STAT3 protects hematopoietic stem cells by preventing activation of a deleterious autocrine type-I interferon response.

Hematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells (LSKs) revealed aberrant activation of cell cycle, p53, and interferon (IFN) pathways in Stat3-deficient HSPCs. Stat3-deficient LSKs accumulated γH2AX and showed increased expression of DNA sensors and type-I IFN (IFN-I), while treatment with A151-ODN inhibited expression of IFN-I and IFN-responsive genes. Further, the blockade of IFN-I receptor signaling suppressed aberrant cell cycling, STAT1 activation, and nuclear p53 accumulation. Collectively, our results show that STAT3 inhibits a deleterious autocrine IFN response in HSCs to maintain long-term HSC function. These data signify the importance of ensuring therapeutic STAT3 inhibitors are targeted specifically to diseased cells to avoid off-target loss of healthy HSPCs.

Natural History of Histopathologic Changes in Cardiomyopathy of Golden Retriever Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked inherited myopathy that causes progressive skeletal and cardiac muscle disease. Heart lesions were described in the earliest DMD reports, and cardiomyopathy is now the leading cause of death. However, diagnostics and treatment for cardiomyopathy have lagged behind those for appendicular and respiratory skeletal muscle disease. Most animal model studies have been done in the mdx mouse, which has a relatively mild form of cardiomyopathy. Dogs with the genetically homologous condition, Golden Retriever muscular dystrophy (GRMD), develop progressive cardiomyopathy analogous to that seen in DMD. Previous descriptive studies of GRMD cardiomyopathy have mostly been limited to selective sampling of the hearts from young dogs. METHODS AND RESULTS: We systematically assessed cardiac lesions in 31 GRMD and carrier dogs aged 3 to 76 months and a separate cohort of 2-10-year-old normal hounds. Both semi-quantitative lesion scoring and quantitation of the cross-sectional area of fibrosis distinguished dogs with GRMD disease from normal dogs. The carriers generally had intermediate involvement but had even greater fibrosis than GRMD dogs. Fatty infiltration was the most prominent feature in some older GRMD dogs. Vascular hypertrophy was increased in GRMD dogs and correlated positively with lesion severity. Purkinje fiber vacuolation was also increased but did not correlate with lesion severity. Histopathologic changes correlated with late gadolinium enhancement on cardiac MRI. CONCLUSION: These features are generally compatible with those of DMD and further validate GRMD as a useful model to study cardiomyopathy pathogenesis and treatment. Additionally, the nature of some degenerative lesions suggests that functional hypoxia or non-thrombotic ischemia may contribute to disease progression.

Do written diagnosis-treatment recommendations on microbiological test reports improve the management of Staphylococcus aureus bacteremia? A single-center, retrospective, observational study.

The objective of this study was to assess the impact of microbiological test reports that provide specific written recommendations on the appropriate management of Staphylococcus aureus bacteremia (SAB). We performed a retrospective analysis of laboratory and clinical data of all SAB patients treated at one German University hospital, 2012-2015. Among 467 included patients, methicillin-resistant S. aureus (MRSA) accounted for 15.2% of all SAB cases. All-cause in-hospital mortality was 25.2%, and was significantly elevated in individuals aged >55 years, in MRSA bacteremia and if the source of infection remained unidentified. Focus identification was achieved in 71.1%, with the most prevalent foci being catheter-associated bloodstream infection (23.1%), soft tissue infection (15.4%), osteomyelitis (5.1%) and endocarditis (4.9%). Standardized written recommendations on microbiological test reports led to a significant increase of transesophageal echocardiography, additional imaging studies for focus identification and more frequent follow-up blood cultures, but no significant effect on mortality was observed.

Trypanosoma cruzi infection in a zoo-housed red panda in Kansas.

A 9-y-old, zoo-housed, male red panda (Ailurus fulgens) became progressively lethargic and inappetent over a 1-wk period. Physical examination was unremarkable. A complete blood count showed mild normocytic, normochromic, non-regenerative anemia with the presence of trypomastigote organisms, consistent with a Trypanosoma sp. The organism was confirmed later as Trypanosoma cruzi lineage TcI via PCR and genome sequencing. The panda was initially treated supportively; however, its clinical status within 24 h from presentation deteriorated, and euthanasia was elected. Autopsy showed severe systemic T. cruzi infection with the presence of amastigotes in the heart, brain, peripheral nerves, skeletal muscles, tongue, liver, and testes. We used genome sequencing and serology in identifying the agent.