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1.
J Neurol Neurosurg Psychiatry ; 94(11): 924-933, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37433662

RESUMO

BACKGROUND: Neurodegeneration in multiple sclerosis (MS) affects the visual system but dynamics and pathomechanisms over several years especially in primary progressive MS (PPMS) are not fully understood. METHODS: We assessed longitudinal changes in visual function, retinal neurodegeneration using optical coherence tomography, MRI and serum NfL (sNfL) levels in a prospective PPMS cohort and matched healthy controls. We investigated the changes over time, correlations between outcomes and with loss of visual function. RESULTS: We followed 81 patients with PPMS (mean disease duration 5.9 years) over 2.7 years on average. Retinal nerve fibre layer thickness (RNFL) was reduced in comparison with controls (90.1 vs 97.8 µm; p<0.001). Visual function quantified by the area under the log contrast sensitivity function (AULCSF) remained stable over a continuous loss of RNFL (0.46 µm/year, 95% CI 0.10 to 0.82; p=0.015) up until a mean turning point of 91 µm from which the AULCSF deteriorated. Intereye RNFL asymmetry above 6 µm, suggestive of subclinical optic neuritis, occurred in 15 patients and was related to lower AULCSF but occurred also in 5 out of 44 controls. Patients with an AULCSF progression had a faster increase in Expanded Disability Status Scale (beta=0.17/year, p=0.043). sNfL levels were elevated in patients (12.2 pg/mL vs 8.0 pg/mL, p<0.001), but remained stable during follow-up (beta=-0.14 pg/mL/year, p=0.291) and were not associated with other outcomes. CONCLUSION: Whereas neurodegeneration in the anterior visual system is already present at onset, visual function is not impaired until a certain turning point. sNfL is not correlated with structural or functional impairment in the visual system.


Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Neurite Óptica , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Células Ganglionares da Retina , Fibras Nervosas , Estudos Prospectivos , Tomografia de Coerência Óptica/métodos
2.
Thorac Cardiovasc Surg ; 69(7): 649-659, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31030422

RESUMO

BACKGROUND: Scientific attempts to create the "ideal" small diameter vascular graft have been compared with the "search of the holy grail." Prosthetic material as expanded polytetrafluoroethylene or Dacron shows acceptable patency rates to large caliber vessels, while small diameter (< 6 mm) prosthetic conduits present unacceptably poor patency rates. Vascular tissue engineering represents a promising option to address this problem. MATERIAL AND METHODS: Thirty-two female Texel-sheep aged 6 months to 2 years underwent surgical common carotid artery (CCA) interposition using different tissue-engineered vascular substitutes. Explantation of the grafts was performed 12 (n = 12) and 36 (n = 20) weeks after surgery. Ultrasound was performed on postoperative day 1 and thereafter every 4 weeks to evaluate the graft patency. RESULTS: The average length of implanted substitutes was 10.3 ± 2.2 cm. Anesthesia and surgical procedure could be performed without major surgical complications in all cases.The grafts showed a systolic blood flow velocity (BFV) of 28.24 ± 13.5 cm/s, a diastolic BFV of 9.25 ± 4.53 cm/s, and a mean BFV of 17.85 ± 9.25 cm/s. Native vessels did not differ relevantly in hemodynamic measurements (systolic: 29.77 cm/s; diastolic: 7.99 cm/s ± 5.35; mean 15.87 ± 10.75). There was no incidence of neurologic complications or subsequent postoperative occlusion. Perioperative morbidity was low and implantation of conduits was generally well tolerated. CONCLUSION: This article aims to give a precise overview of in vivo experiments in sheep for the evaluation of small diameter vascular grafts performing CCA interposition, especially with regard to pitfalls and possible perioperative complications and to discuss advantages and disadvantages of this approach.


Assuntos
Implante de Prótese Vascular , Prótese Vascular , Animais , Implante de Prótese Vascular/efeitos adversos , Feminino , Oclusão de Enxerto Vascular , Politetrafluoretileno , Ovinos , Resultado do Tratamento , Grau de Desobstrução Vascular
3.
J Immunol ; 200(3): 974-982, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29298833

RESUMO

Multiple sclerosis (MS) is a T cell-driven inflammatory disease of the CNS. Research on T cell subsets involved in MS pathogenesis has mainly focused on classical CD4+ T cells, especially Th17 cells, as they produce the proinflammatory, MS-associated cytokine IL-17. However, the abundant unconventional mucosal-associated invariant T (MAIT) cells are also able to produce IL-17. MAIT cells are characterized by high CD161 expression and a semi-invariant Vα7.2 TCR, with which they recognize bacterial and yeast Ags derived from the riboflavin (vitamin B2) metabolism. In this study, we characterized MAIT cells from the peripheral blood of MS patients in comparison with healthy individuals with respect to their type-17 differentiation. We found a specific increase of IL-17+ MAIT cells as well as an increased expression of retinoic acid-related orphan receptor (ROR)γt and CCR6 in MAIT cells from MS patients, whereas the expression of T cell activation markers HLA-DR and CD38 was not different. IL-17 production by MAIT cells furthermore correlated with the surface expression level of the IL-7 receptor α-chain (CD127), which was significantly increased on MAIT cells from MS patients in comparison with healthy individuals. In summary, our findings indicate an augmented type-17 differentiation of MAIT cells in MS patients associated with their IL-7 receptor surface expression, implicating a proinflammatory role of these unconventional T cells in MS immunopathology.


Assuntos
Sistema Nervoso Central/patologia , Interleucina-17/biossíntese , Subunidade alfa de Receptor de Interleucina-7/biossíntese , Células T Invariantes Associadas à Mucosa/imunologia , Esclerose Múltipla/patologia , ADP-Ribosil Ciclase 1/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Sistema Nervoso Central/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Interferon gama/biossíntese , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/metabolismo , Células T Invariantes Associadas à Mucosa/metabolismo , Esclerose Múltipla/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/biossíntese , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossíntese , Receptores de Antígenos de Linfócitos T/imunologia , Receptores CCR6/biossíntese , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/imunologia , Proteínas Supressoras de Tumor/metabolismo
4.
J Vasc Surg ; 68(6S): 177S-187S.e1, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29248244

RESUMO

OBJECTIVE: Despite the clinical success of large-diameter vascular grafts, synthetic grafts in small-diameter vessels are of limited use because of their poor patency rates. Previous experiments of our group provided evidence for good biocompatibility of bacterial nanocellulose (BNC) as a small-vessel graft in the carotid artery in sheep. However, the patency rate of our first-generation tubes after 3 months was only 50%. To advance our concept, we now used modified second-generation tubes with diminished wall thickness and a smoother inner surface to reduce the thrombogenic potential. The aim was to investigate mechanical characteristics of modified second-generation BNC tubes, to evaluate in vivo performance and biocompatibility, and to analyze patency rates. METHODS: We replaced the right carotid artery of 23 sheep with second-generation BNC tubes. Compared with our first-generation tubes, tubes were modified with different surface properties and diminished wall thickness (inner diameter, 4.0-5.0 mm; wall thickness, 1.0-2.5 mm; length, 100 mm) to generate a smoother inner surface with reduced thrombogenic potential and a more porous outer zone, allowing easier cell immigration. RESULTS: At the end of the investigational period, BNC tubes were explanted and grafts were processed for histopathologic analysis. Histologic analysis revealed no acute signs of foreign body reaction such as immigration of giant cells or other acute inflammatory reaction and therefore provided evidence for good biocompatibility of the second-generation tubes. However, all grafts of the sheep without antiplatelet therapy were occluded after 9 months, whereas grafts in sheep receiving dual platelet inhibition showed a patency rate of 67% (six of nine grafts). Further modified grafts revealed a patency rate of 80% (four of five grafts remained open). CONCLUSIONS: Patency rates of the second-generation tubes could be substantially improved compared with our first-generation tubes. However, poor patency rates of tissue-engineered blood vessels still limit their use in clinical studies. Further efforts in terms of in vitro and in vivo studies are essential to improve grafts of BNC.


Assuntos
Materiais Biocompatíveis , Implante de Prótese Vascular/instrumentação , Prótese Vascular , Artérias Carótidas/cirurgia , Celulose/química , Nanopartículas , Polissacarídeos Bacterianos/química , Grau de Desobstrução Vascular , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Artérias Carótidas/fisiopatologia , Oclusão de Enxerto Vascular/patologia , Oclusão de Enxerto Vascular/fisiopatologia , Oclusão de Enxerto Vascular/prevenção & controle , Teste de Materiais , Modelos Animais , Inibidores da Agregação Plaquetária/farmacologia , Porosidade , Desenho de Prótese , Falha de Prótese , Carneiro Doméstico , Propriedades de Superfície , Trombose/patologia , Trombose/fisiopatologia , Trombose/prevenção & controle , Fatores de Tempo , Grau de Desobstrução Vascular/efeitos dos fármacos
5.
J Neurol Neurosurg Psychiatry ; 89(4): 330-338, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29248894

RESUMO

OBJECTIVE: To investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period. RESULTS: The SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75-3.38) to 0.50 (IQR 0.00-1.13; difference -0.625, 95% CI -1.25 to -0.50; P<0.0001) at months 5-8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections. Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug. INTERPRETATION: The oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial. CLINICAL TRIAL REGISTRATION: NCT01450124; Results.


Assuntos
Franquincenso/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Administração Oral , Adulto , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Projetos Piloto , Extratos Vegetais/uso terapêutico , Resultado do Tratamento
6.
Brain ; 138(Pt 11): 3263-74, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26359290

RESUMO

Recent association studies have linked numerous genetic variants with an increased risk for multiple sclerosis, although their functional relevance remains largely unknown. Here we investigated phenotypical and functional consequences of a genetic variant in the CD226 gene that, among other autoimmune diseases, predisposes to multiple sclerosis. Phenotypically, effector and regulatory CD4(+) memory T cells of healthy individuals carrying the predisposing CD226 genetic variant showed, in comparison to carriers of the protective variant, reduced surface expression of CD226 and an impaired induction of CD226 after stimulation. This haplotype-dependent reduction in CD226 expression on memory T cells was abrogated in patients with multiple sclerosis, as CD226 expression was comparable to healthy risk haplotype carriers irrespective of genetic variant. Functionally, FOXP3-positive regulatory T cells from healthy carriers of the genetic protective variant showed superior suppressive capacity, which was again abrogated in multiple sclerosis patients. Mimicking the phenotype of human CD226 genetic risk variant carriers, regulatory T cells derived from Cd226-deficient mice showed similarly reduced inhibitory activity, eventually resulting in an exacerbated disease course of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. Therefore, by combining human and mouse analyses we show that CD226 exhibits an important role in the activation of regulatory T cells, with its genetically imposed dysregulation impairing regulatory T cell function.


Assuntos
Antígenos de Diferenciação de Linfócitos T/genética , Esclerose Múltipla/genética , RNA Mensageiro/metabolismo , Linfócitos T Reguladores/imunologia , Adulto , Animais , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Encefalomielite Autoimune Experimental/genética , Feminino , Fatores de Transcrição Forkhead/metabolismo , Predisposição Genética para Doença , Haplótipos , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Linfócitos T Reguladores/metabolismo
7.
Med ; 5(6): 550-558.e2, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38554710

RESUMO

BACKGROUND: Progressive multiple sclerosis (MS) is characterized by compartmentalized smoldering neuroinflammation caused by the proliferation of immune cells residing in the central nervous system (CNS), including B cells. Although inflammatory activity can be prevented by immunomodulatory therapies during early disease, such therapies typically fail to halt disease progression. CD19 chimeric antigen receptor (CAR)-T cell therapies have revolutionized the field of hematologic malignancies. Although generally considered efficacious, serious adverse events associated with CAR-T cell therapies such as immune effector cell-associated neurotoxicity syndrome (ICANS) have been observed. Successful use of CD19 CAR-T cells in rheumatic diseases like systemic lupus erythematosus and neuroimmunological diseases like myasthenia gravis have recently been observed, suggesting possible application in other autoimmune diseases. METHODS: Here, we report the first individual treatment with a fully human CD19 CAR-T cell therapy (KYV-101) in two patients with progressive MS. FINDINGS: CD19 CAR-T cell administration resulted in acceptable safety profiles for both patients. No ICANS was observed despite detection of CD19 CAR-T cells in the cerebrospinal fluid. In case 1, intrathecal antibody production in the cerebrospinal fluid decreased notably after CAR-T cell infusion and was sustained through day 64. CONCLUSIONS: CD19 CAR-T cell administration in progressive MS resulted in an acceptable safety profile. CAR-T cell presence and expansion were observed in the cerebrospinal fluid without clinical signs of neurotoxicity, which, along with intrathecal antibody reduction, indicates expansion-dependent effects of CAR-T cells on CD19+ target cells in the CNS. Larger clinical studies assessing CD19 CAR-T cells in MS are warranted. FUNDING: Both individual treatments as well the generated data were not based on external funding.


Assuntos
Antígenos CD19 , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Antígenos CD19/imunologia , Receptores de Antígenos Quiméricos/imunologia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Feminino , Adulto , Pessoa de Meia-Idade , Masculino , Esclerose Múltipla/terapia , Esclerose Múltipla/imunologia
8.
Mult Scler Relat Disord ; 82: 105414, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38176284

RESUMO

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) exhibits promising results for multiple sclerosis (MS) in the short term. We investigated the long-term outcome differences in disease progression and cognitive impairment after aHSCT and alemtuzumab treatment. METHODS: 20 patients receiving aHSCT and 21 patients treated with alemtuzumab between 2007 and 2020 were included in this monocentric observational cohort study. The primary objective was to compare the outcome of both groups with regards to achieving No Evidence of Disease Activity (NEDA-3), defined by the absence of relapses, EDSS progression, and MRI activity. Secondary endpoints in the study included the assessment of neurocognitive functioning, quality of life (QoL), Multiple Sclerosis Functional Composite (MSFC), and EDSS improvement. RESULTS: Baseline characteristics between both groups were comparable, except for a longer disease duration in the alemtuzumab group of 11.3 years compared to 5.4 years in aHSCT-treated patients (p = 0.002) and a longer mean follow-up time in the aHSCT cohort of 9.0 (range 2.8-15.7) years compared to 5.9 years (range 0.9-9.2) in alemtuzumab patients. NEDA-3 was more frequently observed in the aHSCT group with 75.0 % and 55.0 % at five and 10 years, respectively, than in the alemtuzumab group with only 40.0 % at five years (p = 0.012). Relapse free survival was higher in the aHSCT group (p < 0.001). None of the aHSCT-treated patients showed new T2-lesions six months after therapy initiation until the end of the observational period in contrast to 35.0 % of the alemtuzumab-treated patients showing new T2-lesions (95 %CI 14.2-98.9, p = 0.002). aHSCT-treated patients showed significantly improved cognitive performance in five out of 12 cognitive tests whereas alemtuzumab treated patients deteriorated in four out of 12 tests. Quality of life remained on a constant level for up to 10 years in patients receiving aHSCT with improved scores for the subscale fatigue (p = 0.013). CONCLUSION: aHSCT seems to be superior to alemtuzumab in maintaining long-term NEDA-3 status, improving cognition and stabilizing quality of life for up to 10 years.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla/tratamento farmacológico , Alemtuzumab/efeitos adversos , Qualidade de Vida , Resultado do Tratamento , Transplante de Células-Tronco Hematopoéticas/métodos , Cognição , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico
9.
Parasitol Res ; 109(3): 627-35, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21424403

RESUMO

Both eosinophil chemotactic factor (ECF) and neutrophil chemotactic factor (NCF) activities were demonstrated in excretory/secretory (ES) products and homogenates of Haemonchus contortus and Teladorsagia circumcincta larvae and adult worms in a modified checkerboard assay using a micro-chemotaxis chamber. Neutrophil chemotaxis was seen in 28 of 35 experiments and eosinophil chemotaxis in 20 of 38 experiments. Chemokinetic activity for neutrophils and eosinophils (accounting for 40-50% of total cell migration) was also apparent in only three parasite products for each cell type. Significant NCF activity was present in six of seven adult worm ES products (three of four from T. circumcincta and in all three from H. contortus) and ECF activity in four of five adult ES products, whereas fewer L3 incubates, particularly of T. circumcincta, contained chemotactic activity. All parasite homogenates, with one exception for ECF, were chemotactic for both neutrophils and eosinophils. The sequential use of cellulose ultrafiltration membranes of decreasing pore size did not identify precisely the molecular weight of the NCF and ECF but indicated that the active chemicals were greater than 10 kDa and probably greater than 30 kDa.


Assuntos
Abomaso/parasitologia , Fatores Quimiotáticos/análise , Eosinófilos/imunologia , Neutrófilos/imunologia , Trichostrongyloidea/química , Animais , Ensaios de Migração de Leucócitos , Fatores Quimiotáticos/química , Fatores Quimiotáticos/imunologia , Peso Molecular , Ovinos , Trichostrongyloidea/imunologia
10.
Front Hum Neurosci ; 12: 226, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29915533

RESUMO

Primary progressive multiple sclerosis (PPMS) shows a highly variable disease progression with poor prognosis and a characteristic accumulation of disabilities in patients. These hallmarks of PPMS make it difficult to diagnose and currently impossible to efficiently treat. This study aimed to identify plasma metabolite profiles that allow diagnosis of PPMS and its differentiation from the relapsing-remitting subtype (RRMS), primary neurodegenerative disease (Parkinson's disease, PD), and healthy controls (HCs) and that significantly change during the disease course and could serve as surrogate markers of multiple sclerosis (MS)-associated neurodegeneration over time. We applied untargeted high-resolution metabolomics to plasma samples to identify PPMS-specific signatures, validated our findings in independent sex- and age-matched PPMS and HC cohorts and built discriminatory models by partial least square discriminant analysis (PLS-DA). This signature was compared to sex- and age-matched RRMS patients, to patients with PD and HC. Finally, we investigated these metabolites in a longitudinal cohort of PPMS patients over a 24-month period. PLS-DA yielded predictive models for classification along with a set of 20 PPMS-specific informative metabolite markers. These metabolites suggest disease-specific alterations in glycerophospholipid and linoleic acid pathways. Notably, the glycerophospholipid LysoPC(20:0) significantly decreased during the observation period. These findings show potential for diagnosis and disease course monitoring, and might serve as biomarkers to assess treatment efficacy in future clinical trials for neuroprotective MS therapies.

11.
Sci Transl Med ; 5(188): 188ra75, 2013 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-23740901

RESUMO

Multiple sclerosis (MS) is a devastating inflammatory disease of the brain and spinal cord that is thought to result from an autoimmune attack directed against antigens in the central nervous system. The aim of this first-in-man trial was to assess the feasibility, safety, and tolerability of a tolerization regimen in MS patients that uses a single infusion of autologous peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG1-20, MOG35-55, MBP13-32, MBP83-99, MBP111-129, MBP146-170, and PLP139-154). An open-label, single-center, dose-escalation study was performed in seven relapsing-remitting and two secondary progressive MS patients who were off-treatment for standard therapies. All patients had to show T cell reactivity against at least one of the myelin peptides used in the trial. Neurological, magnetic resonance imaging, laboratory, and immunological examinations were performed to assess the safety, tolerability, and in vivo mechanisms of action of this regimen. Administration of antigen-coupled cells was feasible, had a favorable safety profile, and was well tolerated in MS patients. Patients receiving the higher doses (>1 × 10(9)) of peptide-coupled cells had a decrease in antigen-specific T cell responses after peptide-coupled cell therapy. In summary, this first-in-man clinical trial of autologous peptide-coupled cells in MS patients establishes the feasibility and indicates good tolerability and safety of this therapeutic approach.


Assuntos
Epitopos/imunologia , Tolerância Imunológica/imunologia , Leucócitos Mononucleares/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Bainha de Mielina/imunologia , Peptídeos/imunologia , Adolescente , Adulto , Contagem de Células Sanguíneas , Demografia , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/fisiopatologia , Adulto Jovem
12.
Glob Chang Biol ; 19(5): 1470-81, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23504984

RESUMO

Recent studies from mountainous areas of small spatial extent (<2500 km(2) ) suggest that fine-grained thermal variability over tens or hundreds of metres exceeds much of the climate warming expected for the coming decades. Such variability in temperature provides buffering to mitigate climate-change impacts. Is this local spatial buffering restricted to topographically complex terrains? To answer this, we here study fine-grained thermal variability across a 2500-km wide latitudinal gradient in Northern Europe encompassing a large array of topographic complexities. We first combined plant community data, Ellenberg temperature indicator values, locally measured temperatures (LmT) and globally interpolated temperatures (GiT) in a modelling framework to infer biologically relevant temperature conditions from plant assemblages within <1000-m(2) units (community-inferred temperatures: CiT). We then assessed: (1) CiT range (thermal variability) within 1-km(2) units; (2) the relationship between CiT range and topographically and geographically derived predictors at 1-km resolution; and (3) whether spatial turnover in CiT is greater than spatial turnover in GiT within 100-km(2) units. Ellenberg temperature indicator values in combination with plant assemblages explained 46-72% of variation in LmT and 92-96% of variation in GiT during the growing season (June, July, August). Growing-season CiT range within 1-km(2) units peaked at 60-65°N and increased with terrain roughness, averaging 1.97 °C (SD = 0.84 °C) and 2.68 °C (SD = 1.26 °C) within the flattest and roughest units respectively. Complex interactions between topography-related variables and latitude explained 35% of variation in growing-season CiT range when accounting for sampling effort and residual spatial autocorrelation. Spatial turnover in growing-season CiT within 100-km(2) units was, on average, 1.8 times greater (0.32 °C km(-1) ) than spatial turnover in growing-season GiT (0.18 °C km(-1) ). We conclude that thermal variability within 1-km(2) units strongly increases local spatial buffering of future climate warming across Northern Europe, even in the flattest terrains.


Assuntos
Biota , Mudança Climática , Fenômenos Fisiológicos Vegetais , Europa (Continente) , Geografia , Modelos Teóricos , Temperatura
13.
J Neuroimmunol ; 242(1-2): 60-71, 2012 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-22169406

RESUMO

Neutrophils are armed with proteases with indiscriminate histotoxic potential, and to minimize tissue injury, their activation involves priming with inflammatory mediators before cells are fully activated in a second step. Here, we show that neutrophils in multiple sclerosis patients are more numerous and exhibit a primed state based on reduced apoptosis, higher expression of TLR-2, fMLP receptor, IL-8 receptor and CD43, enhanced degranulation and oxidative burst as well as higher levels of neutrophil extracellular traps in serum. The chronic inflammatory environment in multiple sclerosis probably underlies this inappropriate neutrophil priming, which may result in enhanced neutrophil activation during infection.


Assuntos
Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/imunologia , Ativação de Neutrófilo/imunologia , Neutrófilos/imunologia , Neutrófilos/patologia , Fenótipo , Adulto , Apoptose/imunologia , Biomarcadores/sangue , Degranulação Celular/imunologia , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Recidivante-Remitente/sangue , Neutrófilos/metabolismo
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