Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study

OBJECTIVE: To investigate the value of serum antitissue transglutaminase IgA antibodies (IgA-TTG) and IgA antiendomysial antibodies (IgA-EMA) in the diagnosis of coeliac disease in cohorts from different geographical areas in Europe. The setting allowed a further comparison between the antibody results and the conventional small-intestinal histology. METHODS: A total of 144 cases with coeliac disease [median age 19.5 years (range 0.9-81.4)], and 127 disease controls [median age 29.2 years (range 0.5-79.0)], were recruited, on the basis of biopsy, from 13 centres in nine countries. All biopsy specimens were re-evaluated and classified blindly a second time by two investigators. IgA-TTG were determined by ELISA with human recombinant antigen and IgA-EMA by an immunofluorescence test with human umbilical cord as antigen. RESULTS: The quality of the biopsy specimens was not acceptable in 29 (10.7%) of 271 cases and a reliable judgement could not be made, mainly due to poor orientation of the samples. The primary clinical diagnosis and the second classification of the biopsy specimens were divergent in nine cases, and one patient was initially enrolled in the wrong group. Thus, 126 coeliac patients and 106 controls, verified by biopsy, remained for final analysis. The sensitivity of IgA-TTG was 94% and IgA-EMA 89%, the specificity was 99% and 98%, respectively. CONCLUSIONS: Serum IgA-TTG measurement is effective and at least as good as IgA-EMA in the identification of coeliac disease. Due to a high percentage of poor histological specimens, the diagnosis of coeliac disease should not depend only on biopsy, but in addition the clinical picture and serology should be considered.     

Critical slowing down suggests that the western Greenland Ice Sheet is close to a tipping point

The Greenland Ice Sheet (GrIS) is a potentially unstable component of the Earth system and may exhibit a critical transition under ongoing global warming. Mass reductions of the GrIS have substantial impacts on global sea level and the speed of the Atlantic Meridional Overturning Circulation, due to the additional freshwater caused by increased meltwater runoff into the northern Atlantic. The stability of the GrIS depends crucially on the positive melt-elevation feedback (MEF), by which melt rates increase as the overall ice sheet height decreases under rising temperatures. Melting rates across Greenland have accelerated nonlinearly in recent decades, and models predict a critical temperature threshold beyond which the current ice sheet state is not maintainable. Here, we investigate long-term melt rate and ice sheet height reconstructions from the central-western GrIS in combination with model simulations to quantify the stability of this part of the GrIS. We reveal significant early-warning signals (EWS) indicating that the central-western GrIS is close to a critical transition. By relating the statistical EWS to underlying physical processes, our results suggest that the MEF plays a dominant role in the observed, ongoing destabilization of the central-western GrIS. Our results suggest substantial further GrIS mass loss in the near future and call for urgent, observation-constrained stability assessments of other parts of the GrIS.

During the last century, the Greenland Ice Sheet (GrIS) has lost mass at an accelerating rate (1, 2). The mass loss is caused by solid ice discharge into the North Atlantic and surface melting due to increasing temperatures. The relative contribution of the latter has increased from 42% before 2005 to 68% between 2009 and 2012, and surface runoff caused 84% of the increase in mass reduction since 2009 (3). The complete melting of the GrIS would cause a global sea level rise of more than 7 m (4, 5). Continued melting of the GrIS has been suggested to potentially lead to a collapse of the Atlantic Meridional Overturning Circulation via increased freshwater flux into the North Atlantic (6, 7), which may, in turn, trigger a cascade of transitions in additional tipping elements such as the Amazon rainforest and the tropical monsoon systems (6, 8–10).In addition to the centennial-scale variability associated with the increasing trend in mean temperatures related to anthropogenic climate change, the pace of mass loss has decadal-scale fluctuations caused by natural variations in external oceanic and atmospheric forcing. The imprints of these natural, decadal-scale fluctuations are spatially heterogeneous across the GrIS. Since the early 2000s, periods of persistently negative phases of the North Atlantic Oscillation (NAO) and a positive phase of the East Atlantic Pattern (11) have led to a weakening and southward shift of the jet stream, and more persistent blocking (12) over Greenland during summer, resulting in overall increased mass reduction rates (2, 13). On the other hand, a slowing down of mass loss since 2013—which inverted again in 2019—was caused by more periods with a persistent positive NAO (14). Moreover, recent observations show that the Jakobshavn glacier has been advancing again since 2016 due to anomalous wintertime heat loss in the boundary current around southern Greenland (15). However, these natural fluctuations do not have a sustained impact on melt rates comparable to the longer-term trend toward overall increasing melt rates caused by anthropogenic global warming (Fig. 1A).Open in a separate windowFig. 1.(A) Summer sea level temperatures from the Ilulissat station in CWG (25) (blue curves) and Arctic temperature anomalies (26) (red curves). The linear trend of the station data (dashed blue curve) corresponds to 1.3 °C warming per century. Arctic temperature anomalies are shown only for comparison; only the station data (blue curves) are used for our analysis. (B) Melt rates from the CWG ice core stack (blue curve) and the NU peninsula core (red curve), given as z scores with respect to a normal distribution (18). (C) Detrended logarithmic CWG (blue curve) and NU (red curve) melt rates. A Gaussian filter with bandwidth σ=30 y was used for detrending. The runoff and melt time series are preprocessed in this way before computing the EWS indicators to exclude potential biases by underlying trends; in particular, we take the logarithm of the melt rates in order to account for skewed data distributions. (D) The variance of the CWG (blue curves) and NU (red curves) melt rates. (E) The AC1 of the CWG (blue curves) and NU (red curves) melt rates. Note that the AC1, despite a significantly positive trend, appears to have at least temporarily stabilized in the last few decades. It should be noted, however, that the AC1 is generally influenced by (multi)decadal variability (27). The window size for computing the variance and the AC1 is w=70 y, and values are plotted at the windows’ endpoints. Data for the first w=70 y are omitted to ensure that all windows contain the same number of data points. The dashed lines in D and E indicate linear trends of the variance and AC1, and P values for positive slopes as determined from a phase surrogate test are indicated in the legend (see Materials and Methods). The statistical significance of the positive trends is robust across wide ranges of the bandwidth σ and the sliding window size (SI Appendix, Fig. S1).Early model simulations suggest that melting of the GrIS is inevitable beyond a critical global mean temperature threshold of 0.8 °C to 3.2 °C above preindustrial levels, with a best estimate of 1.6 °C (16). More recent comprehensive modeling results show that, for the representative concentration pathway 8.5 (RCP8.5), the GrIS melts entirely until AD 3000 (5). Arctic temperatures have increased more than the global average (17) (Fig. 1A), and the nonlinear increase in GrIS melt rates and runoff that have recently been detected (18) (Fig. 1B) suggests that the critical temperature threshold may be closer than previously thought. We emphasize that the surface mass balance turning negative is not a necessary condition for stability loss, and the temperature may reach a critical threshold years before a turning point in the mass balance (16).Idealized models of critical transitions in natural systems suggest that the loss of stability of an equilibrium (fixed point) is observable before the abrupt transition (19). In dynamical systems with random forcing, one can show that, if a system approaches a bifurcation where an equilibrium point loses its stability, the variance of the fluctuations around the equilibrium will increase, as will the characteristic decay time of the autocorrelation function of these fluctuations. The change in dynamics that occurs as stability is lost is often called critical slowing down, and the associated statistical precursor signs in terms of rising variance and lag-one autocorrelation (AC1) are called early-warning signals (EWS) (19). Such statistical EWS associated with critical slowing down are, for example, detectable in the temperature proxy from the North Greenland Ice Core Project before several of the Dansgaard–Oeschger events of the last glacial interval (20, 21), as well as before other abrupt transitions in past climates (22). In the context of anthropogenic global warming, EWS are expected to precede potential abrupt transitions in the Earth system’s major tipping elements, such as the polar ice sheets, the Atlantic Meridional Overturning Circulation, or the tropical monsoon systems (23). We investigate here a possible tipping point for the GrIS based on the theory of critical slowing down.In the following, we will first show that central-western Greenland (CWG) melt rates exhibit robust and significant EWS. We then reconstruct the corresponding CWG ice sheet height changes and show that they can be captured well by a simple model focusing on the melt elevation feedback (MEF). We then demonstrate that pronounced EWS can also be found in the fluctuations of the reconstructed ice sheet height around the equilibrium of the model and show that these EWS are consistent with the theoretical expectations provided by the MEF model.     

Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

BACKGROUND/AIMS: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. METHODS: In 28 liver transplant recipients, bile samples were collected daily posttransplantation for determination of bile composition. Hepatic expression of bile transporters was studied before and after transplantation. Histopathological criteria as well as biliary concentrations of alkaline phosphatase (ALP) and gamma-glutamyltransferase (gamma-GT) were used to quantify bile duct injury. RESULTS: Early after transplantation, bile salt secretion increased more rapidly than phospholipid secretion, resulting in high biliary bile salt/phospholipid ratio (BA/PL). In parallel with this, mRNA levels of the bile salt transporters NTCP and BSEP increased significantly after transplantation, whereas phospholipid translocator MDR3 mRNA levels remained unchanged. Bile duct injury correlated significantly with bile salt secretion and was associated with a high biliary BA/PL ratio. CONCLUSIONS: Bile salt secretion after human liver transplantation recovers more rapidly than phospholipid secretion. This results in cytotoxic bile formation and correlates with bile duct injury. These findings suggest that endogenous bile salts have a role in the pathogenesis of bile duct injury after liver transplantation.     

Intracellular signal transduction by the extracellular calcium-sensing receptor of Xenopus melanotrope cells

The extracellular calcium-sensing receptor (CaR) is expressed in various types of endocrine pituitary cell, but the intracellular mechanism this G protein-coupled receptor uses in these cells is not known. In the present study we investigated possible intracellular signal transduction pathway(s) utilized by the CaR of the endocrine melanotrope cells in the intermediate pituitary lobe of the South African-clawed toad Xenopus laevis. For this purpose, the effects of various pharmacological agents on CaR-evoked secretion of radiolabeled secretory peptides from cultured melanotrope cells were assessed. CaR-evoked secretion, induced by the potent CaR agonist l-phenylalanine (l-Phe), could not be inhibited by cholera toxin, nor by NPC-15437 and PMA, indicating that neither G_s/PKA nor G_q/PKC pathways are involved. However, pertussis toxin (G_i/o protein inhibitor), genistein (inhibitor of PTKs), wortmannin/LY-294002 (PI3-K inhibitor) and U-0126 (inhibitor of extracellular signal-regulated kinase, ERK) all substantially inhibited CaR-evoked secretion, indicating that the Xenopus melanotrope cell possesses a PI3-K/MAPK system that plays some role in CaR-signaling. Since no direct effect of l-Phe on ERK phosphorylation could be shown it is concluded that CaR must act primarily through another, still unknown, signaling pathway in Xenopus melanotropes. Our results indicate that the PI3-K/MAPK system has a facilitating effect on CaR-induced secretion, possibly by sensitizing the CaR.     

Repair of erosions in rheumatoid arthritis does occur. Results from 2 studies by the OMERACT Subcommittee on Healing of Erosions

The committee was charged with determining whether healing of erosions in rheumatoid arthritis (RA) occurs. Two exercises were performed: The first asked the committee members, as a panel of experts, to express agreement or disagreement with the presence of improvement and features of bone reaction to injury in images submitted by members as examples of healing. The second presented panel members with 28 pairs of serial images, 14 chosen to illustrate progression and 14 chosen to illustrate repair. Agreement was tested on 8 items: global judgment on which image in the pair was better, relative size of the erosion in the 2 images, judgment on which image was first, presence and extent of sclerosis, cortication, filling-in, remodeling, and reconstituting normal structure. Our results showed good agreement, among the 15 respondents, on global assessment of which image was better and which image showed the smaller erosion. Correct assignment of sequence was only slightly better than expected by chance (in 65% of the cases). Agreement was poor regarding the presence of morphologic features of bone repair. A majority of a panel of experts agreed on which 2nd images in a set of paired, serial images represented improvement and which showed progression based on global assessment of which was better and on size of erosion. Features of bone repair were not distinctive and did not enable the panel to deduce the correct sequence of the serial images. This study provides evidence that repair of bone damage in RA does occur, resulting in some degree of improvement, which was recognized by a majority of a panel of experts.     

The RAPID3 questionnaire as a screening tool to reduce the number of outpatient clinic visits: a retrospective cohort study

Clinical Rheumatology - Treat-to-target strategies require frequent on-site evaluations of disease activity in patients with rheumatoid arthritis (RA), burdening patients and caregivers. However,...     

Rapid bedside measurement of brain natriuretic peptide in patients with chronic heart failure

BACKGROUND: Brain natriuretic peptide (BNP) levels have been used to assess clinical status and predict prognosis of patients with chronic heart failure (CHF). However, BNP levels can only be measured in specialized laboratories which has hampered its use in daily clinical practice. We compared a new, rapid, BNP assay with a conventional BNP measurement and evaluated the applicability to current practice by comparing it with standard clinical parameters. METHODS: BNP levels were determined in 78 stable CHF patients and 20 controls. The severity of CHF was assessed by determination of New York Heart Association functional class (NYHA), left ventricular ejection fraction (LVEF) and peak oxygen consumption (peak VO(2)), and these parameters were compared to BNP levels. RESULTS: Overall, rapid BNP assessment was highly correlated with the conventional BNP assay (r=0.95, P<0.0001). In the higher ranges (>200 pmol/l), however, correlation was less accurate, and tended to overestimate. BNP levels also strongly correlated with both NYHA class, LVEF and peak VO(2) (all P<0.001). A cut-off value for BNP of 20 pmol/l yielded a sensitivity of 91% and a specificity of 92% to detect the presence of left ventricular systolic dysfunction. CONCLUSIONS: Rapid measurement of BNP levels is comparable to conventional BNP measurement and strongly correlated to clinical tests that are currently used to stratify CHF patients. Wider use of this method may yield a reduction of costly and time-consuming clinical tests and may reduce the medical burden of CHF.