Cortical disease has emerged as a critical aspect of the pathogenesis of multiple sclerosis, being associated with disease progression and cognitive impairment. Most studies of cortical lesions have ...focused on autopsy findings in patients with long-standing, chronic, progressive multiple sclerosis, and the noninflammatory nature of these lesions has been emphasized. Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease.
We evaluated the prevalence and character of demyelinating cortical lesions in patients with multiple sclerosis. Cortical tissues were obtained in passing during biopsy sampling of white-matter lesions. In most cases, biopsy was done with the use of stereotactic procedures to diagnose suspected tumors. Patients with sufficient cortex (138 of 563 patients screened) were evaluated for cortical demyelination. Using immunohistochemistry, we characterized cortical lesions with respect to demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and a topographic association between cortical demyelination and meningeal inflammation. Diagnoses were ascertained in a subgroup of 77 patients (56%) at the last follow-up visit (at a median of 3.5 years).
Cortical demyelination was present in 53 patients (38%) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81% of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72% of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study.
In this cohort of patients with early-stage multiple sclerosis, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. (Funded by the National Multiple Sclerosis Society and the National Institutes of Health.).
Objective
Multiple sclerosis (MS) lesions demonstrate immunopathological heterogeneity in patterns of demyelination. Previous cross‐sectional studies reported immunopatterns of demyelination were ...identical among multiple active demyelinating lesions from the same individual, but differed between individuals, leading to the hypothesis of intraindividual pathological homogeneity and interindividual heterogeneity. Other groups suggested a time‐dependent heterogeneity of lesions. The objective of our present study was to analyze tissue samples collected longitudinally to determine whether patterns of demyelination persist over time within a given patient.
Methods
Archival tissue samples derived from patients with pathologically confirmed central nervous system inflammatory demyelinating disease who had undergone either diagnostic serial biopsy or biopsy followed by autopsy were analyzed immunohistochemically. The inclusion criteria consisted of the presence of early active demyelinating lesions—required for immunopattern classification—obtained from the same patient at 2 or more time points.
Results
Among 1,321 surgical biopsies consistent with MS, 22 cases met the study inclusion criteria. Twenty‐one patients (95%) showed a persistence of immunopathological patterns in tissue sampled from different time points. This persistence was demonstrated for all major patterns of demyelination. A single patient showed features suggestive of both pattern II and pattern III on biopsy, but only pattern II among all active lesions examined at autopsy.
Interpretation
These findings continue to support the concept of patient‐dependent immunopathological heterogeneity in early MS and suggest that the mechanisms and targets of tissue injury may differ among patient subgroups. These observations have potentially significant implications for individualized therapeutic approaches. Ann Neurol 2014;75:728–738
To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum ...disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4-immunoglobulin G (IgG) serologic testing.
This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury.
AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)-positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy.
AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS.
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•A water-based ferrofluid was irradiated with photons and electrons.•The dose was that usually involved in radiation therapy of human subjects (50 Gy).•Electron irradiation induced ...minor change in the colloidal stability of ferrofluid.•Magnetic heating of ferrofluid at 100 kHz is not affected by irradiation.•Magnetic hyperthermia can be applied in the same time period as radiation therapy.
The paper reports on the effect of therapeutic-like irradiation of a water based magnetic fluid with magnetite particles double-surfacted with oleic acid on its magnetic heating characteristics. To assess the effect of irradiation, a quantity of the initial sample was retained as the reference sample. The other part of the ferrofluid was irradiated with a photon beam (with the energy of 10 MeV and the dose of 50 Gy) and with an electron beam (of the energy of 9 MeV and the dose of 50 Gy).
The frequency dependence of the complex magnetic permeability, μ(ω) = μ′(ω)-i μ″(ω), was affected only in the case of the electron irradiated sample and over the approximate range of 10–100 kHz.
The dynamic light scattering investigation revealed a small increase of the average of the size of light scattering entities and of the polydispersity index of the sample irradiated with electrons compared to the reference sample.
Magnetic heating experiments, performed at the frequency of 100 kHz and with various amplitudes of magnetic field, H, (of 25, 50, 75 and 100 Oe) did not reveal significant difference in the heating rate values of the reference sample and of the irradiated samples. Therefore, magnetic hyperthermia can be involved in the therapy plan, in the same period of time as the radiation therapy, provided at the frequency of the alternating magnetic field larger than the frequency corresponding to the Brownian relaxation peak.
T‐cell alloimmunity plays a dominant role in allograft rejection. The precise contribution of naïve and memory T cells to this response however remains unclear. To address this question, we ...established an ex vivo flow‐cytometric assay that simultaneously measures proliferation, precursor frequency and effector molecule (IFNγ, granzyme B/perforin) production of alloreactive T cells. By applying this assay to peripheral blood mononuclear cells from healthy volunteers, we demonstrate that the CD4+ and CD8+ populations mount similar proliferative responses and contain comparable frequencies of alloreactive precursors. Effector molecule expression, however, was significantly higher among CD8+ T cells. Analysis of sorted naïve and memory T cells showed that alloreactive precursors were equally present in both populations. The CD8+ effector and terminally differentiated effector memory subsets contained the highest proportion of granzyme B/perforin after allostimulation, suggesting that these cells present a significant threat to transplanted organs. Finally, we demonstrate that virus‐specific lymphocytes contribute significantly to the alloresponse in certain responder–stimulator HLA combinations, underscoring the importance of T‐cell cross‐reactivity in alloimmunity. These results provide a quantitative assessment of the roles of naïve and memory T‐cell subsets in the normal human alloimmune response and establish a platform for measuring T‐cell alloreactivity pre‐ and posttransplantation.
Using an ex vivo flow‐cytometric assay that simultaneously measures T cell proliferation, precursor frequency, and effector molecules (IFNg, granzyme B/perforin) this study provides a quantitative assessment of the roles of naïve vs memory subsets to the human alloimmune response, and establishes a platform for measuring alloreactivity pre‐ and post‐transplantation.
Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis ...has remained unproved.
We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.
At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval CI, 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31).
Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .).
Acute hemorrhagic leukoencephalitis (AHL) is a fulminant demyelinating disease of unknown etiology. Most cases are fatal within one week from onset. AHL pathology varies with the acuteness of ...disease. Hemorrhages, vessel fibrinoid necrosis, perivascular fibrin exudation, edema and neutrophilic inflammation are early features, while perivascular demyelination, microglial foci and myelin-laden macrophages appear later. Reactive astrocytosis is not present in early hemorrhagic non-demyelinated lesions, but is seen in older lesions. This case report presents the pathology of an AHL case with fulminant course and fatal outcome within 48 hours from presentation. Severe hemorrhages, edema and neutrophilic inflammation in the absence of circumscribed perivascular demyelination affected the temporal neocortex and white matter, hippocampus, cerebellar cortex and white matter, optic chiasm, mammillary bodies, brainstem, cranial nerve roots and leptomeninges. Perivascular end-feet and parenchymal processes of astrocytes exhibited impressive swelling in haemorrhagic but non-demyelinated white matter regions. Astrocytes were dystrophic and displayed degenerating processes. Astrocytic swellings and remnants were immunoreactive for aquaporin-4, aquaporin-1 and glial fibrillary acidic protein. These morphological changes of astrocytes consistent with injury were also observed in haemorrhagic and normal appearing cortex. Our findings reinforce that perivascular demyelination is not present early in AHL. This is the first study that highlights the early and widespread astrocytic injury in the absence of demyelination in AHL, suggesting that, similarly to neuromyelitis optica and central pontine myelinolysis, demyelination in AHL is secondary to astrocyte injury.
The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.
We randomly ...assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m
of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.
We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval CI, <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).
In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).
The environmental impact of inorganic pollution is pronounced in water adjacent to Bor Copper Smelter Complex (RTB Bor, Serbia), with Cu, Zn, Pb, and As being the main determinants of aquatic ...pollution pattern. Communities of microorganisms present in the sediments are mainly affected by heavy metal pollution. Some groups of bacteria can be considered pollution bio-indicators, due to their sensibility and ability to bioaccumulate heavy metals, thus contributing to reducing pollution. This study investigates the relationships between trace element accumulation and heterogeneity in sediment bacteria community structure found in water streams adjacent to the Bor Copper Smelter Complex (RTB Bor, Serbia). Our results showed no contamination with copper, zinc, nickel, iron, and chromium, but did show a low to moderate contamination with lead and a moderate to high contamination with arsenic in aquatic sediments within the area of interest. Spatial heterogeneity in sediment-associated bacterial communities did not relate significantly to location of sampling sites, except for iron reducing bacteria. Iron reducing bacteria and nitrifying bacteria were the best distinguishing groups of bacteria. However, only iron reducing bacteria were significantly influenced by sampling locations. The iron reducing bacteria has correlated negatively with the degree of sediment contamination with lead, and therefore, we suggest that this group of bacteria could serve as potential bio-indicators of inorganic water contamination in Bor RTB area.
L’impact environnemental de la pollution inorganique est détecté dans l’eau adjacente à la fonderie de cuivre de la ville de Bor (RTB Bor, Serbie), le Cu, Zn, Pb, et As étant les principaux déterminants du schéma de pollution aquatique. Les communautés de micro-organismes présents dans les sédiments sont les plus touchés par la pollution des métaux lourds. Certains groupes de bactéries peuvent être considérés comme bio-indicateurs de pollution par leur sensibilité, leur capacité à bio-accumuler d’autres métaux et à contribuer à réduire la pollution. Cette étude s’est penchée sur la relation entre l’accumulation d’oligo-éléments et l’hétérogénéité dans la structure du sédiment de la communauté bactérienne, dans les courants d’eau à proximité de la fonderie de cuivre de la ville de Bor (RTB BOR, Serbie). Nos résultats n’ont montré aucune contamination par le cuivre, zinc, nickel, fer et chrome, mais une contamination faible à modérée par le plomb, et une contamination modérée à forte par l’arsenic dans les sédiments aquatiques des zones d’intérêts. L’hétérogénéité spatiale dans les communautés bactériennes associées aux sédiments n’a pas de lien significatif avec l’emplacement des sites de prélèvements, à l’exception des bactéries réduisant le fer. Les bactéries réduisant le fer et les bactéries nitrifiantes étaient les meilleurs groupes distinctifs de bactéries; ils étaient fortement influencés par l’emplacement de sites d’échantillonnage. Les bactéries réduisant le fer sont négativement corrélées au degré de contamination par le plomb, et par conséquent nous proposons que ce groupe de bactéries serve comme potentiel bio-indicateur de contamination inorganique dans l’eau adjacente à RTB Bor.
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