Multiple sclerosis (MS) is the most frequent demyelinating disease and a leading cause for disability in young adults. Despite significant advances in immunotherapies in recent years, disease ...progression still cannot be prevented. Remyelination, meaning the formation of new myelin sheaths after a demyelinating event, can fail in MS lesions. Impaired differentiation of progenitor cells into myelinating oligodendrocytes may contribute to remyelination failure and, therefore, the development of pharmacological approaches which promote oligodendroglial differentiation and by that remyelination, represents a promising new treatment approach. However, this generally accepted concept has been challenged recently. To further understand mechanisms contributing to remyelination failure in MS, we combined detailed histological analyses assessing oligodendroglial cell numbers, presence of remyelination as well as the inflammatory environment in different MS lesion types in white matter with in vitro experiments using induced-pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) and supernatants from polarized human microglia. Our findings suggest that there are multiple reasons for remyelination failure in MS which are dependent on lesion stage. These include lack of myelin sheath formation despite the presence of mature oligodendrocytes in a subset of active lesions as well as oligodendroglial loss and a hostile tissue environment in mixed active/inactive lesions. Therefore, we conclude that better in vivo and in vitro models which mimic the pathological hallmarks of the different MS lesion types are required for the successful development of remyelination promoting drugs.
With the release of the 2016 edition of the World Health Organization (WHO) Classification of Central Nervous System Tumors, brain invasion in meningiomas has been added as a stand-alone criterion ...for atypia and can therefore impact grading and indirectly adjuvant therapy. Regarding this rising clinical importance, we have reviewed the current knowledge about brain invasion with emphasis on its implications on current and future clinical practice. We found various definitions of brain invasion and approaches for evaluation in surgically obtained specimens described over the past decades. This heterogeneity is reflected by weak correlation with prognosis and remains controversial. Similarly, associated clinical factors are largely unknown. Preoperative, imaging-guided detection of brain invasion is unspecific, and intraoperative assessment using standard and new high-magnification microscopic techniques remains imprecise. Despite the increasing knowledge about molecular alterations of the tumor/ brain surface, pharmacotherapeutic options targeting brain invasive meningiomas are lacking. Finally, we summarize the impact of brain invasion on histopathological grading in the WHO classifications of brain tumors since 1979.In conclusion, standardized neurosurgical sampling and neuropathological analyses could improve diagnostic reliability and reproducibility of future studies. Further research is needed to improve pre- and intraoperative visualization of brain invasion and to develop adjuvant, targeted therapies.
Multiple sclerosis (MS) is the most frequent demyelinating disease in young adults and despite significant advances in immunotherapy, disease progression still cannot be prevented. Promotion of ...remyelination, an endogenous repair mechanism resulting in the formation of new myelin sheaths around demyelinated axons, represents a promising new treatment approach. However, remyelination frequently fails in MS lesions, which can in part be attributed to impaired differentiation of oligodendroglial progenitor cells into mature, myelinating oligodendrocytes. The reasons for impaired oligodendroglial differentiation and defective remyelination in MS are currently unknown. To determine whether intrinsic oligodendroglial factors contribute to impaired remyelination in relapsing–remitting MS (RRMS), we compared induced pluripotent stem cell-derived oligodendrocytes (hiOL) from RRMS patients and controls, among them two monozygous twin pairs discordant for MS. We found that hiOL from RRMS patients and controls were virtually indistinguishable with respect to remyelination-associated functions and proteomic composition. However, while analyzing the effect of extrinsic factors we discovered that supernatants of activated peripheral blood mononuclear cells (PBMCs) significantly inhibit oligodendroglial differentiation. In particular, we identified CD4
+
T cells as mediators of impaired oligodendroglial differentiation; at least partly due to interferon-gamma secretion. Additionally, we observed that blocked oligodendroglial differentiation induced by PBMC supernatants could not be restored by application of oligodendroglial differentiation promoting drugs, whereas treatment of PBMCs with the immunomodulatory drug teriflunomide prior to supernatant collection partly rescued oligodendroglial differentiation. In summary, these data indicate that the oligodendroglial differentiation block is not due to intrinsic oligodendroglial factors but rather caused by the inflammatory environment in RRMS lesions which underlines the need for drug screening approaches taking the inflammatory environment into account. Combined, these findings may contribute to the development of new remyelination promoting strategies.
Estimating the risk of recurrence after surgery remains crucial during care of patients with meningioma. Numerous studies identified correlations of characteristics on routine preoperative magnetic ...resonance imaging (MRI) with postoperative recurrence or high-grade histology but showed partially inconclusive results.
A systematic review of the literature was performed about findings on preoperative MRI and their correlation with high-grade histology and recurrence. Quality of the included studies was analyzed using standardized Quality Assessment of Diagnostic Accuracy Studies criteria.
Among the 35 studies included, quality of the series according to the Quality Assessment of Diagnostic Accuracy Studies criteria differed widely. Remarkably, MRI variables found to be associated with high-grade histology were commonly not consistently associated with prognosis and vice versa. Correlations of the tumor size, the peritumoral edema size, and contrast-enhancement of the tumor capsule with high-grade histology were controversial. In most studies, non-skull base tumor location, cyst formation, heterogenous contrast-enhancement, an irregular tumor shape, and disruption of the tumor/brain border but not intensity of the lesion on T2-weighted images, calcifications, or bone involvement were associated with grade II/III histology. Although tumor and edema size were usually found to correlate with recurrence, heterogenous contrast enhancement, cyst formation, intensity of the tumor on T2-weighted MRI, and enhancement of the tumor capsule were mostly not related with progression.
Several mostly consistent but partially inconsistent variables associated with high-grade histology or prognosis were identified. Although standardized studies are needed to provide further clarification, consideration of these findings can help to improve estimation of prognosis and can therefore improve postoperative care in patients with meningioma.
Abstract Objective In meningioma, correlation of brain invasion with prognosis and clinical variables remains controversial. Methods Correlation of brain invasion with clinical and histopathological ...variables was investigated in 467 patients with primary intracranial meningioma. Results Diffuse (N=3, 10%), cluster- (N=11, 34%) or finger-like (N=18, 56%) invasion was detected in 32 patients (7%). Brain invasion was more common in males than in females (13% vs. 5%; OR: 2.75, 95%CI 1.29-5.89; p=.009) and pattern of invasion differed between genders (p=.037). Brain invasion was absent in 401 benign, present in 48% of 60 atypical (N=29) and 50% of 6 anaplastic (N=3) meningiomas (p<.001) but was independent of tumor location and extend of resection. Progression occurred in 11% and was more frequent (31% vs. 15%, p=.036) in invasive than in non-invasive tumors, but only after gross total resection and in univariate analyses, and independent of invasion pattern. In atypical meningiomas, frequency of adjuvant irradiation was similar comparing invasive and non-invasive tumors and grading solely based on brain invasion (N=20, 33%), other WHO criteria (N=31, 52%) or a combination of both (N=9, 15%). Risk of recurrence was lower (HR: .258, 95%CI .09-.734; p=.011) when grading exclusively based on brain invasion as when further WHO criteria were additionally present and progression free interval among the first was similar to benign tumors. Conclusions Brain invasion and its patterns are correlated to gender. In opposite to the current WHO classification, invasion was associated with recurrence only after gross total resection and not independent of further histopathological criteria of atypia.
OBJECTIVE The purpose of this study was to compare long-term prognosis after meningioma surgery in elderly and younger patients as well as to compare survival of elderly patients with surgically ...treated meningioma to survival rates for the general population. METHODS Five hundred meningioma patients (median follow-up 90 months) who underwent surgery between 1994 and 2009 were subdivided into "elderly" (age ≥ 65 years, n = 162) and "younger" (age < 65 years, n = 338) groups for uni- and multivariate analyses. Mortality was compared with rates for the age- and sex-matched general population. RESULTS The median age at diagnosis was 71 in the elderly group and 51 years in the younger group. Sex, intracranial tumor location, grade of resection, radiotherapy, and histopathological subtypes were similar in the 2 groups. High-grade (WHO Grades II and III) and spinal tumors were more common in older patients than in younger patients (15% vs 8%, p = 0.017, and 12% vs 4%, p = 0.001, respectively). The progression-free interval (PFI) was similar in the 2 groups, whereas mortality at 3 months after surgery was higher and median overall survival (OS) was shorter in older patients (7%, 191 months) than in younger patients (1%, median not reached; HR 4.9, 95% CI 2.75-8.74; p < 0.001). Otherwise, the median OS in elderly patients did not differ from the anticipated general life expectancy (HR 1.03, 95% CI 0.70-1.50; p = 0.886). Within the older patient group, PFI was lower in patients with high-grade meningiomas (HR 24.74, 95% CI 4.23-144.66; p < 0.001) and after subtotal resection (HR 10.57, 95% CI 2.23-50.05; p = 0.003). Although extent of resection was independent of perioperative mortality, the median OS was longer after gross-total resection than after subtotal resection (HR 2.7, 95% CI 1.09-6.69; p = 0.032). CONCLUSIONS Elderly patients with surgically treated meningioma do not suffer from impaired survival compared with the age-matched general population, and their PFI is similar to that of younger meningioma patients. These data help mitigate fears concerning surgical treatment of elderly patients in an aging society.
Macrophages belong to the innate immune system, and we have recently shown that in vitro differentiated human regulatory macrophages (Mreg) release large extracellular vesicles (L-EV
Mreg
) with an ...average size of 7.5 μm which regulate wound healing and angiogenesis in vitro. The aim of this study was to investigate whether L-EV
Mreg
also affect the CD3/CD28-mediated activation of T-cells. Mreg were differentiated using blood monocytes and L-EV
Mreg
were isolated from culture supernatants by differential centrifugation. Activation of human T-cells was induced by CD3/CD28-coated beads in the absence or presence of Mreg or different concentrations of L-EV
Mreg
. Inhibition of T-cell activation was quantified by flow cytometry and antibodies directed against the T-cell marker granzyme B. Phosphatidylserine (PS) exposure on the surface of Mreg and L-EV
Mreg
was analyzed by fluorescence microscopy. Incubation of human lymphocytes with CD3/CD28 beads resulted in an increase of cell size, cell granularity, and number of granzyme B–positive cells (
P
< 0.05) which is indicative of T-cell activation. The presence of Mreg (0.5 × 10
6
Mreg/ml) led to a reduction of T-cell activation (number of granzyme B–positive cells;
P
< 0.001), and a similar but less pronounced effect was also observed when incubating activated T-cells with L-EV
Mreg
(
P
< 0.05 for 3.2 × 10
6
L-EV
Mreg
/ml). A differential analysis of the effects of Mreg and L-EV
Mreg
on CD4
+
and CD8
+
T-cells showed an inhibition of CD4
+
T-cells by Mreg (
P
< 0.01) and L-EV
Mreg
(
P
< 0.05 for 1.6 × 10
6
L-EV
Mreg
/ml;
P
< 0.01 for 3.2 × 10
6
L-EV
Mreg
/ml). A moderate inhibition of CD8
+
T-cells was observed by Mreg (
P
< 0.05) and by L-EV
Mreg
(
P
< 0.01 for 1.6 × 10
6
L-EV
Mreg
/ml and 3.2 × 10
6
L-EV
Mreg
/ml). PS was restricted to confined regions of the Mreg surface, while L-EV
Mreg
showed strong signals for PS in the exoplasmic leaflet. L-EV
Mreg
attenuate CD3/CD28-mediated activation of CD4
+
and CD8
+
T-cells. L-EV
Mreg
may have clinical relevance, particularly in the treatment of diseases associated with increased T-cell activity.
Key messages
Mreg release large extracellular vesicles (L-EV
Mreg
) with an average size of 7.5 µm
L-EV
Mreg
exhibit phosphatidylserine positivity
L-EV
Mreg
suppress CD4
+
and CD8
+
T-cells
L-EV
Mreg
hold clinical potential in T-cell-related diseases
Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading ...necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of
CDKN2A/B
(66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting
NF1
, followed by
BRAF
and
FGFR1
) and mutations of
ATRX
or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were
IDH1/2
wildtype. The
MGMT
promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than
IDH
wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of
CDKN2A/B
and
ATRX
, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
Patients with diabetes mellitus are at increased risk of cardiovascular morbidity and mortality. Atherothrombosis, defined as atherosclerotic lesion disruption with superimposed thrombus formation, ...is the most common cause of death among these patients. Following plaque rupture, adherence of platelets is followed by local activation of coagulation, the formation of a cross-linked fibrin clot and the development of an occlusive platelet rich fibrin mesh. Patients with diabetes exhibit a thrombotic risk clustering which is composed of hyper-reactive platelets, up regulation of pro-thrombotic markers and suppression of fibrinolysis. These changes are mainly mediated by the presence of insulin resistance and dysglycaemia and an increased inflammatory state which directly affects platelet function, coagulation factors and clot structure. This prothrombotic state is related to increased cardiovascular risk and may account for the reduced response to antithrombotic therapeutic approaches, underpinning the need for adequate antithrombotic therapy in patients with diabetes to reduce their cardiovascular mortality.
The risk of climate change impacts occurring is a function of a socioecological system’s exposure and vulnerability to climate-related hazards. Vulnerability itself is the result of a system's ...sensitivity and adaptive capacity. The potential climate change driven biophysical impacts on the municipality Totonicapán in the western highlands of Guatemala are well documented in outcome vulnerability studies and projected to be severe. They include droughts, frosts, forest fires and life zone changes which also represent important hazards to the municipality’s population. Yet, recent detailed socioeconomic information on the municipality’s contextual vulnerability is scarce. Moreover, social capital which is central to the yet successful management of the unique communal coniferous forests is poorly understood. The present study evaluates the contextual vulnerability of the municipality's population and communal forests using 5 interviews and 167 household surveys from 3 communities for 15 socioeconomic indicators. Qualitative analysis of the interviews urges for further investigation into the link between emigration to the USA, the loss of social capital and communal forest management. Quantitative analysis of the indicators and their aggregation into a vulnerability index by Principal Component Analysis demonstrates that education is the most important vulnerability factor, followed by income which was negatively related to natural resource dependency. An overarching theme was gender inequality. The study is a plea for location and population specific research and adaptation strategies as it identifies significant differences even between communities of the same municipality.
El riesgo de que ocurran impactos climáticos es la función de la exposición y vulnerabilidad de un sistema socioecológico frente a peligros. La vulnerabilidad es el resultado de la sensibilidad y capacidad adaptativa de un sistema. Los posibles impactos biofísicos debido al cambio climático en el municipio de Totonicapán en el Altiplano de Guatemala son bien documentados en estudios de vulnerabilidad resultante y proyectados a ser severos. Se tratan de sequías, heladas, incendios forestales y cambios en las zonas de vida, que también representan peligros importantes para la población del municipio. Sin embargo, información socioeconómica actualizada y detallada sobre la vulnerabilidad contextual del municipio es escasa. Además, el capital social del municipio que es clave para el manejo exitoso de sus bosques comunales es poco entendido. El presente estudio evalúa la vulnerabilidad contextual de la población del municipio y de los bosques comunales usando 5 entrevistas y 167 encuestas de hogares de 3 comunidades, analizando 15 indicadores socioeconómicos. El análisis cualitativo de las entrevistas resalta que la comprensión del vínculo entre la emigración a los Estados Unidos, la pérdida de capital social y el manejo de los bosques comunales requiere un mayor esfuerzo investigativo. El análisis cuantitativo de los indicadores y su agregación a un índice de vulnerabilidad mediante el Análisis de Componentes Principales demuestra que la educación es el factor más importante de la vulnerabilidad, seguido por el ingreso, que guarda una relación inversa con la dependencia en recursos naturales. Un tema transversal ha sido la desigualdad de género. Identificando diferencias significativas incluso entre comunidades de la misma municipalidad, el estudio es una súplica para investigaciones locales y estrategias de adaptación.
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