Uric acid excretion in healthy subjects: a nomogram to assess the mechanisms underlying purine metabolic disorders

The reference range for urinary uric acid excretion has not been precisely defined. Different urinary variables have been proposed to determine the renal contribution to increased or decreased serum urate concentrations. We examined which urinary variable best indicates uric acid excretion over a wide range of serum urate concentrations. Purine metabolism was studied in 10 healthy male subjects (aged 26-58 years) both at their endogenous normal serum urate levels (normouricemic state) and after the oral administration of allopurinol (300 mg/24 h for 5 days) and ribonucleic acid (4 g/8 h for 4 days) to decrease (hypouricemic state) and increase (hyperuricemic state) serum urate concentrations, respectively. The results from patients with several conditions known to affect uric acid synthesis and/or the renal excretion of uric acid were used to validate a constructed nomogram. Over a wide range of mean serum urate levels (from 2.7 to 9.5 mg/dL) and mean 24-hour urinary uric acid excretion (171 to 1368 mg/[24 h 1.73 m(2)]), the highest correlation coefficient between serum urate and uric acid excretion was obtained for the 24-hour uric acid determination (r = 0.928; P < .001). The constructed nomogram allowed the definition of the mechanism underlying hyperuricemia and hypouricemia in patients with a myriad of diseases known to affect purine metabolism. The urinary variable that best correlates with a wide range of serum urate concentrations is 24-hour urinary uric acid excretion. The constructed nomogram allows the identification of the kidney contribution to a given purine metabolic abnormality.     

MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response

MicroRNAs (miRNAs) are small noncoding RNAs, 19-24 nucleotides in length, that regulate gene expression and are expressed aberrantly in most types of cancer. MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers. It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs. Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism, by binding as ligands to receptors of the Toll-like receptor (TLR) family, murine TLR7 and human TLR8, in immune cells, triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis. Thus, by acting as paracrine agonists of TLRs, secreted miRNAs are key regulators of the tumor microenvironment. This mechanism of action of miRNAs is implicated in tumor-immune system communication and is important in tumor growth and spread, thus representing a possible target for cancer treatment.     

The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations

The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified to mark long-lived multipotent ISCs by lineage tracing in mice; however, the functional distinctions between these two populations remain undefined. Here, we demonstrate that Bmi1 and Lgr5 mark two functionally distinct ISCs in vivo. Lgr5 marks mitotically active ISCs that exhibit exquisite sensitivity to canonical Wnt modulation, contribute robustly to homeostatic regeneration, and are quantitatively ablated by irradiation. In contrast, Bmi1 marks quiescent ISCs that are insensitive to Wnt perturbations, contribute weakly to homeostatic regeneration, and are resistant to high-dose radiation injury. After irradiation, however, the normally quiescent Bmi1(+) ISCs dramatically proliferate to clonally repopulate multiple contiguous crypts and villi. Clonogenic culture of isolated single Bmi1(+) ISCs yields long-lived self-renewing spheroids of intestinal epithelium that produce Lgr5-expressing cells, thereby establishing a lineage relationship between these two populations in vitro. Taken together, these data provide direct evidence that Bmi1 marks quiescent, injury-inducible reserve ISCs that exhibit striking functional distinctions from Lgr5(+) ISCs and support a model whereby distinct ISC populations facilitate homeostatic vs. injury-induced regeneration.     

Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation

The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs), for which hematopoietic cell transplantation (HCT) is applied to repopulate the recipient myeloid compartment, including microglia, with cells expressing the defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points after HCT, we showed the occurrence of a short-term wave of brain infiltration by a fraction of the transplanted hematopoietic progenitors, independently from the administration of a preparatory regimen and from the presence of a disease state in the brain. However, only the use of a conditioning regimen capable of ablating functionally defined brain-resident myeloid precursors allowed turnover of microglia with the donor, mediated by local proliferation of early immigrants rather than entrance of mature cells from the circulation.     

After treat-to-target: can a targeted ultrasound initiative improve RA outcomes?

For patients with rheumatoid arthritis (RA), remission can be achieved with tight control of inflammation and early use of disease modifying agents. The importance of remission as an outcome has been recently highlighted by European League Against Rheumatism recommendations. However, remission when defined by clinical remission criteria (disease activity score, simplified disease activity index, etc) does not always equate to the complete absence of inflammation as measured by new sensitive imaging techniques such as ultrasound (US) . There is evidence that imaging synovitis is frequently found in these patients and associated with adverse clinical and functional outcomes. This article reviews the data regarding remission, ultrasound imaging and outcomes in patients with RA to provide the background to a consensus statement from an international collaboration of ultrasonographers and rheumatologists who have recently formed a research network--the Targeted Ultrasound Initiative (TUI) group. The statement proposes that targeting therapy to PD activity provides superior outcomes compared with treating to clinical targets alone and introduces the rationale for a new randomised trial using targeted ultrasound in RA.