Primary soft tissue Ewing’s sarcoma of the maxillary sinus in elderly patients: presentation,management and prognosis

Nonosseous or soft tissue Ewing’s sarcoma is a rare form of Ewing’s sarcoma/primitive neuroectodermal tumour that seldom affects the head and neck region. Involvement of the nose and paranasal sinuses is extremely uncommon, with only eight of such patients being reported to date, mostly affecting adolescents and young adults. To our knowledge, this study is the first comprehensive report of primary soft tissue Ewing’s sarcoma involving the paranasal sinuses in an elderly patient who successfully completed treatment. We herein discuss the pathogenesis, management and factors affecting the prognosis of this rare group of tumours involving the nose and paranasal sinuses, in relation to the available literature.     

Cardiovascular risk stratification in diabetic patients following stress single-photon emission-computed tomography myocardial perfusion imaging: The impact of achieved exercise level

Background

Previous studies have demonstrated that diabetic patients undergoing exercise stress single-photon emission-computed tomography (SPECT) myocardial perfusion imaging (MPI) have significantly lower cardiac events when compared to the diabetic patients undergoing pharmacologic stress SPECT MPI across all perfusion categories. However, there are limited data on the level of exercise achieved during exercise SPECT MPI among diabetic patients and its impact on cardiovascular outcomes.

Methods

We retrospectively analyzed 14,849 consecutive patients (3,654 diabetics and 11,195 non-diabetics) undergoing exercise stress, combined exercise and pharmacologic stress, and pharmacologic stress SPECT MPI from 1996 to 2005 at a single tertiary care center. Diabetic and non-diabetic patients were categorized into 3 groups based on the metabolic equivalents (METs) achieved: ≥5 METs, <5 METs, and pharmacologic stress groups. All studies were interpreted using the 17-segment ASNC model. The presence, extent, severity of perfusion defects were calculated using the summed stress score (SSS), and patients were classified into normal (SSS < 4), mildly abnormal (SSS 4-8), and moderate-severely abnormal (SSS > 8) categories. Annualized event rates (AER) for the composite end point of non-fatal myocardial infarction and cardiac death were calculated over a mean follow-up period of 2.4 ± 1.4 years with a maximum of 6 years.

Results

In moderate-severe perfusion abnormality (SSS > 8) category, diabetic patients who were able to achieve ≥5 METs had significantly lower AER compared to diabetic patients who were unable to achieve ≥5 METs (3% vs 5.5%, P = .04), and non-diabetic patients unable to achieve ≥5 METs (3% vs 4.8%, P < .001). Diabetic patients who achieved a high workload of ≥10 METs had a very low AER of 0.9%. Diabetic patients, who attempted exercise but were unable to achieve ≥5 METs, still had significantly lower AER than diabetics undergoing pharmacologic stress MPI across all perfusion categories [1.5% vs 3.2%, P = .006 (SSS < 4); 2.5% vs 4.9%, P = .032 (SSS 4-8); 5.5% vs 10.3%, P = .003 (SSS > 8)]. After adjustment for cardiovascular risk factors, the percentage decrease in cardiac event rate for every 1-MET increment in exercise capacity was 10% in the overall cohort, 12% in diabetic group, and 8% in non-diabetic group.

Conclusions

Despite significant perfusion defects, diabetic patients who achieve ≥5 METs during stress SPECT MPI have significantly reduced risk for future cardiac events. Diabetic patients who achieve ≥10 METs have a very low annualized event rate. These findings support that exercise capacity obtained during SPECT MPI is a surrogate for outcomes among diabetic patients undergoing nuclear stress testing.     

α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons,Thus Contributing to Synapse Loss

Synaptic and neuronal loss are major neuropathological characteristics of Parkinson''s disease. Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of α-synuclein (αSyn), are associated with disease progression, and have also been linked to other neurodegenerative diseases, including Lewy body dementia, Alzheimer''s disease, and frontotemporal dementia. However, the effects of αSyn and its mechanism of synaptic damage remain incompletely understood. Here, we show that αSyn oligomers induce Ca²⁺-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing αSyn manifest increased tonic release of glutamate in vivo. In turn, this extracellular glutamate activates glutamate receptors, including extrasynaptic NMDARs (eNMDARs), on neurons both in culture and in hippocampal slices of αSyn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized αSyn can directly activate eNMDARs. In organotypic slices, oligomeric αSyn induces eNMDAR-mediated synaptic loss, which can be reversed by the drug NitroSynapsin. When we expose human induced pluripotent stem cell-derived cerebrocortical neurons to αSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric αSyn-induced damage in our model systems, thus meriting further study for its therapeutic potential.SIGNIFICANCE STATEMENT Loss of synaptic function and ensuing neuronal loss are associated with disease progression in Parkinson''s disease (PD), Lewy body dementia (LBD), and other neurodegenerative diseases. However, the mechanism of synaptic damage remains incompletely understood. α-Synuclein (αSyn) misfolds in PD/LBD, forming Lewy bodies and contributing to disease pathogenesis. Here, we found that misfolded/oligomeric αSyn releases excessive astrocytic glutamate, in turn activating neuronal extrasynaptic NMDA receptors (eNMDARs), thereby contributing to synaptic damage. Additionally, αSyn oligomers directly activate eNMDARs, further contributing to damage. While the FDA-approved drug memantine has been reported to offer some benefit in PD/LBD (Hershey and Coleman-Jackson, 2019), we find that the improved eNMDAR antagonist NitroSynapsin ameliorates αSyn-induced synaptic spine loss, providing potential disease-modifying intervention in PD/LBD.     

Brain lesions in chronic granulomatous disease

Summary In chronic granulomatous disease (CGD) enzyme-deficient neutrophils and mononuclear cells lack the respiratory brust required for biocidal activity. Recurrent infections lead to granulomas in various organs but brain lesions are rare. In the present case, a 23-year-old male with numerous infections since early childhood died of overwhelming pulmonary aspergillosis. He first began to experience neurological deficits at the age of 17. Computerized tomography and magnetic rsonance imaging revealed fleeting white matter lesions that were interpreted as multiple sclerosis (MS). At post mortem, three types of brain lesions were found: (1) Pigmented macrophages in perivascular spaces and the leptomeninges similar to those reported previously. They contained fine, golden-brown, lipofuscin-like material whose chemical composition included a sulfur peak by X-ray analysis. (2) Focal, well-demarcated, burnt out white matter lesions with loss of both myelin and axons and intense sclerosis. (3) Diffuse areas of mild pallor in the centrum ovale which spared the U fibers. The pigmented macrophages are characteristic of those seen in the periphery in CGD. The origin of the discrete, destructive white matter lesions is unclear. They may have resulted from: (i) earlier activity by CGD macrophages; (ii) previous infections due to sepsis or embolism; or (iii) possibly post-infectious encephalomyelitis. The more diffuse, mild, white matter lesions are attributed to edema. Evidence for MS, progressive multifocal leukoencephalopathy, or human immunodeficiency virus encephalitis was lacking. This case is presented to alert us to look more carefully for brain lesions in CGD, characterize them and to help determine their cause.This case was presented at the American Association of Neuropathologists' Annual Meeting, San Francisco, CA, June 13–17, 1990 (abstract no. 199)     

Zoonoses and bats: a look from human health viewpoint

Bats are the most abundant and most widely distributed mammals on the Earth after humans. Except Antarctica and some small remote islands, they are prevalent worldwide. Although the actual role played by bats as reservoir or in disseminating zoonoses is still enigmatic a multitude of zoonotic diseases are known to be associated with bats. Such diseases including viral, bacterial, parasitic, fungal and rickettsial diseases, reported from all over the world including India have been briefed in this article as an informative approach because dramatically increased and diversified human activities during the last few decades perturbing natural ecosystems are enough to compel public health personnel to have an investigative look at these flying mammals.     

Observation of non-Hermitian topology and its bulk–edge correspondence in an active mechanical metamaterial

Topological edge modes are excitations that are localized at the materials’ edges and yet are characterized by a topological invariant defined in the bulk. Such bulk–edge correspondence has enabled the creation of robust electronic, electromagnetic, and mechanical transport properties across a wide range of systems, from cold atoms to metamaterials, active matter, and geophysical flows. Recently, the advent of non-Hermitian topological systems—wherein energy is not conserved—has sparked considerable theoretical advances. In particular, novel topological phases that can only exist in non-Hermitian systems have been introduced. However, whether such phases can be experimentally observed, and what their properties are, have remained open questions. Here, we identify and observe a form of bulk–edge correspondence for a particular non-Hermitian topological phase. We find that a change in the bulk non-Hermitian topological invariant leads to a change of topological edge-mode localization together with peculiar purely non-Hermitian properties. Using a quantum-to-classical analogy, we create a mechanical metamaterial with nonreciprocal interactions, in which we observe experimentally the predicted bulk–edge correspondence, demonstrating its robustness. Our results open avenues for the field of non-Hermitian topology and for manipulating waves in unprecedented fashions.

The inclusion of non-Hermitian features in topological insulators has recently seen an explosion of activity. Exciting developments include tunable wave guides that are robust to disorder (1–3), structure-free systems (4, 5), and topological lasers and pumping (6–10). In these systems, active components are introduced to typically 1) break time-reversal symmetry to create topological insulators with unidirectional edge modes (1–5) and 2) pump topologically protected edge modes, thus harnessing Hermitian topology in non-Hermitian settings (6–9, 11). In parallel, extensive theoretical efforts have generalized the concept of a topological insulator to truly non-Hermitian phases that cannot be realized in Hermitian materials (12–14). However, such non-Hermitian topology and its bulk–edge correspondence remain a matter of intense debate. On the one hand, it has been argued that the usual bulk–edge correspondence breaks down in non-Hermitian settings, while on the other hand, new topological invariants specific to non-Hermitian systems have been proposed to capture particular properties of their edge modes (15–20).Here, focusing on a non-Hermitian version of the Su–Schrieffer–Heeger (SSH) model (15–17, 21) with an odd number of sites (Fig. 1A), we find that a change in the bulk non-Hermitian topological invariant is accompanied by a localization change in the zero-energy edge modes. This finding suggests the existence of a bulk–edge correspondence for this type of truly non-Hermitian topology. We further construct a mechanical analogue of the non-Hermitian quantum model (Fig. 1B) and create a mechanical metamaterial (Fig. 1C) in which we observe the predicted correspondence between the non-Hermitian topological invariant and the topological edge mode. In particular, we report that the edge mode in the non-Hermitian topological phase has a peculiar nature, as it is localized on the rigid rather than the floppy side of the mechanical metamaterial.Open in a separate windowFig. 1.Quantum-to-classical mapping of a chain with non-Hermitian topology. (A) An SSH chain with two sublattices, A (in red) and B (in blue), augmented with nonreciprocal variations in the hopping amplitudes (indicated by ±ε). (B) The nonreciprocal classical analog of the augmented SSH chain, in which the classical masses (in red) correspond to the A sites in the quantum model, while the nonreciprocal springs (in blue) are analogous to the B sites. (C) Picture of the mechanical metamaterial realizing the nonreciprocal classical analogue of the augmented SSH model.