Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure

<p>Abstract</p> <p>Background</p> <p>Monoclonal free light chains (FLCs) frequently cause rapidly progressive renal failure in patients with multiple myeloma. Immunoassays which provide quantitative measurement of FLCs in serum, have now been adopted into screening algorithms for multiple myeloma and other lymphoproliferative disorders. The assays indicate monoclonal FLC production by the presence of an abnormal κ to λ FLC ratio (reference range 0.26–1.65). Previous work, however, has demonstrated that in patients with renal failure the FLC ratio can be increased above normal with no other evidence of monoclonal proteins suggesting that in this population the range should be extended (reference range 0.37–3.1). This study evaluated the diagnostic sensitivity and specificity of the immunoassays in patients with severe renal failure.</p> <p>Methods</p> <p>Sera from 142 patients with new dialysis-dependent renal failure were assessed by serum protein electrophoresis (SPE), FLC immunoassays and immunofixation electrophoresis. The sensitivity and specificity of the FLC ratio's published reference range was compared with the modified renal reference range for identifying patients with multiple myeloma; by receiver operating characteristic curve analysis.</p> <p>Results</p> <p>Forty one patients had a clinical diagnosis of multiple myeloma; all of these patients had abnormal serum FLC ratios. The modified FLC ratio range increased the specificity of the assays (from 93% to 99%), with no loss of sensitivity. Monoclonal FLCs were identified in the urine from 23 of 24 patients assessed.</p> <p>Conclusion</p> <p>Measurement of serum FLC concentrations and calculation of the serum κ/λ ratio is a convenient, sensitive and specific method for identifying monoclonal FLC production in patients with multiple myeloma and acute renal failure. Rapid diagnosis in these patients will allow early initiation of disease specific treatment, such as chemotherapy plus or minus therapies for direct removal of FLCs.</p

Linking magmatism with collision in an accretionary orogen

A compilation of U-Pb age, geochemical and isotopic data for granitoid plutons in the southern Central Asian Orogenic Belt (CAOB), enables evaluation of the interaction between magmatism and orogenesis in the context of Paleo-Asian oceanic closure and continental amalgamation. These constraints, in conjunction with other geological evidence, indicate that following consumption of the ocean, collision-related calc-alkaline granitoid and mafic magmatism occurred from 255 ± 2 Ma to 251 ± 2 Ma along the Solonker-Xar Moron suture zone. The linear or belt distribution of end-Permian magmatism is interpreted to have taken place in a setting of final orogenic contraction and weak crustal thickening, probably as a result of slab break-off. Crustal anatexis slightly post-dated the early phase of collision, producing adakite-like granitoids with some S-type granites during the Early-Middle Triassic (ca. 251-245 Ma). Between 235 and 220 Ma, the local tectonic regime switched from compression to extension, most likely caused by regional lithospheric extension and orogenic collapse. Collision-related magmatism from the southern CAOB is thus a prime example of the minor, yet tell-tale linking of magmatism with orogenic contraction and collision in an archipelago-type accretionary orogen

The Role of Glypicans in Wnt Inhibitory Factor-1 Activity and the Structural Basis of Wif1's Effects on Wnt and Hedgehog Signaling

Proper assignment of cellular fates relies on correct interpretation of Wnt and Hedgehog (Hh) signals. Members of the Wnt Inhibitory Factor-1 (WIF1) family are secreted modulators of these extracellular signaling pathways. Vertebrate WIF1 binds Wnts and inhibits their signaling, but its Drosophila melanogaster ortholog Shifted (Shf) binds Hh and extends the range of Hh activity in the developing D. melanogaster wing. Shf activity is thought to depend on reinforcing interactions between Hh and glypican HSPGs. Using zebrafish embryos and the heterologous system provided by D. melanogaster wing, we report on the contribution of glypican HSPGs to the Wnt-inhibiting activity of zebrafish Wif1 and on the protein domains responsible for the differences in Wif1 and Shf specificity. We show that Wif1 strengthens interactions between Wnt and glypicans, modulating the biphasic action of glypicans towards Wnt inhibition; conversely, glypicans and the glypican-binding “EGF-like” domains of Wif1 are required for Wif1's full Wnt-inhibiting activity. Chimeric constructs between Wif1 and Shf were used to investigate their specificities for Wnt and Hh signaling. Full Wnt inhibition required the “WIF” domain of Wif1, and the HSPG-binding EGF-like domains of either Wif1 or Shf. Full promotion of Hh signaling requires both the EGF-like domains of Shf and the WIF domains of either Wif1 or Shf. That the Wif1 WIF domain can increase the Hh promoting activity of Shf's EGF domains suggests it is capable of interacting with Hh. In fact, full-length Wif1 affected distribution and signaling of Hh in D. melanogaster, albeit weakly, suggesting a possible role for Wif1 as a modulator of vertebrate Hh signaling

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Injection drug use and HIV antiretroviral therapy discontinuation in a Canadian setting

We investigated whether drug-related behaviors predicted antiretroviral therapy (ART) discontinuation among a cohort of injection drug users (IDU) in a Canadian setting. Cox regression analyses were used to investigate the impact of drug use patterns on rates of ART discontinuation among a sample of HIV-positive IDU in Vancouver, Canada between May 1996 and April 2008. In total, 408 HIV-positive IDU initiated ART during the study period, among whom 257 (63.0%) discontinued ART at least once. Rates of ART discontinuation were not significantly elevated among those who reported ongoing injection of heroin, cocaine, or other illicit drugs in comparison to those who reported not injecting drugs. However, public drug use was significantly predictive of ART discontinuation. Our findings may contribute to a reconsideration of the role of active drug use in determining retention in ART programs among IDU.Medicine, Faculty ofOther UBCMedicine, Department ofPopulation and Public Health (SPPH), School ofReviewedFacultyResearche

Modern alongside traditional taxonomy-Integrative systematics of the genera Gymnangium Hincks, 1874 and Taxella Allman, 1874 (Hydrozoa, Aglaopheniidae).

We studied the diversity within the former genus Gymnangium in the South West Indian Ocean by using an integrative approach of both traditional (morphology-based) and modern molecular taxonomy. Nine species were recorded in the material collected. A total of 97 16S mitochondrial DNA sequences and 54 Calmodulin nuclear sequences from eight Gymnangium/Taxella species were analyzed. We found both morphological and molecular differences in the studied Gymnangium species that make it necessary to split the genus. It is proposed to revalidate the genus Taxella which is currently regarded as a synonym of Gymnangium. Two species of the genus Taxella (T. eximia and T. gracilicaulis), until now regarded as distinct species based on morphological characteristics, cluster together in one phylogenetic clade. Possible explanations are discussed. Two species from Madagascar new to science are herein described and rare species from the Indian Ocean islands are re-described