Citations

Abstract BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF–APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF-κB activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF–APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation.

Three normal, three stable diabetic, and eight unstable diabetic subjects were investigated, with continuous automated blood glucose analysis for forty-eight-hour periods, during metabolic balance studies of six days' duration under near normal conditions (fed and ambulatory) after the attainment of clinically optimal diabetic regulation. The studies on unstable diabetics were performed during constant dietary intake, with one or two daily injections of intermediate-acting insulin and then repeated with four daily injections of short-acting insulin. A characteristic of blood glucose behavior, the mean amplitude of glycemic excursion (MAGE), was measured. MAGE was small for normals (range, 22 to 60 mg./100 ml.), larger for stable diabetics (67 to 82 mg./100 ml.), and largest for unstable diabetics (119 to 200 mg./100 ml.). Associated with a significant decrease (p = 0.004) in the mean diurnal glycemic level (from 146 to 244 mg,/100 ml. to 101 to 152 mg./100 ml.) achieved through the use of four daily doses of short-acting insulin there was a significant increase (p = 0.006) in hypoglycemic episodes (from 0 to 4/48 hr. to 3 to 6/48 hr.) without significant change in MAGE. The persistently large value of MAGE despite therapy with multiple injections of short-acting insulin appears to be a characteristic of unstable diabetes.

Abstract BACKGROUND N-terminal pro B-type natriuretic peptide (NT-proBNP) has strong prognostic value for all-cause mortality in the general population. High-sensitivity assays now allow detection of cardiac troponins even in asymptomatic populations. We examined the association between NT-proBNP, high-sensitivity cardiac troponin T (hs-cTnT), and hs-cTnI and all-cause mortality in older adults. METHODS We conducted a longitudinal cohort study [Activity and Function in the Elderly in Ulm (ActiFE Ulm)] including 1506 community-dwelling adults ≥65 years old with NT-proBNP, hs-cTnT, and hs-cTnI measured at baseline. We evaluated the associations between log-transformed biomarker concentrations and 4-year total mortality, accounting for possible confounders, with Cox proportional hazards models. RESULTS We observed 125 deaths among 1422 participants (median follow-up 4 years). We detected effect modification by sex for all biomarkers (all P values <0.05) expressed as hazard ratio (HR) for death per 1-unit increment of ln(biomarker concentration) in women (n = 618, 37 deaths) compared with men (n = 804, 88 deaths): HR 2.97 (95% CI 2.04–4.33) vs 1.73 (1.40–2.13) for NT-proBNP; 3.67 (2.31–5.81) vs 2.15 (1.61–2.87) for hs-cTnT; and 3.32 (2.13–5.18) vs 1.92 (1.55–2.38) for hs-cTnI. Among 777 participants with undetectable hs-cTnT (<5 ng/L), hs-cTnI remained associated with all-cause mortality in age- and sex-adjusted analysis. CONCLUSIONS NT-proBNP, hs-cTnT, and hs-cTnI were independently associated with all-cause mortality in older adults. The strength of these associations varied between men and women, emphasizing the need for additional sex-specific research among older people.

Vasopressin and V2 receptor signaling promote polycystic kidney disease (PKD) progression, raising the question whether suppression of vasopressin release through enhanced hydration can delay disease advancement. Enhanced hydration by adding 5% glucose to the drinking water has proven protective in a rat model orthologous to autosomal recessive PKD. We wanted to exclude a glucose effect and explore the influence of enhanced hydration in a mouse model orthologous to autosomal dominant PKD. PCK rats were assigned to normal water intake (NWI) or high water intake (HWI) groups achieved by feeding a hydrated agar diet (HWI-agar) or by adding 5% glucose to the drinking water (HWI-glucose), with the latter group used to recapitulate previously published results. Homozygous Pkd1 R3277C ( Pkd1RC/RC) mice were assigned to NWI and HWI-agar groups. To evaluate the effectiveness of HWI, kidney weight and histomorphometry were assessed, and urine vasopressin, renal cAMP levels, and phosphodiesterase activities were measured. HWI-agar, like HWI-glucose, reduced urine vasopressin, renal cAMP levels, and PKD severity in PCK rats but not in Pkd1RC/RC mice. Compared with rat kidneys, mouse kidneys had higher phosphodiesterase activity and lower cAMP levels and were less sensitive to the cystogenic effect of 1-deamino-8-d-arginine vasopressin, as previously shown for Pkd1RC/RC mice and confirmed here in Pkd2WS25/− mice. We conclude that the effect of enhanced hydration in rat and mouse models of PKD differs. More powerful suppression of V2 receptor-mediated signaling than achievable by enhanced hydration alone may be necessary to affect the development of PKD in mouse models.

The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vaptans acting on the vasopressin V2 receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization.

ABSTRACT A process employing patient- or parent-collected pharyngeal swabs for group A Streptococcus (GAS) testing would expedite diagnosis and treatment, reduce patient exposure to the health care setting, and decrease health care costs. Our aim was to determine the concordance between patient- or parent-collected (self-collected) and health care worker (HCW)-collected pharyngeal swabs for detection of GAS by PCR. From 9 October 2012 to 21 March 2013, patients presenting with a sore throat meeting criteria for GAS testing and not meeting criteria for severe disease were offered the opportunity to collect their own pharyngeal swab. The HCW also collected a swab. Paired swabs were tested by GAS real-time PCR, allowing semiquantitative comparisons between positive results. Of the 402 participants, 206 had a swab collected by the patient and 196 a swab collected by the parent. The percent positivity results were 33.3% for HCW-collected swabs and 34.3% for self-collected swabs ( P = 0.41). The overall concordance between the two collection strategies was 94.0% (95% confidence interval [CI], 91.3 to 96.0). Twenty-four of the paired swabs had discordant results, with 10 and 14 positives detected only with the HCW- and self-collected swabs, respectively ( P = 0.41). The person collecting the swab in the self-collected arm, the order of collection, and prior swab collection training did not influence results. Among the 124 specimens that were positive by both collection methods, the amount of GAS DNA was higher in the self-collected versus the HCW-collected swabs ( P = 0.008). Self-collected pharyngeal swabs provide a reliable alternative to HCW collection for detection of GAS and offer a strategy for improved health care delivery.

Background and aims Peripancreatic fat necrosis occurs frequently in necrotising pancreatitis. Distinguishing markers from mediators of severe acute pancreatitis (SAP) is important since targeting mediators may improve outcomes. We evaluated potential agents in human pancreatic necrotic collections (NCs), pseudocysts (PCs) and pancreatic cystic neoplasms and used pancreatic acini, peripheral blood mononuclear cells (PBMC) and an acute pancreatitis (AP) model to determine SAP mediators. Methods We measured acinar and PBMC injury induced by agents increased in NCs and PCs. Outcomes of caerulein pancreatitis were studied in lean rats coadministered interleukin (IL)-1β and keratinocyte chemoattractant/growth-regulated oncogene, triolein alone or with the lipase inhibitor orlistat. Results NCs had higher fatty acids, IL-8 and IL-1β versus other fluids. Lipolysis of unsaturated triglyceride and resulting unsaturated fatty acids (UFA) oleic and linoleic acids induced necro-apoptosis at less than half the concentration in NCs but other agents did not do so at more than two times these concentrations. Cytokine coadministration resulted in higher pancreatic and lung inflammation than caerulein alone, but only triolein coadministration caused peripancreatic fat stranding, higher cytokines, UFAs, multisystem organ failure (MSOF) and mortality in 97% animals, which were prevented by orlistat. Conclusions UFAs, IL-1β and IL-8 are elevated in NCs. However, UFAs generated via peripancreatic fat lipolysis causes worse inflammation and MSOF, converting mild AP to SAP.

Background The greatest potential to reduce the burden of stroke is by primary prevention of first-ever stroke, which constitutes three quarters of all stroke. In addition to population-wide prevention strategies (the ‘mass’ approach), the ‘high risk’ approach aims to identify individuals at risk of stroke and to modify their risk factors, and risk, accordingly. Current methods of assessing and modifying stroke risk are difficult to access and implement by the general population, amongst whom most future strokes will arise. To help reduce the burden of stroke on individuals and the population a new app, the Stroke Riskometer™, has been developed. We aim to explore the validity of the app for predicting the risk of stroke compared with current best methods. Methods 752 stroke outcomes from a sample of 9501 individuals across three countries (New Zealand, Russia and the Netherlands) were utilized to investigate the performance of a novel stroke risk prediction tool algorithm (Stroke Riskometer™) compared with two established stroke risk score prediction algorithms (Framingham Stroke Risk Score [FSRS] and QStroke). We calculated the receiver operating characteristics (ROC) curves and area under the ROC curve (AUROC) with 95% confidence intervals, Harrels C-statistic and D-statistics for measure of discrimination, R2 statistics to indicate level of variability accounted for by each prediction algorithm, the Hosmer-Lemeshow statistic for calibration, and the sensitivity and specificity of each algorithm. Results The Stroke Riskometer™ performed well against the FSRS five-year AUROC for both males (FSRS = 75·0% (95% CI 72·3%–77·6%), Stroke Riskometer™ = 74·0(95% CI 71·3%–76·7%) and females [FSRS = 70·3% (95% CI 67·9%–72·8%, Stroke Riskometer™ = 71·5% (95% CI 69·0%–73·9%)], and better than QStroke [males–59·7% (95% CI 57·3%–62·0%) and comparable to females = 71·1% (95% CI 69·0%–73·1%)]. Discriminative ability of all algorithms was low (C-statistic ranging from 0·51–0·56, D-statistic ranging from 0·01–0·12). Hosmer-Lemeshow illustrated that all of the predicted risk scores were not well calibrated with the observed event data ( P < 0·006). Conclusions The Stroke Riskometer™ is comparable in performance for stroke prediction with FSRS and QStroke. All three algorithms performed equally poorly in predicting stroke events. The Stroke Riskometer™ will be continually developed and validated to address the need to improve the current stroke risk scoring systems to more accurately predict stroke, particularly by identifying robust ethnic/race ethnicity group and country specific risk factors.

Lung diseases, such as bronchopulmonary dysplasia (BPD), wheezing, and asthma, remain significant causes of morbidity and mortality in the pediatric population, particularly in the setting of premature birth. Pulmonary outcomes in these infants are highly influenced by perinatal exposures including prenatal inflammation, postnatal intensive care unit interventions, and environmental agents. Here, there is strong evidence that perinatal supplemental oxygen administration has significant effects on pulmonary development and health. This is of particular importance in the preterm lung, where premature exposure to room air represents a hyperoxic insult that may cause harm to a lung primed to develop in a hypoxic environment. Preterm infants are also subject to increased episodes of hypoxia, which may also result in pulmonary damage and disease. Here, we summarize the current understanding of the effects of oxygen on the developing lung and how low vs. high oxygen may predispose to pulmonary disease that may extend even into adulthood. Better understanding of the underlying mechanisms will help lead to improved care and outcomes in this vulnerable population.

Serum amyloid A (A‐SAA/Saa3) was shown before to affect osteoblastic metabolism. Here, using RT‐quantitative PCR and/or immunoblotting, we show that expression of mouse Saa3 and human SAA1 and SAA2 positively correlates with increased cellular maturation toward the osteocyte phenotype. Expression is not detected in C3H10T1/2 embryonic fibroblasts but is successively higher in preosteoblastic MC3T3‐E1 cells, late osteoblastic MLO‐A5 cells, and MLO‐Y4 osteocytes, consistent with findings using primary bone cells from newborn mouse calvaria. Recombinant Saa3 protein functionally inhibits osteoblast differentiation as reflected by reductions in the expression of osteoblast markers and decreased mineralization in newborn mouse calvaria. Yet, Saa3 protein enhances osteoclastogenesis in mouse macrophages/monocytes based on the number of multinucleated and tartrate‐resistant alkaline phosphatase‐positive cells and Calcr mRNA expression. Depletion of Saa3 in MLO osteocytes results in the loss of the mature osteocyte phenotype. Recombinant osteocalcin, which is reciprocally regulated with Saa3 at the osteoblast/osteocyte transition, attenuates Saa3 expression in MLO‐Y4 osteocytes. Mechanistically, Saa3 produced by MLO‐Y4 osteocytes is integrated into the extracellular matrix of MC3T3‐E1 osteoblasts, where it associates with the P2 purinergic receptor P2rx7 to stimulate Mmp13 expression via the P2rx7/MAPK/ERK/activator protein 1 axis. Our data suggest that Saa3 may function as an important coupling factor in bone development and homeostasis.—Thaler, R., Sturmlechner, I., Spitzer, S., Riester, S. M., Rumpler, M., Zwerina, J., Klaushofer, K., vanWijnen, A. J., Varga, F. Acute‐phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis. FASEB J. 29, 1344‐1359 (2015). www.fasebj.org