Citations

Mammalian urine contains a range of macromolecule proteins that play critical roles in renal stone formation, among which Tamm-Horsfall protein (THP) is by far the most abundant. While THP is a potent inhibitor of crystal aggregation in vitro and its ablation in vivo predisposes one of the two existing mouse models to spontaneous intrarenal calcium crystallization, key controversies remain regarding the role of THP in nephrolithiasis. By carrying out a long-range follow-up of more than 250 THP-null mice and their wild-type controls, we demonstrate here that renal calcification is a highly consistent phenotype of the THP-null mice that is age and partially gene dosage dependent, but is gender and genetic background independent. Renal calcification in THP-null mice is progressive, and by 15 mo over 85% of all the THP-null mice develop spontaneous intrarenal crystals. The crystals consist primarily of calcium phosphate in the form of hydroxyapatite, are located more frequently in the interstitial space of the renal papillae than intratubularly, particularly in older animals, and lack accompanying inflammatory cell infiltration. The interstitial deposits of hydroxyapatite observed in THP-null mice bear strong resemblances to the renal crystals found in human kidneys bearing idiopathic calcium oxalate stones. Compared with 24-h urine from the wild-type mice, that of THP-null mice is supersaturated with brushite (calcium phosphate), a stone precursor, and has reduced urinary excretion of citrate, a stone inhibitor. While less frequent than renal calcinosis, renal pelvic and ureteral stones and hydronephrosis occur in the aged THP-null mice. These results provide direct in vivo evidence indicating that normal THP plays an important role in defending the urinary system against calcification and suggest that reduced expression and/or decreased function of THP could contribute to nephrolithiasis.

Abstract Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS. Metformin is the most widely used drug for diabetes and mediates its action via activating AMP-activated protein kinase (AMPK). We provide evidence that metformin attenuates the induction of EAE by restricting the infiltration of mononuclear cells into the CNS, down-regulating the expression of proinflammatory cytokines (IFN-γ, TNF-α, IL-6, IL-17, and inducible NO synthase (iNOS)), cell adhesion molecules, matrix metalloproteinase 9, and chemokine (RANTES). Furthermore, the AMPK activity and lipids alterations (total phospholipids and in free fatty acids) were restored by metformin treatment in the CNS of treated EAE animals, suggesting the possible involvement of AMPK. Metformin activated AMPK in macrophages and thereby inhibited biosynthesis of phospholipids as well as neutral lipids and also down-regulated the expression of endotoxin (LPS)-induced proinflammatory cytokines and their mediators (iNOS and cyclooxygenase 2). It also attenuated IFN-γ and IL-17-induced iNOS and cyclooxygenase 2 expression in RAW267.4 cells, further supporting its anti-inflammatory property. Metformin inhibited T cell-mediated immune responses including Ag-specific recall responses and production of Th1 or Th17 cytokines, while it induced the generation of IL-10 in spleen cells of treated EAE animals. Altogether these findings reveal that metformin may have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases.

A prospective multicenter trial was conducted to evaluate the safety and feasibility of granulocyte colony-stimulating factor (G-CSF)–primed bone marrow (G-BM) in children receiving allogeneic bone marrow transplantation (BMT). A total of 42 children with a median age of 9.8 years (range, 0.8-17 years) were enrolled. Donors with median age of 9.2 years (range, 1.1-22 years) received 5 μg/kg per day of subcutaneous G-CSF for 5 consecutive days. BM was harvested on the fifth day. No donor experienced complications related to G-CSF administration or marrow har-vest. Median nucleated (NC) and CD34 cells infused was 6.7 × 108/kg (range, 2.4-18.5 × 108/kg) and 7.4 × 106/kg (range, 2-27.6 × 106/kg), respectively. Neutrophil and platelet engraftment was at a median of 19 days (range, 13-28 days) and 20 days (range, 9-44 days), respectively. A total of 13 (32%) patients developed grade 2 graft-versus-host disease (GVHD), and 5 (13%) of 40 evaluable patients developed chronic GVHD (3 limited and 2 extensive). Higher cell dose was not associated with increased risk of acute or chronic GVHD. Overall survival and event-free survival at 2 years were 81% and 69%, respectively. Collection of G-BM from pediatric donors is safe, and can result in high NC and CD34 cell doses that facilitate engraftment after myeloablative BMT without a discernable increase in the risk of GVHD.

Attenuation of endothelial-dependent coronary vasodilation has been reported in idiopathic dilated cardiomyopathy and anatomically normal coronaries; however, data are insufficient for understanding the incidence and extent of this finding. The response of conductance and resistance coronary arteries to endothelial stimulation with acetylcholine was examined in 25 patients. Coronary blood flow had a variable response to acetylcholine and suggested coronary endothelial dysfunction in approximately half of the patients. Abnormal endothelial dysfunction involved the large conductance epicardial coronary arteries and the small resistance vessels. Abnormal endothelial response of coronary blood flow to acetylcholine could not be predicted by demographic and hemodynamic data. Conclusions: Coronary artery endothelial function is heterogeneous in patients with idiopathic dilated cardiomyopathy. Endothelial dysfunction is present in approximately half of the cases and involves both resistance as well as conductance coronary blood vessels. Furthermore, coronary endothelial function cannot be predicted by demographic and hemo-dynamic parameters or left ventricular ejection fraction.

Purpose MDX-060 is a human anti-CD30 immunoglobulin (Ig) G1κ monoclonal antibody that inhibits growth of CD30-expressing tumor cells in preclinical models. To determine the safety, maximum-tolerated dose (MTD), and efficacy of MDX-060 in patients with relapsed or refractory CD30+ lymphomas, sequential phase I and II studies were performed. Patients and Methods In the phase I portion, MDX-060 was administered intravenously at doses of 0.1, 1, 5, or 10 mg/kg weekly for 4 weeks to cohorts of three to six patients. Twenty-one patients—16 with Hodgkin's lymphoma (HL), three with anaplastic large-cell lymphoma (ALCL), and two with CD30+ T-cell lymphoma—were enrolled. Because of the lack of a defined MTD or dose-response correlation, the phase II portion was amended to include several dose levels. In the phase II portion, an additional 51 patients, 47 with HL and four with ALCL, were treated at doses of 1, 5, 10, and 15 mg/kg. Results MDX-060 was well tolerated, and an MTD has not been identified. Only 7% of patients experienced grade 3 or 4 treatment-related adverse events. Among the 72 patients treated, clinical responses were observed in six. Twenty-five patients had stable disease, including five who remained free from progression 1 year after treatment. Conclusion MDX-060 was well tolerated at doses up to 15 mg/kg. MDX-060 has limited activity as a single agent, but the minimal toxicity observed and the significant proportion of patients with stable disease suggests that further study of MDX-060 in combination with other therapies is warranted.

OBJECTIVE—To characterize potential differences in glycemic control, plasma lipid level, and weight in a cohort of patients previously treated with troglitazone (TROG) who were switched to either pioglitazone or rosiglitazone. RESEARCH DESIGN AND METHODS—After a 2-week washout from TROG, 186 patients were randomly assigned to receive either pioglitazone (PIO) or rosiglitazone (ROSI). Weight, HbA1c, and fasting lipid profile were documented before discontinuing TROG and at 4 months after starting either pioglitazone or rosiglitazone. Secondarily, the effect of concurrent medications on study outcomes was assessed. RESULTS—A total of 127 patients completed follow-up: 67 individuals in the PIO group (32 women, 35 men) and 60 individuals in the ROSI group (33 women, 27 men). There were no significant differences in gender mix, age, weight, fasting lipid profile, or HbA1c between the ROSI and PIO groups. After 4 months of randomized treatment, no change in HbA1c from baseline between or within groups was noted. Both groups experienced an equal and significant increase in weight from baseline of ∼2.0 kg. Thiazolidinedione and HMG-CoA reductase inhibitor therapy had significant and independent effects on lipid profile (P < 0.005). Significant improvements in lipid profile were noted in the PIO group (P < 0.01), whereas none were detected with conversion to ROSI. Specifically, the PIO group experienced an average decrease in total cholesterol of ∼20 mg/dl. CONCLUSIONS—Differing effects on lipid profile were apparent after random conversion from TROG to either PIO or ROSI, despite similar weight increase and glycemic control. The clinical significance of these differences remains to be determined, and further comparative research is warranted.

Abstract Overexpression of fibroblast growth factor receptor 3 (FGFR3) is a hallmark of t(4;14) multiple myeloma (MM). To dissect the mechanism of FGFR3 oncogenesis in MM, we used 3 FGFR selective kinase inhibitors—CHIR258, PD173074, and SU5402—and FGFR3-specific siRNA to modulate FGFR3 activity. Conversely, the ligand FGF was used to stimulate FGFR3 function in human MM cells. The transcriptional response to FGFR3 modification was recorded, and gene expression changes common to all 5 modifiers were documented. Ten genes were commonly regulated. Macrophage inflammatory protein-1 alpha (MIP-1α) was the single most differentially altered gene. MIP-1 α promoter function, gene expression, and protein secretion were each down-regulated following inhibition of FGFR3 signaling. Down-regulation of MIP-1 α was not, however, observed following FGFR3 inhibition in MM cells with RAS mutations implicating RAS-MAPK in MIP-1 α regulation. As confirmation, inhibition of ERK1 also down-regulated MIP-1 α in FGFR3 inhibitor-resistant cells harboring RAS mutations. MIP-1 α is implicated in the survival and proliferation of MM cells and the pathogenesis of MM bone disease. Our observation is the first to directly link an initiating IgH translocation not only to MM-cell growth and survival but also to the disease-associated bone disease.