Secondary Hemophagocytic Lymphohistiocytosis Causing Hemorrhagic Encephalomyelitis and Spinal Subarachnoid Hemorrhage: A Case Report.

We are writing to present an interesting and novel case from our practice of a patient who presented with altered mental status and a rapidly progressive paraplegia as well as high fevers and pancytopenia. A bone marrow biopsy was diagnostic of hemophagocytic lymphohistiocytosis (HLH) and MRI showed hemorrhagic encephalitis and spinal subarachnoid hemorrhage. This case demonstrates the diverse neurological symptoms with which HLH presents, including spinal cord pathology. The astute neurologist should consider this diagnosis in the appropriate clinical context and diagnosis may require imaging to the complete neuraxis.

Mutagenesis of human genomes by endogenous mobile elements on a population scale.

Several large-scale Illumina whole-genome sequencing (WGS) and whole-exome sequencing (WES) projects have emerged recently that have provided exceptional opportunities to discover mobile element insertions (MEIs) and study the impact of these MEIs on human genomes. However, these projects also have presented major challenges with respect to the scalability and computational costs associated with performing MEI discovery on tens or even hundreds of thousands of samples. To meet these challenges, we have developed a more efficient and scalable version of our mobile element locator tool (MELT) called CloudMELT. We then used MELT and CloudMELT to perform MEI discovery in 57,919 human genomes and exomes, leading to the discovery of 104,350 nonredundant MEIs. We leveraged this collection (1) to examine potentially active L1 source elements that drive the mobilization of new Alu, L1, and SVA MEIs in humans; (2) to examine the population distributions and subfamilies of these MEIs; and (3) to examine the mutagenesis of GENCODE genes, ENCODE-annotated features, and disease genes by these MEIs. Our study provides new insights on the L1 source elements that drive MEI mutagenesis and brings forth a better understanding of how this mutagenesis impacts human genomes.

PD-1 deficiency augments bone marrow failure in a minor-histocompatibility antigen mismatch lymphocyte infusion model.

Although PD-1 blockade has revolutionized cancer immunotherapy, immune-related adverse events (irAEs) present life-threatening complications. Recent reports of aplastic anemia (AA) as irAEs implicate PD-1/PD-L1 as important in preventing immune-mediated destruction of the hematopoietic niche. Infusion of PD-1-deficient (PD-1 knockout [KO]) lymph node (LN) cells into minor-antigen mismatched mice resulted in early mortality, as well as more severe bone marrow (BM) hypoplasia, anemia, and BM microarchitecture disruption in PD-1 KO LN-infused mice relative to mice that received B6 LN cell infusion. Mice that received PD-1 KO LN cells had more CD8+ T-cell infiltration of the BM and greater expansion of H60-specific CD8+ T cells than did their B6 LN-infused counterparts. In the spleen, CD8+ T cells were skewed to an effector memory phenotype, suggesting accelerated differentiation of PD-1 KO T cells. Our data suggest that PD-1 dysregulation has a role in murine BM failure and vigilance in irAE monitoring may be desirable to treat early AA and related cytopenias.

Assessment of cardiovascular disease risk factors in the coastal region of South Carolina.

OBJECTIVE: To assess risk factors for cardiovascular disease, barriers to health care, and desired health care education topics for Hispanics in the coastal region of South Carolina known as the Lowcountry. METHODS: 174 Hispanic adults were surveyed at visits at the Mexican consulate using a novel interview instrument. The prevalence of cardiovascular risk factors was compared to the Behavioral Risk Factor Surveillance System (BRFSS), an annual telephone survey, to evaluate the validity of the survey instrument. RESULTS: Results are comparable to the BRFSS telephone study of the Hispanics in the same area. However, participants in our study were older (Age > 35 = 41.4% vs. 34.9%) and reported fewer years of formal education (higher level education = 12.9% vs. 44.2%). Cost of care (72.8%) and language barriers (46.8%) were the main difficulties reported in obtaining health care access. The main educational topics of interest were diabetes (61.5%), hypertension (43.7%), stress (42.5%), and cardiac disease (40.2%). CONCLUSION: Our study supports the evidence that there is a demand and need for cardiovascular disease and diabetes education among Hispanics. Our study also shows that a large proportion of Hispanics experience barriers to health care. and that large telephone studies may underrepresent higher risk Hispanic populations.

G-CSF/anti-G-CSF antibody complexes drive the potent recovery and expansion of CD11b+Gr-1+ myeloid cells without compromising CD8+ T cell immune responses.

BACKGROUND: Administration of recombinant G-CSF following cytoreductive therapy enhances the recovery of myeloid cells, minimizing the risk of opportunistic infection. Free G-CSF, however, is expensive, exhibits a short half-life, and has poor biological activity in vivo. METHODS: We evaluated whether the biological activity of G-CSF could be improved by pre-association with anti-G-CSF mAb prior to injection into mice. RESULTS: We find that the efficacy of G-CSF therapy can be enhanced more than 100-fold by pre-association of G-CSF with an anti-G-CSF monoclonal antibody (mAb). Compared with G-CSF alone, administration of G-CSF/anti-G-CSF mAb complexes induced the potent expansion of CD11b+Gr-1+ myeloid cells in mice with or without concomitant cytoreductive treatment including radiation or chemotherapy. Despite driving the dramatic expansion of myeloid cells, in vivo antigen-specific CD8+ T cell immune responses were not compromised. Furthermore, injection of G-CSF/anti-G-CSF mAb complexes heightened protective immunity to bacterial infection. As a measure of clinical value, we also found that antibody complexes improved G-CSF biological activity much more significantly than pegylation. CONCLUSIONS: Our findings provide the first evidence that antibody cytokine complexes can effectively expand myeloid cells, and furthermore, that G-CSF/anti-G-CSF mAb complexes may provide an improved method for the administration of recombinant G-CSF.