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GDNF signaling through the Ret receptor tyrosine kinase (RTK) is required for ureteric bud (UB) branching morphogenesis during kidney development in mice and humans. Furthermore, many other mutant genes that cause renal agenesis exert their effects via the GDNF/RET pathway. Therefore, RET signaling is believed to play a central role in renal organogenesis. Here, we re-examine the extent to which the functions of Gdnf and Ret are unique, by seeking conditions in which a kidney can develop in their absence. We find that in the absence of the negative regulator Spry1, Gdnf, and Ret are no longer required for extensive kidney development. Gdnf−/−;Spry1−/− or Ret−/−;Spry1−/− double mutants develop large kidneys with normal ureters, highly branched collecting ducts, extensive nephrogenesis, and normal histoarchitecture. However, despite extensive branching, the UB displays alterations in branch spacing, angle, and frequency. UB branching in the absence of Gdnf and Spry1 requires Fgf10 (which normally plays a minor role), as removal of even one copy of Fgf10 in Gdnf−/−;Spry1−/− mutants causes a complete failure of ureter and kidney development. In contrast to Gdnf or Ret mutations, renal agenesis caused by concomitant lack of the transcription factors ETV4 and ETV5 is not rescued by removing Spry1, consistent with their role downstream of both RET and FGFRs. This shows that, for many aspects of renal development, the balance between positive signaling by RTKs and negative regulation of this signaling by SPRY1 is more critical than the specific role of GDNF. Other signals, including FGF10, can perform many of the functions of GDNF, when SPRY1 is absent. But GDNF/RET signaling has an apparently unique function in determining normal branching pattern. In contrast to GDNF or FGF10, Etv4 and Etv5 represent a critical node in the RTK signaling network that cannot by bypassed by reducing the negative regulation of upstream signals.

TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ.

Hematopoietic stem cells (HSCs) produce most cellular energy through glycolysis rather than through mitochondrial respiration. Consistent with this notion, mitochondrial mass has been reported to be low in HSCs. However, we found that staining with mitotracker green, a commonly used dye to measure mitochondrial content, leads to artifactually low fluorescence specifically in HSCs because of dye efflux. Using mtDNA quantification, enumeration of mitochondrial nucleoids and fluorescence intensity of a genetically encoded mitochondrial reporter we unequivocally show here that HSCs and multipotential progenitors (MPPs) have higher mitochondrial mass than lineage-committed progenitors and mature cells. Despite similar mitochondrial mass, respiratory capacity of MPPs exceeds that of HSCs. Furthermore, although elevated mitophagy has been invoked to explain low mitochondrial mass in HSCs, we observed that mitochondrial turnover capacity is comparatively low in HSCs. We propose that the role of mitochondria in HSC biology may have to be revisited in light of these findings.

Objective: To measure longitudinal use of stroke prevention medications following stroke hospital discharge. We hypothesized that a combination of patient-, provider-, and system-level factors influence medication-taking behavior. Design: Observational cohort design. Setting: One hundred six US hospitals participating in the American Heart Association Get With The Guidelines-Stroke program. Patients: Two thousand eight hundred eighty-eight patients 18 years or older admitted with ischemic stroke or transient ischemic attack. Main Outcome Measure: Regimen persistence, including use of antiplatelet therapies, warfarin, antihypertensive therapies, lipid-lowering therapies, or diabetes medications, from discharge to 3 months. Reasons for nonpersistence were also ascertained. Results: Two thousand five hundred ninety-eight patients (90.0%) were eligible for analysis. At 3 months, 75.5% of subjects continued taking all secondary prevention medications prescribed at discharge. Persistence at 3 months was associated with decreasing number of medication classes prescribed, increasing age, medical history, less severe stroke disability, having insurance, working status, understanding why medications are prescribed and how to refill them, increased quality of life, financial hardship, geographic region, and hospital size. Conclusions: One-quarter of stroke patients reported discontinuing 1 or more of their prescribed regimen of secondary prevention medications within 3 months of hospitalization for an acute stroke. Several modifiable factors associated with regimen persistence were identified and could be targets for improving long-term secondary stroke prevention.

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