Emerging treatment strategies for COVID-19 infection

Clinical and Experimental Medicine - The new type of coronavirus (COVID-19), SARS-CoV-2 originated from Wuhan, China and has led to a worldwide pandemic. COVID-19 is a novel emerging infectious...     

The Acute and Early Effects of Whole-Brain Irradiation on Glial Activation,Brain Metabolism,and Behavior: a Positron Emission Tomography Study

Molecular Imaging and Biology - Radiotherapy is a frequently applied treatment modality for brain tumors. Concomitant irradiation of normal brain tissue can induce various physiological responses....     

Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by beta-amyloid (A beta) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5' region of CH25H revealed three common haplotypes, CH25Hchi2, CH25Hchi3 and CH25Hchi4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hchi4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain A beta deposits in carriers of CH25Hchi4 and CH25Hchi3 haplotypes, whereas no A beta deposits were present in CH25Hchi2 carriers. Together, these results are compatible with a role of CH25Hchi4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain A beta deposition.     

Angiogenesis in Waldenström's Macroglobulinemia

Angiogenesis represents an essential step of disease progression in several hematological malignancies. In Waldenström's macroglobulinemia (WM) the bone marrow microvessel density is increased in 30%–40% of patients but seems to have no impact on survival. Angiogenic cytokines, such as angiogenin, vascular endothelial growth factor, and basic fibroblast growth factor are increased in the serum of WM or IgM-MGUS patients, while the ratio of angiopoietin-1/angiopoietin-2 is reduced in WM but not in IgM—monoclonal gammopathy of undetermined significance (MGUS). Angiogenin and angiopoietin-1/angiopoietin-2 ratio correlates with disease activity and clinical features of WM. Macrophage and mast-cell chemoattractants, such as macrophage inflammatory protein-1 alpha are also elevated in the serum of patients with WM, while both macrophages and mast cells that are increased in the WM microenvironment have angiogenic properties and participate in the angiogenesis process in several malignancies. This review summarizes all data available by November 2008 (end of literature search) for the role of angiogenesis in the biology of WM and its correlation with clinical and laboratory features of the disease.     

Correlates of protection efficacy induced by vaccinia virus‐specific CD8+ T‐cell epitopes in the murine intranasal challenge model

The recent identification of a large array of different vaccinia virus‐derived CD8⁺ T‐cell epitopes offers a unique opportunity to systematically analyze the correlation between protective efficacy and variables such as kinetics of expression and function of viral proteins, binding affinity to MHC molecules, immunogenicity, and viral antigen processing/presentation. In the current study, 49 different H‐2^b restricted epitopes were tested for their ability to protect peptide‐immunized C57Bl/6 mice from lethal i.n. challenge with vaccinia virus. The epitopes varied greatly in their ability to confer protection, ranging from complete protection with minimal disease to no protection at all. The function or kinetics of the viral antigen expression did not correlate with protective efficacy. However, binding affinity partially predicted protection efficacy and ultimately epitope immunogenicity and recognition of infected cells offered the best correlation.     

Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8

The secreted phosphatidylserine-binding protein milk fat globule epidermal growth factor 8 (Mfge8) mediates engulfment of apoptotic germinal center B cells by tingible-body macrophages (TBMphis). Impairment of this process can contribute to autoimmunity. We show that Mfge8 is identical to the mouse follicular dendritic cell (FDC) marker FDC-M1. In bone-marrow chimeras between wild-type and Mfge8(-/-) mice, all splenic Mfge8 was derived from FDCs rather than TBMphis. However, Mfge8(-/-) TBMphis acquired and displayed Mfge8 only when embedded in Mfge8(+/+) stroma, or when situated in lymph nodes draining exogenous recombinant Mfge8. These findings indicate a licensing role for FDCs in TBMphi-mediated removal of excess B cells. Lymphotoxin-deficient mice lacked FDCs and splenic Mfge8, and suffer from autoimmunity similar to Mfge8(-/-) mice. Hence, FDCs facilitate TBMphi-mediated corpse removal, and their malfunction may be involved in autoimmunity.     

Long‐term outcomes of primary systemic light chain (AL) amyloidosis in patients treated upfront with bortezomib or lenalidomide and the importance of risk adapted strategies

Bortezomib and lenalidomide are increasingly used in patients with AL amyloidosis, but long term data on their use as primary therapy in AL amyloidosis are lacking while early mortality remains significant. Thus, we analyzed the long term outcomes of 85 consecutive unselected patients, which received primary therapy with bortezomib or lenalidomide and we prospectively evaluated a risk adapted strategy based on bortezomib/dexamethasone to reduce early mortality. Twenty‐six patients received full‐dose bortezomib/dexamethasone, 36 patients lenalidomide with oral cyclophosphamide and low‐dose dexamethasone and 23 patients received bortezomib/dexamethasone at a dose and schedule adjusted to the risk of early death. On intent to treat, 67% of patients achieved a hematologic response (24% hemCRs) and 34% an organ response; both were more frequent with bortezomib. An early death occurred in 20%: in 36% of those treated with full‐dose bortezomib/dexamethasone, in 22% of lenalidomide‐treated patients but only in 4.5% of patients treated with risk‐adapted bortezomib/dexamethasone. Activity of full vs. adjusted dose bortezomib/dexamethasone was similar; twice weekly vs. weekly administration of bortezomib also had similar activity. After a median follow up of 57 months, median survival is 47 months and is similar for patients treated with bortezomib vs. lenalidomide‐based regimens. However, risk adjusted‐bortezomib/dexamethasone was associated with improved 1‐year survival vs. full‐dose bortezomib/dexamethasone or lenalidomide‐based therapy (81% vs. 56% vs. 53%, respectively). In conclusion, risk‐adapted bortezomib/dexamethasone may reduce early mortality and preserve activity while long term follow up indicates that remissions obtained with lenalidomide or bortezomib may be durable, even without consolidation with alkylators.Am. J. Hematol. 90:E60–E65, 2015. © 2015 Wiley Periodicals, Inc.     

Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome

Introduction

The aim of this study was to investigate the kinetics of immunoglobulin M (IgM) during the different stages of sepsis.

Methods

In this prospective multicenter study, blood sampling for IgM measurement was done within the first 24 hours from diagnosis in 332 critically ill patients; in 83 patients this was repeated upon progression to more severe stages. Among these 83 patients, 30 patients with severe sepsis progressed into shock and IgM was monitored daily for seven consecutive days. Peripheral blood mononuclear cells (PBMCs) were isolated from 55 patients and stimulated for IgM production.

Results

Serum IgM was decreased in septic shock compared to patients with systemic inflammatory response syndrome (SIRS) and patients with severe sepsis. Paired comparisons at distinct time points of the sepsis course showed that IgM was decreased only when patients deteriorated from severe sepsis to septic shock. Serial measurements in these patients, beginning from the early start of vasopressors, showed that the distribution of IgM over time was significantly greater for survivors than for non-survivors. Production of IgM by PBMCs was significantly lower at all stages of sepsis compared with healthy controls.

Conclusions

Specific changes of circulating IgM occur when patients with severe sepsis progress into septic shock. The distribution of IgM is lower among non-survivors.