Citations

Abstract Background Prior work has shown that urinary soluble CD163 (usCD163) displays excellent biomarker characteristics for detection of active renal vasculitis using samples that included new diagnoses with highly active renal disease. This study focused on the use of usCD163 in the detection of the more clinically relevant state of mild renal flare and compared results of usCD163 testing directly to testing of urinary monocyte chemoattractant protein-1 (uMCP-1). Methods Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV, n = 88) were identified within a serially sampled, longitudinal and multicentre cohort. Creatinine-normalized usCD163 and uMCP-1 levels were measured by enzyme-linked immunosorbent assay and, both alone and in combination, were compared between times of active renal AAV and during remission and/or active non-renal AAV. Results Samples from 320 study visits included times of active renal vasculitis (n = 39), remission (n = 233) and active extrarenal vasculitis (n = 48). Median creatinine levels were 0.9 mg/dL [interquartile range (IQR) 0.8–1.2] in remission and 1.4 mg/dL (IQR 1.0–1.8) during renal flare. usCD163 levels were higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 162 ng/mmol (IQR 79–337), 44 (17–104) and 38 (7–76), respectively (P < 0.001). uMCP-1 levels were also higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 10.6 pg/mmol (IQR 4.6–23.5), 4.1 (2.5–8.4) and 4.1 (1.9–6.8), respectively (P < 0.001). The proposed diagnostic cut-points for usCD163 and uMCP-1 were 72.9 ng/mmol and 10.0 pg/mmol, respectively. usCD163 and uMCP-1 levels were marginally correlated (r2 = 0.11, P < 0.001). Combining novel and existing biomarkers using recursive tree partitioning indicated that elevated usCD163 plus either elevated uMCP-1 or new/worse proteinuria improved the positive likelihood ratio (PLR) of active renal vasculitis to 19.2. Conclusion A combination of usCD163 and uMCP-1 measurements appears to be useful in identifying the diagnosis of subtle renal vasculitis flare.

Angiography in patients with unstable angina or myocardial infarction with subtotal coronary occlusions reveals eccentric stenoses with irregularborders suggesting ruptured atherosclerotic plaques. In addition, the closer the angiogram is to the time of chest pain the higher is the likelihoodof observing a thrombotic filling defect distal to the stenotic region. Thus, we: 1) have investigated the relationship among platelet-vessel wall interaction, rheology, andthrombogenicsubstrate and 2) propose a hypothesisaccounting for thrombosis in the acute coronary syndromes.1) Platelet Vessel Wall Interactions, Rheology and Substrate - We have studied substrate and rheology in both an 'ex vivo' perfusion chamber and 'in vivo'swine model. Qur results, combinedwith those of others, show the following:-Platelet Vessel Wall Interaction and Thrombus Formation - a) In superficial arterial injury plateletsadherevia platelet membrane glycoprotein (GP) lb to the vessel wall to form a monolayer. Von Willebrand Factor (vWF), a high molecular weight glycoprotein found in plasma, platelets, and endothelial cells, binds GPIb and supports platelet adhesion. Platelet derived growth factors(PDGF) from these adherent platelets may contribute to atherogenesis. b) In deep arterial injury, plateletsare stimulated by three pathways -arachidonate, ADP and the "third pathway" -leading to exposure of platelet receptors (GPIIb/IIIa), and subsequent aggregation. Fibrinogenand vWF participate in aggregation bybinding to GPIIb/IIIa. Simultaneously, thrombin stimulates aggregation andthe formation of fibrin that stabilizes platelet aggregates, c) Both a platelet monolayer and aggregation with thrombosis, produce vasoconstriction due to release of platelet products (serotonin, thromboxane A2,and PDGF).- Rheology - a) Stenotic lesions produce a high local shear rate, whichenhances platelet-vessel wall interaction and, in the presence of acute rupture, platelet deposition and subsequent thrombus formation, b) Platelet deposition and thrombosis are particularly favored if the site of rupture includes the stenosis with its high shear rate,while the stasis in the post-stenotic region favors proprogationof thrombus.- Substrate - a) Plaque rupture produces a rough surface and exposes collagen and fat to flowing blood. Thisstimulates mural thrombosis, b) Such thrombus is either fixed or labile depending on the degree of plaque rupture or damage.2) Acute and Subacute Coronary Syndromes - The above observations in the swine model, coupled with recent clinical and pathological observations support the following:-Unstable Angina - Mild or restricted plaque rupture with or without activated mural thrombus, by increasingthe stenosis, explains the increase in exertional angina; subsequent labile thrombosis with platelet-related vasoconstriction explains the resting angina.-Q Wave Myocardial Infarction - The thrombus is occlusive and fixed or persistent because the damage to the vessel wall or to the plaque is more severe or extensive than in unstable angina.-Non-Q Wave Myocardial Infarction -In this syndrome, intermediate between unstable angina and Q wave myocardial infarction, the occlusive thrombus is more transient than in Q wave infarction because of less substrate exposure or damage.

SummaryWe have developed a sensitive and quantitative method of “ex vivo” evaluation of platelet deposition on collagen strips, from rabbit Achilles tendon, superfused by flowing blood and applied it to four animal species, cat, rabbit, dog and pig. Autologous platelets were labeled with indium-111-tropolone, injected to the animal 24 hr before the superfusion and the number of deposited platelets was quantitated from the tendon gamma-radiation and the blood platelet count.We detected some platelet consumption with superfusion time when blood was reinfused entering the contralateral jugular vein after collagen contact but not if blood was discarded after the contact. Therefore, in order to have a more physiological animal model we decided to discard blood after superfusion of the tendon.In all species except for the cat there was a linear relationship between increase of platelet on the tendon and time of exposure to blood superfusion. The highest number of platelets deposited on the collagen was found in cats, the lowest in dogs.Ultrastructural analysis showed the platelets were deposited as aggregates after only 5 min of superfusion.

Objectives Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early‐onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD‐ and schizophrenia (SCZ)‐associated risk variants is associated with an earlier AAO in BD patients. Methods A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn‐Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD‐ and SCZ‐PRSs and AAO were evaluated with regression models. Results BD‐ and SCZ‐PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. Conclusions The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR) meta = 2.95, p < 2.0 × 10 −16 ). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (OR avg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR meta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10 −16 ) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

Introduction A retrospective chart review was conducted of visual analog scale (VAS) scores completed before and after trigger point injections (TPIs) for pelvic floor myofascial spasm to evaluate response. Methods Sixty-eight female patients who underwent TPIs from October 9, 2007 to March 12, 2015 were included. The primary end point was the difference between scores. Secondary analyses were conducted for patients who needed repeat TPIs. Descriptive and paired t test analyses were used. Results The key result was an improvement in VAS scores for 65% (44/68) of patients (p<0.0001). The median pre-injection VAS score was 7 (1 to 10), (mean 6.3). The median post-injection VAS score was 4 (0 to 9), (mean 4.3). The median difference between scores in patients who improved was 3 (1 to 8), (mean 3.6). Seventeen of 68 (25%) patients needed repeat TPI, and the median time between injections was 1.5 months (1 to 7 months), (mean 2.2 months). When analyzing pre-injection VAS scores in patients who underwent subsequent repeat injection when compared to patients who did not require repeat injection, there was no difference (p = 0.32). In addition, the differences between pre- and post-injection VAS scores in the patients who underwent repeat injection and those who did not was not significant (p = 0.26). Conclusions We report on 68 women who underwent TPIs, with an improvement in VAS pain scores in 65%. It appears that TPIs for pelvic floor myofascial spasm are successful in reducing pain scores for patients who are refractory to primary therapy.