: Among 241 patients (median age = 80 years, interquartile range [IQR] = 73-84; median time from onset to admission = 2 hours, IQR = 1-4.5 hours; median RivLev = 89ng/ml, IQR = 31-194), 190 had AIS and 51 had ICH. RivLev was similar in AIS patients (82ng/ml, IQR = 30-202) and ICH patients (102ng/ml, IQR = 51-165; p = 0.24). Trough RivLev occurred in 126/190 (66.3%) AIS and 34/51 (66.7%) ICH patients. Among AIS patients, 108/190 (56.8%) had RivLev ≤ 100ng/ml. In ICH patients, 33/51 (64.7%) had RivLev ≥ 75ng/ml. RivLev was associated with rivaroxaban dosage, and inversely with renal function and time since last intake (each p < 0.05). INR ≤ 1.0 had a specificity of 98.9% and a sensitivity of 25.7% to predict RivLev ≤ 100ng/ml. INR ≥ 1.4 had a sensitivity of 59.3% and specificity of 90.1% to predict RivLev ≥ 75ng/ml.

Interpretation: RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under rivaroxaban had a RivLev low enough to consider thrombolysis. In ICH patients, two-thirds had a RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR thresholds perform poorly to inform treatment decisions in individual patients. Ann Neurol 2018;83:451-459.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25165DOI Listing
March 2018

Intravenous Thrombolysis in Patients with Stroke Taking Rivaroxaban Using Drug Specific Plasma Levels: Experience with a Standard Operation Procedure in Clinical Practice.

J Stroke 2017 09 6;19(3):347-355. Epub 2017 Sep 6.

Stroke Center and Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.

Background And Purpose: Standard operating procedures (SOP) incorporating plasma levels of rivaroxaban might be helpful in selecting patients with acute ischemic stroke taking rivaroxaban suitable for IVthrombolysis (IVT) or endovascular treatment (EVT).

Methods: This was a single-center explorative analysis using data from the Novel-Oral-Anticoagulants-in-Stroke-Patients-registry (clinicaltrials.gov:NCT02353585) including acute stroke patients taking rivaroxaban (September 2012 to November 2016). The SOP included recommendation, consideration, and avoidance of IVT if rivaroxaban plasma levels were <20 ng/mL, 20‒100 ng/mL, and >100 ng/mL, respectively, measured with a calibrated anti-factor Xa assay. Patients with intracranial artery occlusion were recommended IVT+EVT or EVT alone if plasma levels were ≤100 ng/mL or >100 ng/mL, respectively. We evaluated the frequency of IVT/EVT, door-to-needle-time (DNT), and symptomatic intracranial or major extracranial hemorrhage.

Results: Among 114 acute stroke patients taking rivaroxaban, 68 were otherwise eligible for IVT/EVT of whom 63 had plasma levels measured (median age 81 years, median baseline National Institutes of Health Stroke Scale 6). Median rivaroxaban plasma level was 96 ng/mL (inter quartile range [IQR] 18‒259 ng/mL) and time since last intake 11 hours (IQR 4.5‒18.5 hours). Twenty-two patients (35%) received IVT/EVT (IVT n=15, IVT+EVT n=3, EVT n=4) based on SOP. Median DNT was 37 (IQR 30‒60) minutes. None of the 31 patients with plasma levels >100 ng/mL received IVT. Among 14 patients with plasma levels ≤100 ng/mL, the main reason to withhold IVT was minor stroke (n=10). No symptomatic intracranial or major extracranial bleeding occurred after treatment.

Conclusions: Determination of rivaroxaban plasma levels enabled IVT or EVT in one-third of patients taking rivaroxaban who would otherwise be ineligible for acute treatment. The absence of major bleeding in our pilot series justifies future studies of this approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5853/jos.2017.00395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647628PMC
September 2017

Oligodendrocyte ablation triggers central pain independently of innate or adaptive immune responses in mice.

Nat Commun 2014 Dec 1;5:5472. Epub 2014 Dec 1.

Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.

Mechanisms underlying central neuropathic pain are poorly understood. Although glial dysfunction has been functionally linked with neuropathic pain, very little is known about modulation of pain by oligodendrocytes. Here we report that genetic ablation of oligodendrocytes rapidly triggers a pattern of sensory changes that closely resemble central neuropathic pain, which are manifest before overt demyelination. Primary oligodendrocyte loss is not associated with autoreactive T- and B-cell infiltration in the spinal cord and neither activation of microglia nor reactive astrogliosis contribute functionally to central pain evoked by ablation of oligodendrocytes. Instead, light and electron microscopic analyses reveal axonal pathology in the spinal dorsal horn and spinothalamic tract concurrent with the induction and maintenance of nociceptive hypersensitivity. These data reveal a role for oligodendrocytes in modulating pain and suggest that perturbation of oligodendrocyte functions that maintain axonal integrity can lead to central neuropathic pain independent of immune contributions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms6472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268702PMC
December 2014

Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication.

PLoS Biol 2013 Jul 9;11(7):e1001604. Epub 2013 Jul 9.

Department of Molecular Cell Biology, University of Mainz, Mainz, Germany.

Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca²⁺ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pbio.1001604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706306PMC
July 2013

Increased basic fibroblast growth factor release and proliferation in xenotransplanted squamous cell carcinoma after combined irradiation/anti-vascular endothelial growth factor treatment.

Oncol Rep 2012 May 26;27(5):1573-9. Epub 2012 Jan 26.

Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Novel strategies of cancer therapy combine irradiation and anti-angiogenic active compounds. However, little is known concerning the undesired cellular and molecular effects caused by this novel treatment concept. We used a mouse squamous cell carcinoma (SCC) xenotransplantation model to evaluate the potential undesired effects which compromise the success of this therapeutic combination. SCCs were subcutanously implanted in nude mice. Animals were treated with a fractionated irradiation scheme (5x4 Gy) alone or in combination with daily injections of anti-vascular endothelial growth factor (VEGF) antibodies. Controls remained untreated. Before and after treatment, resonance imaging (MRI), ultrasound and near-infrared spectrometry were used to evaluate tumor vessel integrity. Finally, tumors were explanted and VEGF, basic fibroblast growth factor (bFGF), vessel density, proliferation and apoptotic activity were analyzed by immunohistochemistry. Irradiation caused VEGF release and we found evidence for VEGF-mediated vessel protection. In the tumors derived from the combined treatment, blood volume was decreased, and apoptotic indices were increased. Remarkably, bFGF levels and proliferative indices were also increased. Combined irradiation/anti-VEGF treatment resulted in the desired VEGF depletion and increased tumor cell apoptosis. Nonetheless, bFGF and proliferation also increased, possibly suggesting a compensatory response. The application of additional targeted drugs may help develop more effective SCC treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/or.2012.1654DOI Listing
May 2012

Demyelination and axonal preservation in a transgenic mouse model of Pelizaeus-Merzbacher disease.

EMBO Mol Med 2010 Feb;2(2):42-50

Institute of Comparative Medicine, University of Glasgow, Scotland, UK.

It is widely thought that demyelination contributes to the degeneration of axons and, in combination with acute inflammatory injury, is responsible for progressive axonal loss and persistent clinical disability in inflammatory demyelinating disease. In this study we sought to characterize the relationship between demyelination, inflammation and axonal transport changes using a Plp1-transgenic mouse model of Pelizaeus-Merzbacher disease. In the optic pathway of this non-immune mediated model of demyelination, myelin loss progresses from the optic nerve head towards the brain, over a period of months. Axonal transport is functionally perturbed at sites associated with local inflammation and 'damaged' myelin. Surprisingly, where demyelination is complete, naked axons appear well preserved despite a significant reduction of axonal transport. Our results suggest that neuroinflammation and/or oligodendrocyte dysfunction are more deleterious for axonal health than demyelination per se, at least in the short term.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/emmm.200900057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377270PMC
February 2010