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1.
Mol Cell Neurosci ; : 103499, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32389805

RESUMO

Platinum-based chemotherapeutics still play an important role in cancer therapy, however, severe side effects, such as painful neuropathy, occur frequently. The pathophysiologic mechanisms depend on the applied chemotherapeutic agent and are still controversial. In addition to neuronal damage, disturbance of glial cell activity may contribute to neurotoxicity. Here, we focused on the effect of oxaliplatin on satellite glial cell (SGC) function and on the activity of the dorsal root ganglion (DRG) neurons. SGCs were isolated as high-purity cultures and treated with 1 and 10 µM oxaliplatin for 2, 4 and 24 h. Subsequently, glial fibrillary acid protein (GFAP), reactive oxygen species (ROS), Connexin-43 (Cx-43), and inward rectifier potassium channel 4.1 (Kir4.1) expression was determined by immunocytochemical staining (ICC) and Western blot analyses. Immunochemical staining and Western blot analysis showed an increase in the immune reactivity (IR) and protein levels of ROS, GFAP, and Cx-43. Furthermore, reduction of the IR and protein levels and current density were demonstrated using patch-clamp measurements, of Kir4.1 channels after oxaliplatin exposure. Cytokine release in SGCs was measured using enzyme-linked immunosorbent assays (ELISA) after oxaliplatin exposure and indicated an increased release of IL-6 and TNFα, while IL-1ß was decreased. The direct influence of SGC-secreted factors in the supernatant after oxaliplatin treatment led to the hyperexcitability of cultured DRG neurons. In summary, oxaliplatin has a direct impact on the modulation and function of different SGC proteins. Furthermore, SGC-released factors influence the excitability of sensory neurons, qualifying SGCs as potential targets for the prevention and treatment of oxaliplatin-induced polyneuropathy.

2.
Stroke ; : STROKEAHA119028012, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32312217

RESUMO

Background and Purpose- Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) were shown to induce neurological recovery after focal cerebral ischemia in rodents and to reverse postischemic lymphopenia in peripheral blood. Since peripheral blood cells, especially polymorphonuclear neutrophils (PMNs), contribute to ischemic brain injury, we analyzed brain leukocyte responses to sEVs and investigated the role of PMNs in sEV-induced neuroprotection. Methods- Male C57Bl6/j mice were exposed to transient intraluminal middle cerebral artery occlusion. After reperfusion, vehicle or sEVs prepared from conditioned media of MSCs raised from bone marrow samples of 3 randomly selected healthy human donors were intravenously administered. sEVs obtained from normoxic and hypoxic MSCs were applied. PMNs were depleted in vehicle and MSC-sEV-treated mice. Neurological deficits, ischemic injury, blood-brain barrier integrity, peripheral blood leukocyte responses, and brain leukocyte infiltration were evaluated over 72 hours. Results- sEV preparations of all 3 donors collected from normoxic MSCs significantly reduced neurological deficits. Preparations of 2 of these donors significantly decreased infarct volume and neuronal injury. sEV-induced neuroprotection was consistently associated with a decreased brain infiltration of leukocytes, namely of PMNs, monocytes/macrophages, and lymphocytes. sEVs obtained from hypoxic MSCs (1% O2) had similar effects on neurological deficits and ischemic injury as MSC-sEVs obtained under regular conditions (21% O2) but also reduced serum IgG extravasation-a marker of blood-brain barrier permeability. PMN depletion mimicked the effects of MSC-sEVs on neurological recovery, ischemic injury, and brain PMN, monocyte, and lymphocyte counts. Combined MSC-sEV administration and PMN depletion did not have any effects superior to PMN depletion in any of the readouts examined. Conclusions- Leukocytes and specifically PMNs contribute to MSC-sEV-induced ischemic neuroprotection. Individual MSC-sEV preparations may differ in their neuroprotective activities. Potency assays are urgently needed to identify their therapeutic efficacy before clinical application.

3.
Clin Sci (Lond) ; 134(9): 1049-1061, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32309850

RESUMO

Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Chronic inflammation and excessive matrix remodelling are considered important in AAA pathogenesis. Kinins are bioactive peptides important in regulating inflammation. Stimulation of the kinin B2 receptor has been previously reported to promote AAA development and rupture in a mouse model. The endogenous B2 receptor agonist, bradykinin, is generated from the kallikrein-kinin system following activation of plasma kallikrein by Factor XII (FXII). In the current study whole-body FXII deletion, or neutralisation of activated FXII (FXIIa), inhibited expansion of the suprarenal aorta (SRA) of apolipoprotein E-deficient mice in response to angiotensin II (AngII) infusion. FXII deficiency or FXIIa neutralisation led to decreased aortic tumor necrosis factor-α-converting enzyme (TACE/a disintegrin and metalloproteinase-17 (aka tumor necrosis factor-α-converting enzyme) (ADAM-17)) activity, plasma kallikrein concentration, and epithelial growth factor receptor (EGFR) phosphorylation compared with controls. FXII deficiency or neutralisation also reduced Akt1 and Erk1/2 phosphorylation and decreased expression and levels of active matrix metalloproteinase (Mmp)-2 and Mmp-9. The findings suggest that FXII, kallikrein, ADAM-17, and EGFR are important molecular mediators by which AngII induces aneurysm in apolipoprotein E-deficient mice. This could be a novel pathway to target in the design of drugs to limit AAA progression.

4.
Lancet Neurol ; 19(4): 317-325, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32199097

RESUMO

BACKGROUND: Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy. METHODS: We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5q spinal muscular atrophy (age 16-65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702). FINDINGS: Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39], p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 [35%] patients), back pain (38 [22%]), and nausea (19 [11%]). No serious adverse events were reported. INTERPRETATION: Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q spinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort. FUNDING: None.

5.
J Neuroimmunol ; 342: 577216, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32199198

RESUMO

Regulatory T cells (Treg) maintain immunological self-tolerance and their functional or numerical deficits are associated with progression of several neurological diseases. We examined the effects of Treg absence on the structure and integrity of the unchallenged murine brain. When compared to control, Treg-deficient FoxP3sf mutant mice showed no differences in brain size, myelin amount and oligodendrocyte numbers. FoxP3sf strain displayed no variations in quantity of neurons and astrocytes, whereas microglia numbers were slightly reduced. We demonstrate lack of neuroinflammation and parenchymal responses in the brains of Treg-deficient mice, suggesting a minor Treg role in absence of blood-brain barrier breakdown.

6.
Eur Radiol ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32179994

RESUMO

OBJECTIVE: Previous studies provided evidence that gadolinium can be found in the aqueous chamber (AC) of the eye several hours post injection (p.i.) of gadolinium-based contrast agents (GBCAs). This study aimed to investigate whether gadolinium can be detected promptly after injection of a macrocyclic GBCA on contrast-enhanced T1-weighted MRI in the AC of children. METHODS: This retrospective study encompassed MRI of 200 healthy eyes of children suffering from retinoblastoma of the contralateral eye. MRI was performed with an orbital coil with the children in a state of general anesthesia. Differences of signal intensity ratios (∆SIRs) of the AC to the lens were determined between pre and post contrast-enhanced T1-weighted images (Dotarem®, Guerbet, 0.1 ml/kg body weight, mean (standard deviation) p.i. time = 12:24 (± 2:31) min). RESULTS: A highly significant signal intensity increase was found in the AC of healthy eyes 12 min after GBCA injection (median ∆SIR (interquartile range) = + 0.08 (0.05-0.12), p < 0.0001). In addition, gadolinium enhancement showed a strong negative correlation with children's age in multivariate analysis with adjustment for p.i. time (p < 0.0001). CONCLUSIONS: GBCA leakage into the AC of healthy infantile eyes was found promptly after injection. The negative correlation between patient age and GBCA enhancement might be explained by a maturation process of the blood-aqueous barrier or Schlemm's canal. Future studies should assess the duration and potential diagnostic applications as well as possible safety concerns of gadolinium presence in the AC. KEY POINTS: • Leakage of gadolinium-based contrast agent into the aqueous chamber of infantile eyes was found promptly after intravenous injection (p < 0.0001). • Gadolinium enhancement of the anterior eye chamber was negatively correlated with the children's age (p < 0.0001).

8.
J Peripher Nerv Syst ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32077159

RESUMO

PHARC syndrome is a rare neurodegenerative disorder caused by mutations in the ABHD12 gene. It is a genetically heterogeneous and clinically variable disease, which is characterized by demyelinating polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa, and early-onset cataract and can easily be misdiagnosed as other neurologic disorders with a similar clinical picture, such as Charcot-Marie-Tooth disease and Refsum disease. We describe the genotype-phenotype correlation of two siblings with a novel genotype underlying PHARC syndrome. The genotype was identified using next-generation sequencing. We examined both patients by means of thorough history taking and clinical examination, nerve conduction studies (NCS), brain imaging, and optical coherence tomography to establish a genotype-phenotype correlation. We identified a novel homozygous point mutation (c.784C > T, p.Arg262*) in the ABHD12 gene. This mutation was detected in both siblings, who had bilateral hearing loss and cataracts, signs of cerebellar ataxia, and neuropathy with a primarily demyelinating pattern in NCS. In one case, retinitis pigmentosa was also evident. As PHARC syndrome is a rare autosomal recessive disorder, our findings highlight the importance of an interdisciplinary diagnostic workup with clinical and molecular genetic testing to avoid a misdiagnosis as Charcot-Marie-Tooth disease or Refsum disease.

9.
Transl Stroke Res ; 11(1): 135-146, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30887279

RESUMO

Malnutrition predisposes to poor stroke outcome. In animal models, undernutrition protected against ischemic injury in some, but not in other studies. In view of diverse stroke models and food restriction paradigms, the consequences of undernutrition are poorly understood. Herein, we exposed mice to energy-reduced and protein-energy-reduced diets for 7-30 days and subsequently induced intraluminal middle cerebral artery occlusion. Undernutrition phase dependently influenced ischemic injury. Short-lasting 7 days of protein-energy undernutrition, but not energy undernutrition, decreased post-ischemic brain leukocyte infiltration and microglial activation and reduced brain Il-1ß mRNA, but did not protect against ischemic injury. Fourteen days of energy and protein-energy undernutrition, on the other hand, reduced ischemic injury despite absence of anti-inflammatory effects. Anti-oxidant genes (Sod-1, Sod-2, and Cat mRNAs) were regulated in the liver and, to a lesser extent, the ischemic brain, indicating an adapted, compensated stage. Conversely, 30 days of energy and protein-energy undernutrition caused progressive animal exhaustion associated with post-ischemic hypoperfusion, rise of metabolic markers (Sirt-1 and Glut-1 mRNAs, Sirt-1 protein) in the ischemic brain, and reregulation of pro- and anti-oxidant markers (now also Nox-4 and Gpx-3 mRNAs) in the liver. In the latter condition, no neuroprotection was noted. Our study suggests an adaptation of metabolic systems that provides neuroprotection in a circumscribed time window.

10.
J Stroke Cerebrovasc Dis ; 29(2): 104515, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31786042

RESUMO

BACKGROUND: Many acute ischemic stroke (AIS) patients present with unknown time of symptom onset (UTO). In these situations, wake-up MRI protocols can guide treatment decisions: patients with DWI (diffusion-weighted imaging) but no fluid-attenuated inversion recovery lesion were shown to benefit from IVT (intravenous thrombolysis). However, initial MRI of some stroke patients is DWI negative, leaving it unclear whether this subgroup profits from IVT. Therefore, we aimed to compare the safety and efficacy of IVT in wake-up AIS patients with or without a DWI lesion in initial imaging. METHODS: We performed a case-control study. All AIS patients with UTO who underwent wake-up MRI and were treated with IVT at a German University Hospital from 2013 to 2017 were included. Patients without (DWI-) were compared to patients with DWI lesion (DWI+) regarding clinico-radiological characteristics, adverse events, and outcome at discharge. Likely stroke mimics were excluded. RESULTS: Eleven DWI- and 32 DWI+ patients were included. There were no statistically significant differences regarding functional scores, age, sex, door-to-needle time, bleeding complications, and death. DWI+ patients more frequently had anterior circulation stroke (P = .049) and higher modified Rankin Scale (mRS) scores at discharge (P = .048). Solely in the DWI+ group 3 bleeding complications (2 asymptomatic hemorrhagic transformations, 1 muscle hematoma) and 3 deaths occurred (P = .29). A favourable outcome (mRS≤ 2) was achieved in 82% of the DWI- and in 58% of the DWI+ group (p > .05). CONCLUSIONS: Our data suggest that IVT may be used in DWI- patients with UTO with acute neurological symptoms very likely to be related to AIS.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Imagem de Difusão por Ressonância Magnética , Fibrinolíticos/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/fisiopatologia , Tomada de Decisão Clínica , Técnicas de Apoio para a Decisão , Avaliação da Deficiência , Feminino , Fibrinolíticos/efeitos adversos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Tempo para o Tratamento , Resultado do Tratamento
11.
J Cancer Res Clin Oncol ; 146(3): 787-792, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31828428

RESUMO

PURPOSE: In the EF-14 trial for newly diagnosed glioblastoma (ndGBM) patients addition of Tumour Treating Fields (TTFields) to temozolomide treatment resulted in a significantly improved overall survival (OS). In the NOA-09/CeTeG trial, combination of lomustine and temozolomide was superior to temozolomide monotherapy in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylated (MGMTm) ndGBM. We evaluated combination of these two treatment modalities in patients with MGMTm ndGBM. There have been so far no data on the combination of these two efficient regimens. METHODS: This bicentric retrospective analysis investigated 16 patients. Parameters evaluated included safety outcome as measured by Common Toxicity Criteria for Adverse Events (CTCAE), clinical outcomes, and compliance to treatment. RESULTS: Hematologic adverse events CTCAE ≥ 3 were observed in seven, hepatotoxic adverse events of CTCAE ≥ 3 in four patients. Mild to moderate skin toxicity was detected in six patients. At data cutoff, patients demonstrated a median progression-free survival (PFS) of 20 months. The usage rate of TTFields showed a high median adherence (83%) to the therapy. CONCLUSIONS: This analysis provides first indication that the combination of TTFields/lomustine/temozolomide is safe and feasible. The observed survival outcomes might suggest potential beneficial effects.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Terapia por Estimulação Elétrica/métodos , Glioblastoma/terapia , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Quimiorradioterapia/métodos , Terapia Combinada , Intervalo Livre de Doença , Terapia por Estimulação Elétrica/mortalidade , Feminino , Glioblastoma/mortalidade , Humanos , Lomustina/administração & dosagem , Masculino , Estudos Retrospectivos , Temozolomida/administração & dosagem
12.
Neurology ; 94(5): e529-e537, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31831598

RESUMO

OBJECTIVE: To determine the role of olfactory function in patients with glioblastoma multiforme (GBM) as a prognostic clinical measure. METHODS: In a prospective case-control study, olfactory testing was performed in 73 patients with primary GBM at baseline during first-line treatment and at later follow-ups. An age-matched control cohort consisted of 49 patients with neurologic diseases, excluding those known to affect olfactory function per se. Depending on the olfactory testing score, patients were allotted to a hyposmia group (HG) or normosmia group (NG). MRI analysis was performed to assess whether tumor location affects olfactory pathways. RESULTS: Patients with GBM had olfactory dysfunction significantly more often compared to the control cohort (p = 0.003). Tumor location could not explain this finding since no relevant difference in MRI-based olfactory pathway involvement was found between HG and NG (p = 0.131). Patients with olfactory dysfunction had significantly worse overall survival (OS) and progression-free survival (PFS) compared to those without dysfunction (median OS 20.9 vs 40.6 months, p = 0.035; median PFS, 9 vs 19 months, p = 0.022). Multivariate analysis in patients without MRI-based involvement of olfactory pathways confirmed olfaction is an independent prognostic factor for OS (hazard ratio [HR] 0.43; p = 0.042) and PFS (HR 0.51; p = 0.049). CONCLUSION: This pilot study provides the first indication that olfactory dysfunction is frequently observed in GBM and may be associated with worse survival outcome in GBM. However, validation of these results in an independent cohort is needed.

13.
Front Neurol ; 10: 1166, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787921

RESUMO

Background: Spinal muscular atrophy (SMA) is a genetic disorder that leads to progressive tetraparesis. Nusinersen is the first approved drug for the treatment of SMA and is administered via intrathecal injections. Neuromyopathic scoliosis and spondylodesis can impede lumbar punctures, thus necessitating the use of radiological imaging. Furthermore, dosimetry of this potentially lifelong therapy should be supervised. Methods: Fluoroscopy-assisted or computed tomography (CT)-guided intrathecal injections of nusinersen were performed in adult patients with SMA type 2 and 3. The mean effective dose was compared in patients with and without spondylodesis as well as in those with SMA type 2 and 3. The dosimetry was analyzed in relation to the motor function evaluated with the Revised Upper Limb module (RULM) score and the Hammersmith Functional Motor Scale-Expanded (HFMSE) score. Results: Fifteen patients with SMA type 2 and 3 underwent radiological imaging-assisted intrathecal injections. The mean effective dose per CT-guided injection per patient was 2.59 (±1.67) mSv (n = 12). The mean dose area product (DAP) per fluoroscopy-guided injection per patient was 200.48 (±323.67) µGym2 (n = 3). With increase in the number of injections, the effective dose (r = -0.23) (p < 0.05) and the DAP (r = -0.09) (p > 0.05) decreased. The mean effective dose in 4 patients without spinal fusion (SMA type 2) was 1.39 (±0.51) mSv, whereas that in 8 patients with spondylodesis (SMA type 2 and 3) was 3.21 (±1.73) mSv. The mean effective dose in 5 SMA type 2 patients with spondylodesis was 2.68 (±1.47) mSv (n = 5) and in 3 SMA type 3 patients was 4.00 (±1.82) mSv. Dosimetry did not show significant correlation with the clinical severity of the disease (RULM score: r = -0.045, p > 0.05 and HFMSE score: r = -0.001, p > 0.05). Conclusions: In SMA type 2 and 3 patients undergoing radiological imaging-assisted injections, the effective dose and DAP decreased during therapy with nusinersen. The mean effective dose in patients with spondylodesis was higher than that in patients without spondylodesis. Dosimetry should be monitored carefully in order to detect and prevent unnecessary radiation exposure.

14.
Fortschr Neurol Psychiatr ; 87(12): 703-710, 2019 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-31847032

RESUMO

With Nusinersen, a first causative treatment for 5q-associated spinal muscular atrophy (SMA) has been available in Europe since 2017. Real-world data from neuromuscular clinical centers in Germany increasingly show a therapeutic benefit of nusinersen also in adult SMA patients of both sexes: in many cases, relevant improvements in or at least a stabilization of motor functions are achieved, potentially leading to enhanced autonomy in activities of daily life and to improved quality of living. Even in patients with severe spinal deformities, intrathecal application is usually feasible and safe using imaging modalities. Regular systematic evaluation of the motor status with validated instruments is crucial for adequate monitoring of the therapeutic effects. The documentation in SMA registries enables systematic development of a database for further development of this novel treatment paradigm. Relevant aspects of this novel therapeutic principle were discussed at an experts conference in Frankfurt / Main in February 2019.


Assuntos
Atrofia Muscular Espinal , Oligonucleotídeos , Adulto , Feminino , Alemanha , Humanos , Masculino , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos/uso terapêutico
15.
Int J Mol Sci ; 20(21)2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31671515

RESUMO

Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.

16.
Front Cell Neurosci ; 13: 412, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572128

RESUMO

ATP-binding cassette (ABC) transporters prevent the access of pharmacological compounds to the ischemic brain, thereby impeding the efficacy of stroke therapies. ABC transporters can be deactivated by selective inhibitors, which potently increase the brain accumulation of drugs. Concerns have been raised that long-term ABC transporter deactivation may promote neuronal degeneration and, under conditions of ischemic stroke, compromise neurological recovery. To elucidate this issue, we exposed male C57BL/6 mice to transient intraluminal middle cerebral artery occlusion (MCAO) and examined the effects of the selective ABCB1 inhibitor tariquidar (8 mg/kg/day) or ABCC1 inhibitor MK-571 (10 mg/kg/day), which were administered alone or in combination with each other over up to 28 days, on neurological recovery and brain injury. Mice were sacrificed after 14, 28, or 56 days. The Clark score, RotaRod, tight rope, and open field tests revealed reproducible motor-coordination deficits in mice exposed to intraluminal MCAO, which were not influenced by ABCB1, ABCC1, or combined ABCB1 and ABCC1 deactivation. Brain volume, striatum volume, and corpus callosum thickness were not altered by ABCB1, ABCC1 or ABCB1, and ABCC1 inhibitors. Similarly, neuronal survival and reactive astrogliosis, evaluated by NeuN and GFAP immunohistochemistry in the ischemic striatum, were unchanged. Iba1 immunohistochemistry revealed no changes of the overall density of activated microglia in the ischemic striatum of ABC transporter inhibitor treated mice, but subtle changes of microglial morphology, that is, reduced microglial cell volume by ABCB1 deactivation after 14 and 28 days and reduced microglial ramification by ABCB1, ABCC1 and combined ABCB1 and ABCC1 deactivation after 56 days. Endogenous neurogenesis, assessed by BrdU incorporation analysis, was not influenced by ABCB1, ABCC1 or combined ABCB1 and ABCC1 deactivation. Taken together, this study could not detect any exacerbation of neurological deficits or brain injury after long-term ABC transporter deactivation in this preclinical stroke model.

17.
BMC Cancer ; 19(1): 995, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646997

RESUMO

BACKGROUND: Leptomeningeal metastasis (LM) is a predominantly late stage, devastating complication of a variety of malignant solid tumors. Diagnosis relies predominantly on neurological, radiographic, and cerebrospinal fluid (CSF) assessments. Recently, liquid biopsy tests derived from CSF has shown to be a feasible, noninvasive promising approach to tumor molecular profiling for proper brain cancer diagnostic treatment, thereby providing an opportunity for CSF-based personalized medicine. However, LM is typically misleadingly assumed to originate from only one primary tumor type. CASE PRESENTATION: In this case report, we provide first evidence of the co-occurrence of LM originating from more than one primary tumor types. DISCUSSION AND CONCLUSIONS: Based on this patient case profile, the co-occurrence of LM from two or more primary tumor types should be accounted for when deriving diagnostic conclusions from liquid biopsy tests.


Assuntos
Adenocarcinoma de Pulmão/secundário , Neoplasias Pulmonares/patologia , Melanoma/secundário , Neoplasias Meníngeas/secundário , Adenocarcinoma de Pulmão/líquido cefalorraquidiano , Adenocarcinoma de Pulmão/terapia , Idoso , Evolução Fatal , Feminino , Humanos , Biópsia Líquida , Neoplasias Pulmonares/terapia , Melanoma/líquido cefalorraquidiano , Melanoma/terapia , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/terapia
18.
Stroke ; 50(11): 3238-3245, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31551038

RESUMO

Background and Purpose- Ischemic stroke is one of the leading causes of disability and death. The principal goal of acute stroke treatment is the recanalization of the occluded cerebral arteries, which is, however, only effective in a very narrow time window. Therefore, neuroprotective treatments that can be combined with recanalization strategies are needed. Calcium overload is one of the major triggers of neuronal cell death. We have previously shown that capacitative Ca2+ entry, which is triggered by the depletion of intracellular calcium stores, contributes to ischemia-induced calcium influx in neurons, but the responsible Ca2+ channel is not known. Methods- Here, we have generated mice lacking the calcium channel subunit Orai2 and analyzed them in experimental stroke. Results- Orai2-deficient mice were protected from ischemic neuronal death both during acute ischemia under vessel occlusion and during ischemia/reperfusion upon successful recanalization. Calcium signals induced by calcium store depletion or oxygen/glucose deprivation were significantly diminished in Orai2-deficient neurons demonstrating that Orai2 is a central mediator of neuronal capacitative Ca2+ entry and is involved in calcium overload during ischemia. Conclusions- Our experimental data identify Orai2 as an attractive target for pharmaceutical intervention in acute stroke.

19.
Nervenarzt ; 90(10): 995-1004, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31560112

RESUMO

Over the past decade innovations regarding antithrombotic treatment for secondary stroke prevention have been particularly dominated by the non-vitamin K dependent anticoagulants in patients with cardioembolic stroke; however, several studies investigating other important aspects have also recently been published. This update focuses on new trials on intensified antiplatelet therapy in the early phase of (mild) stroke and transient ischemic attacks (TIA) as well as studies on secondary prevention in patients with embolic stroke of undetermined source (ESUS). Data from these studies are critically reviewed to demonstrate strategies for clinical implementation.


Assuntos
Isquemia Encefálica , Ataque Isquêmico Transitório , Acidente Vascular Cerebral , Anticoagulantes/uso terapêutico , Isquemia Encefálica/prevenção & controle , Fibrinolíticos/uso terapêutico , Humanos , Ataque Isquêmico Transitório/prevenção & controle , Inibidores da Agregação de Plaquetas/uso terapêutico , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controle
20.
BMC Geriatr ; 19(1): 221, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412787

RESUMO

BACKGROUND: Hospitals are in need of valid and economic screening and assessment tools that help identifying older patients at risk for complications which require intensified support during their hospital stay. METHODS: Five hundred forty-seven internal medicine in-patients (mean age 78.14 ± 5.96 years; 54.7% males) prospectively received Identification of Seniors at Risk (ISAR) screening. If screening results were positive (ISAR score ≥ 2), a comprehensive geriatric assessment (CGA) was performed. We explored sensitivity and specificity of different ISAR and CGA cutoffs. Further, we analyzed the risk of falls and how patients got discharged from hospital. RESULTS: ISAR+/CGA abnormal patients spent more days in hospital (16.1 ± 14.5), received more nursing hours per day (3.0 ± 2.3), more hours of physiotherapy during their hospital stay (2.2 ± 3.2), and had more falls (10.1%) compared to ISAR+/CGA normal (10.9 ± 12.3, 2.0 ± 1.2, 1.2 ± 4.3, and 2.8%, respectively, all p ≤ 0.016) and ISAR- (9.6 ± 11.5, 2.3 ± 4.5, 0.7 ± 2.0, and 2.2%, respectively, all p ≤ 0.002) patients. ISAR+/CGA abnormal patients terminated their treatment regularly with being discharged back home less often (59.6%) compared to ISAR+/CGA normal (78.5%, p = 0.002) and ISAR- (78.2%, p = 0.056) patients. ISAR cutoff≥2 and CGA defined as abnormal in case of impairment of ADL plus another CGA domain achieved best sensitivity/specificity. CONCLUSIONS: Abnormal geriatric risk screening and assessment are associated with longer hospital stay and higher amount of nursing and physiotherapy during hospital stay, greater risk of falling, and a lower percentage of successfully terminated treatment in older in-patients.

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