Initiation of Allopurinol at First Medical Contact for Acute Attacks of Gout: A Randomized Clinical Trial

ObjectiveStreamlining the initiation of allopurinol could result in a cost benefit for a common medical problem and obviate the perception that no treatment is required once acute attacks have resolved. Our objective was to test the hypothesis that there is no difference in patient daily pain or subsequent attacks with early versus delayed initiation of allopurinol for an acute gout attack.MethodsA total of 57 men with crystal-proven gout were randomized to allopurinol 300 mg daily or matching placebo for 10 days. All subjects received indomethacin 50 mg 3 times per day for 10 days, a prophylactic dose of colchicine 0.6 mg 2 times per day for 90 days, and open-label allopurinol starting at day 11. Primary outcome measures were pain on visual analogue scale (VAS) for the primary joint on days 1 to 10 and self-reported flares in any joint through day 30.ResultsOn the basis of 51 evaluable subjects (allopurinol in 26, placebo in 25), mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10. Initial VAS pain scores for allopurinol and placebo arms were 6.72 versus 6.28 (P = .37), declining to 0.18 versus 0.27 (P = .54) at day 10, with neither group consistently having more daily pain. Subsequent flares occurred in 2 subjects taking allopurinol and 3 subjects taking placebo (P = .60). Although urate levels decreased rapidly in the allopurinol group (from 7.8 mg/dL at baseline to 5.9 mg/dL at day 3), sedimentation rates and C-reactive protein levels did not differ between groups at any point.ConclusionsAllopurinol initiation during an acute gout attack caused no significant difference in daily pain, recurrent flares, or inflammatory markers.     

Discovery of putative salivary biomarkers for Sjögren's syndrome using high resolution mass spectrometry and bioinformatics

The purpose of the current study was to determine if saliva contains biomarkers that can be used as diagnostic tools for Sj?gren's syndrome (SjS). Twenty seven SjS patients and 27 age-matched healthy controls were recruited for these studies. Unstimulated glandular saliva was collected from the Wharton's duct using a suction device. Two μl of salvia were processed for mass spectrometry analyses on a prOTOF 2000 matrix-assisted laser desorption/ionization orthogonal time of flight (MALDI O-TOF) mass spectrometer. Raw data were analyzed using bioinformatic tools to identify biomarkers. MALDI O-TOF MS analyses of saliva samples were highly reproducible and the mass spectra generated were very rich in peptides and peptide fragments in the 750-7,500 Da range. Data analysis using bioinformatic tools resulted in several classification models being built and several biomarkers identified. One model based on 7 putative biomarkers yielded a sensitivity of 97.5%, specificity of 97.8% and an accuracy of 97.6%. One biomarker was present only in SjS samples and was identified as a proteolytic peptide originating from human basic salivary proline-rich protein 3 precursor. We conclude that salivary biomarkers detected by high-resolution mass spectrometry coupled with powerful bioinformatic tools offer the potential to serve as diagnostic/prognostic tools for SjS.     

Serial head circumference and neurodevelopmental screening after surgical correction for single- and multiple-suture craniosynostosis

Objective : To evaluate serial head circumference (HC) measurements and neurodevelopmental (ND) screening before and after surgical revision for craniosynostosis. Design : Retrospective assessment. Setting : Tertiary institutional. Patients, Participants : All children treated with single-stage frontal-orbital advancement or total calvarial expansion for single-suture (SS) or multiple-suture (MS) craniosynostosis over a 7-year period. Main Outcome Measures : Changes in ND and HC were measured over postoperative visits after the primary surgery. More importantly, ND and HC changes were measured prerevision and postrevision. Results : Of 183 patients undergoing primary surgery, complete records and adequate follow-up were available for 112 patients. The overall revision rate was 21% (n = 23). Postrevision follow-up was adequate for 18 of the 23 revisions. After primary surgery, but prior to revision, children demonstrated a larger decline in HC (z-score, median = -1) along with higher ND findings (median = 2) from one postoperative visit to the next than those who did not go on revision (HC z-score median = 0, ND median = 0). After revision, patients demonstrated a significant improvement in ND screening findings (median ΔND findings = -2) compared with prerevision ND (p < .001). Head circumference also significantly increased by a z-score of +1 postrevision (p = .001). Conclusions : Patients chosen for revision surgery display not only a larger decline in HC but also more ND findings prior to revision. Furthermore, surgical revision has a significant association with both improved ND screening and HC.     

Fatal immune dysregulation due to a gain of glycosylation mutation in lymphocyte perforin

Mutations in the perforin gene (PRF1) are a common cause of the fatal immune dysregulation disorder, familial hemophagocytic lymphohistiocytosis (type 2 FHL, FHL2). Here we report a female infant born with biallelic PRF1 mutations: a novel substitution, D49N, and a previously identified in-frame deletion, K285del. We assessed the effects of each mutation on the cytotoxicity of human NK cells in which the expression of endogenous perforin was ablated with miR30-based short hairpin (sh) RNAs. Both mutations were detrimental for function, thereby explaining the clinically severe presentation and rapidly fatal outcome. We demonstrate that D49N exerts its deleterious effect by generating an additional (third) N-linked glycosylation site, resulting in protein misfolding and degradation in the killer cell. Our data provide a rationale for treating some cases of type 2 familial hemophagocytic lymphohistiocytosis, based on the pharmacologic inhibition or modification of glycosylation.     

The thrombopoietin/MPL/Bcl-xL pathway is essential for survival and self-renewal in human preleukemia induced by AML1-ETO

AML1-ETO (AE) is a fusion product of translocation (8;21) that accounts for 40% of M2 type acute myeloid leukemia (AML). In addition to its role in promoting preleukemic hematopoietic cell self-renewal, AE represses DNA repair genes, which leads to DNA damage and increased mutation frequency. Although this latter function may promote leukemogenesis, concurrent p53 activation also leads to an increased baseline apoptotic rate. It is unclear how AE expression is able to counterbalance this intrinsic apoptotic conditioning by p53 to promote survival and self-renewal. In this report, we show that Bcl-xL is up-regulated in AE cells and plays an essential role in their survival and self-renewal. Further investigation revealed that Bcl-xL expression is regulated by thrombopoietin (THPO)/MPL-signaling induced by AE expression. THPO/MPL-signaling also controls cell cycle reentry and mediates AE-induced self-renewal. Analysis of primary AML patient samples revealed a correlation between MPL and Bcl-xL expression specifically in t(8;21) blasts. Taken together, we propose that survival signaling through Bcl-xL is a critical and intrinsic component of a broader self-renewal signaling pathway downstream of AML1-ETO-induced MPL.