So the doctor is burned out: What does it mean for patient care?

Abstract

The current state of physician burnout has become an increasingly popular topic of discussion and concern. Depending on how it is defined and measured by researchers, the prevalence of physician burnout ranges anywhere from 0 to 80%.¹ Emergency medicine is often cited as the specialty with some of the highest reported levels of physician burnout.² Regardless of what the "true" prevalence of physician burnout may be, most of these studies suggest the presence of a crisis. The detrimental impact of burnout on physicians is certainly of interest to physicians. What is missing from these discussions is the impact of burnout on patients, their families, and objective clinical outcomes.

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Involvement of the Na,K‐ATPase isoforms in control of cerebral perfusion

New Findings

What is the topic of this review? This review considers the role of the Na,K‐ATPase in cerebrovascular function and how it might be changed in familial hemiplegic migraine type 2 (FHM2). The primary focus will be involvement of the Na,K‐ATPase isoforms in regulation of cerebrovascular tone. What advances does it highlight? The review discusses three overall distinct mechanisms whereby the Na,K‐ATPase might be capable of regulating cerebrovascular tone. Furthermore, it discusses how changes in the Na,K‐ATPase in cerebral arteries might affect brain perfusion and thereby be involved in the FHM2 pathology.

Abstract

FHM2 has been characterized by biphasic changes in cerebral blood flow during a migraine attack; initial hypoperfusion followed by abnormal hyperperfusion of the affected hemisphere. We suggested that FHM2‐associated loss‐of‐function mutation(s) in the Na,K‐ATPase α2 isoform may be responsible for these biphasic changes in several ways. We found that reduced expression of the α2 isoform leads to sensitization of the contractile machinery to intracellular Ca²⁺ ([Ca²⁺]_i) via Src kinase dependent signal transduction. This change in sensitivity may be the underlying mechanism for both abnormally potentiated vasoconstriction and exaggerated vasorelaxation. Moreover, functional significance of the Na,K‐ATPase α2 isoform in astrocytes provides for the possibility of elevated extracellular potassium signaling from astrocytic endfeet to the vascular wall in neurovascular coupling.

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Identification of novel HLA‐A*11:01‐restricted CTL epitopes derived from the osteosarcoma antigen PBF

Abstract

Osteosarcoma is the most common malignancy of bone that affects young people. Neoadjuvant chemotherapy and surgery have significantly improved the prognosis. However, the prognosis of non‐responders to chemotherapy is still poor. To develop peptide‐based immunotherapy for osteosarcoma, we previously identified CTL epitopes derived from papillomavirus binding factor (PBF) in the context of HLA‐A2, HLA‐A24 and HLA‐B55. In the present study, we identified two novel CTL epitopes, QVT (QVTVWLLEQK) and LSA (LSALPPPLHK), in the context of HLA‐A11 using a sequence of screenings based on the predicted affinity of peptides, in vitro folding ability of a peptide/HLA‐A11 complex, reactivity of a peptide/HLA‐A11 tetramer and IFN‐γ production of T cells that was induced by mixed lymphocyte peptide culture under a limiting dilution condition. CTL clones directed to QVT and LSA peptides showed specific cytotoxicity against HLA‐A11⁺PBF⁺ osteosarcoma (HOS‐A11) cells. On the other hand, another epitope, ASV (ASVLSRRLGK), could highly induce cognate tetramer‐positive CTLs. This might be because the ASV peptide mimics the peptide ASV (R6Q) (ASVLSQRLGK) derived from bacterial polypeptides, ROK family proteins. However, ASV‐induced CTLs did not show cytokine production against the cognate peptide. In conclusion, the CTL epitopes QVT and LSA peptides might be useful for the development of immunotherapy targeting PBF for patients with osteosarcoma.

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Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long‐term hematopoiesis

Summary

Adult long‐term hematopoiesis depends on sustaining hematopoietic stem/progenitor cells (HSPCs) in bone marrow (BM) niches, where their balance of quiescence, self‐renewal, and hematopoietic differentiation is tightly regulated. While various BM stroma cells that produce niche factors have been identified, regulation of the intrinsic responsiveness of HSPCs to the niche factors remains elusive. We previously reported that mice deficient for Sipa1, a Rap1 GTPase‐activating protein, develop diverse hematopoietic disorders of late onset. Here we demonstrated that the transplantation of BM cells expressing membrane‐targeted C3G (C3G‐F), a Rap1 GTP/GDP exchanger, resulted in the progressive decline of the numbers of HSPC repopulated in BM with time and impaired long‐term hematopoiesis of all cell lineages. The C3G‐F/HSPCs were sustained for months in spleen retaining hematopoietic potential, but these cells inefficiently contributed to the overall hematopoietic reconstitution. C3G‐F/HSPCs exhibited enhanced proliferation and differentiation with accelerated progenitor cell exhaustion in response to stem cell factor (SCF). Using a Ba/F3 cell line, we confirmed that the increased basal Rap1GTP levels with C3G‐F expression caused a markedly prolonged activation of c‐Kit receptor and downstream signalling via SCF ligation. A minor population of C3G‐F/HSPCs also exhibited the enhanced proliferation in the presence of thrombopoietin (TPO) compared to Vect/HSPCs. Current results suggest an important role of the basal Rap1 activation status of HSPCs in their maintenance in BM sustaining long‐term adult hematopoiesis.

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Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

Summary

Objective

Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3‐dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N‐methyl‐d‐aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis.

Methods

C57BL/6J and Ido1 knockout mice (Ido1‐KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real‐time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry.

Results

Infected C57BL/6J mice up‐regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1‐KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1‐KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1‐KO mice.

Significance

Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.

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Issue Information

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Issue Information

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