Inhibitory effects of rat alpha2 macroferoprotein (alphaMFP), an acute phase globulin, on galactosamine hepatitis.

Refractoriness to Gal N toxicity occurs especially in fetal rats, newborn rats, and in rats after partial hepatectomy. An injury however (laparotomy, incision on the back or ip BaSO₄ suspension), prior to Gal N administration, also inhibits Gal N toxicity. In all these circumstances high levels of rat α₂-macrofetoprotein (α_MFP) occur. This protein is an acute phase reactant and is identical to rat α₂-macroglobulin. α_MFP isolated from the serum of injured rats and then administered to normal rats strongly inhibits Gal N toxicity. When time interval between the preceding injury, provoking α_MFP production and Gal N administration shortens, the inhibiting effects are less and α_MFP production remains low.During resistance to Gal N, the primary and secondary biochemical lesions of Gal N persist and the protecting effect of α_MFP must be due to another mechanism, operating in later phases of cell injury. Very probably this is attributable to the stabilizing effect on membranes of hepatocytic organelles and the plasma membranes. As α_MFP is an acute phase reactant the importance of these proteins to the course of hepatitis must be considered.     

Impact of antigen expression kinetics on the effectiveness of HIV-specific cytotoxic T lymphocytes

Recent studies indicate that the time required for virus-infected cells to become vulnerable for the activity of CTL is of significance for the capacity of CTL to control ongoing viral reproduction. To investigate whether this applies to the effectiveness of HIV-1-specific CTL, we measured virus production in cultures containing CD4(+) T cells inoculated with HIV at low multiplicity of infection, and CTL directed against an early protein, Rev, or a late protein, RT. The Rev-specific CTL prevented at least 2 log(10) more HIV-1 production, in 10 days, than similar numbers of RT-specific CTL. To study how CTL effectiveness depends on variations in the potency of effector functions and kinetics of HIV protein expression, we developed a mathematical model describing CTL-target cell interactions during successive infection cycles. The results show that substantially higher CTL-mediated target cell elimination rates are required to achieve control as there is less time for CTL to act before infected cells release progeny virions. Furthermore, in vitro experiments with HIV recombinant viruses showed that the RT-specific CTL were at least as effective as the Rev-specific CTL, but only if the RT epitope was expressed as part of the early protein Nef. Together these results indicate that CTL control ongoing HIV reproduction more effectively if they are able to recognize infected cells earlier during individual viral replication cycles. This provides rationale for immunization strategies that aim at inducing, boosting or skewing CTL responses to early regulatory proteins in AIDS vaccine development.     

Unfiltered coffee increases plasma homocysteine concentrations in healthy volunteers: a randomized trial

BACKGROUND: An elevated plasma homocysteine concentration is a putative risk factor for cardiovascular disease. Observational studies have reported an association between coffee consumption and plasma homocysteine concentrations. OBJECTIVE: We studied the effect of coffee consumption on plasma homocysteine in a crossover trial. We used unfiltered coffee so as to include the possible effects of coffee diterpenes, which are removed by filtering. DESIGN: Sixty-four healthy volunteers (31 men and 33 women) with a mean (+/-SD) age of 43 +/- 11 y were randomly assigned to 2 groups. One group (n = 30) drank 1 L unfiltered cafetière (French press) coffee daily for 2 wk. Such coffee is rich in the cholesterol-raising diterpenes kahweol and cafestol. The other group (n = 34) received water, milk, broth, tea, and chocolate drinks instead of coffee. After a washout period of 8 wk, both groups received the alternate intervention for another 2 wk. RESULTS: Consumption of 1 L unfiltered coffee/d for 2 wk significantly raised fasting plasma homocysteine concentrations by 10%, from 12.8 to 14.0 micromol/L. CONCLUSIONS: Unfiltered coffee increases plasma homocysteine concentrations in volunteers with normal initial concentrations. It is unclear whether the effect is caused by the cholesterol-raising diterpenes present exclusively in unfiltered coffee or by factors that are also present in filtered coffee.     

Effects of radiotherapy planning with a dedicated combined PET-CT-simulator of patients with non-small cell lung cancer on dose limiting normal tissues and radiation dose-escalation: a planning study.

BACKGROUND AND PURPOSE: To investigate the effect of radiotherapy planning with a dedicated combined PET-CT simulator of patients with locally advanced non-small cell lung cancer. PATIENTS AND METHODS: Twenty-one patients underwent a pre-treatment simulation on a dedicated hybrid PET-CT-simulator. For each patient, two 3D conformal treatment plans were made: one with a CT based PTV and one with a PET-CT based PTV, both to deliver 60Gy in 30 fractions. The maximum tolerable prescribed radiation dose for CT versus PET-CT PTV was calculated based on constraints for the lung, the oesophagus, and the spinal cord, and the Tumour Control Probability (TCP) was estimated. RESULTS: For the same toxicity levels of the lung, oesophagus and spinal cord, the dose could be increased from 55.2+/-2.0Gy with CT planning to 68.9+/-3.3Gy with the use of PET-CT (P=0.002), with corresponding TCP's of 6.3+/-1.5% for CT and 24.0+/-5.6% for PET-CT planning (P=0.01). CONCLUSIONS: The use of a combined dedicated PET-CT-simulator reduced radiation exposure of the oesophagus and the lung, and thus allowed significant radiation dose escalation whilst respecting all relevant normal tissue constraints.     

Chronischer Unterschenkelschmerz: Einklemmung des N. peronaeus communis oder des N. tibialis

Die Unfallchirurgie - Junge Menschen mit chronischen belastungsabhängigen Unterschenkelschmerzen, bei denen normale Druckverhältnisse im Muskelkompartiment herrschen und ein...     

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.     

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,...