Prognostic indicators for the onset of ischaemic versus haemorrhagic stroke in stable coronary artery disease

The incidence of stroke may be increased in patients with coronary artery disease (CAD). We aimed to investigate the specific risk factors for the development of ischaemic and haemorrhagic stroke in stable CAD patients.Patients with stable CAD were prospectively enrolled for future cardiovascular events in Taiwan. All the patients had received coronary interventions and were stable for least 1 month before enrolment. The incidence of ischaemic stroke was identified and confirmed by telephone and hospital records. Baseline characteristics, including demographic data, lipid profiles, medications, and biomarkers for potential inflammatory and atherosclerosis, were analysed.In total, 1428 patients (age, 63.07 ± 11.4 years; 1207 males) were under standard medical treatment and regularly followed-up for at least 4 years. Multivariate logistic regression analysis showed that baseline serum myeloperoxidase (MPO) level (hazard ratio [HR]: 1.89, 95% CI: 1.16–3.10, P = .01) and statin use (HR: 0.37; 95% CI: 0.17–0.79, P = .01) were independently associated with the onset of ischaemic stroke. Age (HR: 1.07, 95% CI: 1.00–1.14, P = .04) and angiotensin receptor blocker (ARB) use (HR: 0.37, 95% CI: 0.17–0.79, P = .01) were independently associated with future onset of intracranial haemorrhage (ICH), implying the different mechanisms of ischaemic stroke and ICH.Age and ARB use were related to ICH onset. Baseline MPO level and statin use were independently associated with longer and shorter future ischaemic stroke onset in stable CAD patients, respectively. Further studies are indicated to confirm the potential mechanisms and advance individual risk stratification for the onset of different types of stroke in clinical CAD.     

Inside the phagosome: A bacterial perspective

The neutrophil phagosome is one of the most hostile environments that bacteria must face and overcome if they are to succeed as pathogens. Targeting bacterial defense mechanisms should lead to new therapies that assist neutrophils to kill pathogens, but this has not yet come to fruition. One of the limiting factors in this effort has been our incomplete knowledge of the complex biochemistry that occurs within the rapidly changing environment of the phagosome. The same compartmentalization that protects host tissue also limits our ability to measure events within the phagosome. In this review, we highlight the limitations in our knowledge, and how the contribution of bacteria to the phagosomal environment is often ignored. There appears to be significant heterogeneity among phagosomes, and it is important to determine whether survivors have more efficient defenses or whether they are ingested into less threatening environments than other bacteria. As part of these efforts, we discuss how monitoring or recovering bacteria from phagosomes can provide insight into the conditions they have faced. We also encourage the use of unbiased screening approaches to identify bacterial genes that are essential for survival inside neutrophil phagosomes.     

Myeloperoxidase creates a permissive microenvironmental niche for the progression of multiple myeloma

Expression of myeloperoxidase (MPO), a key inflammatory enzyme restricted to myeloid cells, is negatively associated with the development of solid tumours. Activated myeloid cell populations are increased in multiple myeloma (MM); however, the functional consequences of myeloid-derived MPO within the myeloma microenvironment are unknown. Here, the role of MPO in MM pathogenesis was investigated, and the capacity for pharmacological inhibition of MPO to impede MM progression was evaluated. In the 5TGM1-KaLwRij mouse model of myeloma, the early stages of tumour development were associated with an increase in CD11b⁺ myeloid cell populations and an increase in Mpo expression within the bone marrow (BM). Interestingly, MM tumour cell homing was increased towards sites of elevated myeloid cell numbers and MPO activity within the BM. Mechanistically, MPO induced the expression of key MM growth factors, resulting in tumour cell proliferation and suppressed cytotoxic T-cell activity. Notably, tumour growth studies in mice treated with a small-molecule irreversible inhibitor of MPO (4-ABAH) demonstrated a significant reduction in overall MM tumour burden. Taken together, our data demonstrate that MPO contributes to MM tumour growth, and that MPO-specific inhibitors may provide a new therapeutic strategy to limit MM disease progression.     

Immunohistochemical study of chicken fat clots: Investigation of the formation mechanism

In forensic practice, the presence of chicken fat clots (CFCs) in the heart and/or large blood vessels of cadavers has been empirically used to estimate the time from the onset of fatal events to death. However, little scientific evidence of its significance exists, and the mechanism of its formation has not been elucidated. CFCs contain large amounts of leukocytes; thus, we hypothesized that leukocytes might contribute to their formation. Since leukocytes, especially neutrophils, are considered to be involved in blood coagulation through the formation of neutrophil extracellular traps (NETs), we aimed to investigate whether NETs are related to the formation of CFCs through immunohistochemistry. Most cells in the CFCs were myeloperoxidase- and neutrophil elastase-positive, strongly suggesting that they were neutrophils. Since chromatin is released extracellularly during NET formation, immunostaining was performed against some types of histones in CFCs. A certain number of neutrophils in CFCs showed positive extra-nuclear and extracellular signals of histones. In addition, citrullination of histone H3, which is considered important for histone release, was immunohistochemically detected in some neutrophils. These results suggest that neutrophils may affect the formation of CFCs through histone release. Although it was not clear how and when citrullination and extracellular release of histones in CFCs occur in this study, our findings provide insights into the events occurring at the time of death in a human body.     

French practical guidelines for the diagnosis and management of relapsing polychondritis

Relapsing polychondritis is a rare systemic disease. It usually begins in middle-aged individuals. This diagnosis is mainly suggested in the presence of chondritis, i.e. inflammatory flares on the cartilage, in particular of the ears, nose or respiratory tract, and more rarely in the presence of other manifestations. The formal diagnosis of relapsing polychondritis cannot be established with certainty before the onset of chondritis, which can sometimes occur several years after the first signs. No laboratory test is specific of relapsing polychondritis, the diagnosis is usually based on clinical evidence and the elimination of differential diagnoses. Relapsing polychondritis is a long-lasting and often unpredictable disease, evolving in the form of relapses interspersed with periods of remission that can be very prolonged. Its management is not codified and depends on the nature of the patient's symptoms and association or not with myelodysplasia/vacuoles, E1 enzyme, X linked, autoinflammatory, somatic (VEXAS). Some minor forms can be treated with non-steroidal anti-inflammatory drugs, or a short course of corticosteroids with possibly a background treatment of colchicine. However, the treatment strategy is often based on the lowest possible dosage of corticosteroids combined with background treatment with conventional immunosuppressants (e.g. methotrexate, azathioprine, mycophenolate mofetil, rarely cyclophosphamide) or targeted therapies. Specific strategies are required if relapsing polychondritis is associated with myelodysplasia/VEXAS. Forms limited to the cartilage of the nose or ears have a good prognosis. Involvement of the cartilage of the respiratory tract, cardiovascular involvement, and association with myelodysplasia/VEXAS (more frequent in men over 50 years of age) are detrimental to the prognosis of the disease.     

Auer rods and faggot cells: A review of the history,significance and mimics of two morphological curiosities of enduring relevance

Myeloid differentiation in blasts is distinguished by the presence of one or more needle-shaped crystalline structures called Auer rods. Auer rods manifest either alone or as faggot cells (containing bundles of Auer rods) in various types of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). Their presence largely portends a better prognosis in AML (as markers of maturation/differentiation) and upstages cases of MDS and MDS/MPN. Observation of these rods in residual blasts in treated cases of AML indicates an absence of remission. This article traces their historical discovery and examines their pathogenetic intricacies, as well as our current understanding of their relevance in myeloid neoplasms. Studies evaluating their prognostic impact in AML and MDS are catalogued. We also discuss a variety of other hematological and non-hematological neoplasms where structures potentially mistakable for Auer rods have been described. Even as the diagnostic approach to hematological malignancies has evolved from a morphology + cytochemistry + immunophenotyping-dependent one in the last century to a predominantly molecular genetics-based classification currently, and even as high-throughput sequencing and structural variation detection techniques surpass morphology in detecting clinically-relevant sub-categories of similar-appearing tumours, we review these curious microscopic structures that have withstood the test of time with respect to their diagnostic relevance.