Tranexamic acid, an inhibitor of plasminogen activation, reduces urinary collagen cross-link excretion in both experimental and rheumatoid arthritis

The plasminogen activation system is one of the enzyme systems held responsible for bone and cartilage degradation in rheumatoid arthritis (RA). In this study, we evaluated the effect of tranexamic acid (TEA), an inhibitor of plasminogen activation, on urinary collagen cross-link excretion and radiological joint damage in rat adjuvant arthritis (AA) and on urinary collagen cross-link excretion in patients with RA. In the animal study, adjuvant arthritis was induced in male Lewis rats. From day 7 onward, high-dose TEA (500 mg/kg body weight, once daily) or placebo was administered orally. Study groups consisted of TEA-treated normal rats (C + TEA), placebo-treated normal rats (C + plac), AA rats treated with TEA (AA + TEA) or with placebo (AA + plac). To monitor joint destruction, urinary collagen cross-link excretion (pyridinoline, HP; deoxypyridinoline, LP) was measured by high-performance liquid chromatography at days 14 and 21. Radiological evaluation of joints was performed at day 21. In the patient study, TEA was administered to nine patients with RA as adjuvant medication (approximately 20 mg/kg body weight, three times daily) for 12 weeks. Urinary HP and LP excretion levels were measured before and during TEA treatment, and 4 weeks after the cessation of TEA treatment. In AA + TEA rats, a significant reduction of HP and a tendency towards a reduction of LP excretion were found compared with AA + plac rats (P < 0.05), at day 14, whereas the HP/LP ratio did not change. No difference was observed in HP, LP excretion, HP/LP ratio and radiological damage score between the TEA- and placebo-treated AA rats at day 21. In RA patients, a significant reduction of HP and LP excretion was found during the TEA treatment period (P < 0.05). After the cessation of TEA treatment, HP and LP excretion increased towards baseline levels. No effect on disease activity was observed. The plasmin antagonist TEA reduced the excretion of collagen pyridinoline cross-links in both experimental and rheumatoid arthritis. As such, this study not only supports the involvement of the plasminogen activation system in the destructive phase of arthritis, but also suggests a beneficial effect of therapeutic strategies directed against inhibition of matrix proteolysis.      

Cytogenetic clonality in myelodysplastic syndromes studied with fluorescence in situ hybridization: lineage, response to growth factor therapy, and clone expansion

Clonality in myelodysplastic syndromes (MDS) has been studied with various techniques including glucose-6-phosphate dehydrogenase (G6PD) isoenzyme and cytogenetic analyses, and with molecular techniques such as gene deletion studies and the analysis of restriction fragment- length polymorphisms (RFLP) of X-linked genes. In this study, we investigated the use of fluorescence in situ hybridization (FISH) with a chromosome-specific probe to examine cytogenetic clonality in peripheral blood (PB) cells from three patients with MDS. In each case, trisomy 8 was shown by conventional cytogenetic analysis at the time of the initial diagnosis. By using FISH with a probe for the centromere of chromosome 8, we identified the trisomy in individual PB cells from Wright-stained smears. With this technique, we could determine the cell lineage involved by the trisomy, and through serial analyses we could assess the response of the clonal and nonclonal cells to growth-factor therapy, and the expansion of the trisomic clone over time. In each of the three cases, various proportions of granulocytes, monocytes, eosinophils, and basophils showed trisomy 8 by FISH analysis. In none of the cases did we detect trisomy 8 in lymphocytes. By analysis of PB cells before and during therapy with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), we found that GM-CSF stimulated both trisomic and disomic cells. During a 1-year period of sequential study, we detected an abrupt increase in the percentage of trisomic cells in one patient, a stable percentage in another, and a slowly increasing percentage in the third. The abrupt increase in the first patient preceded a transformation to a more acute phase by 2 months. We conclude that FISH analysis of PB cells of patients with MDS offers an additional approach to the study of clonality in this disorder. In some cases this analysis may provide a useful and simple means of assessing response to therapy and progression of disease.     

Staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility in perfused rat hearts: role of thromboxane generation

BACKGROUND: Cardiac performance is severely depressed in septic shock. Endotoxin has been implicated as the causative agent in Gram-negative sepsis, but similar abnormalities are encountered in Gram-positive sepsis. We investigated the influence of the major exotoxin of Staphylococcus aureus, staphylococcal alpha-toxin, in isolated perfused rat hearts. METHODS AND RESULTS: Alpha-toxin 0.25 to 1 microg/mL caused a dose-dependent increase in coronary perfusion pressure that more than doubled. In parallel, we noted a decrease in left ventricular developed pressure and the maximum rate of left ventricular pressure rise (dP/dt(max)), dropping to a minimum of <60% of control. These changes were accompanied by a liberation of thromboxane A(2) and prostacyclin into the coronary effluent. The release of creatine kinase, lactate dehydrogenase, potassium, and lactate did not surpass control heart values, and leukotrienes were also not detected. Indomethacin, acetylsalicylic acid, and the thromboxane receptor antagonist daltroban fully blocked the alpha-toxin-induced coronary vasoconstrictor response and the decrease in left ventricular developed pressure and dP/dt(max), whereas the lipoxygenase inhibitor nordihydroguaiaretic acid, the platelet activating factor antagonist WEB 2086, and the alpha-adrenergic antagonist phentolamine were entirely ineffective. Inhibition of nitric oxide synthase even enhanced the alpha-toxin-induced increase in coronary perfusion pressure and the loss in myocardial performance. CONCLUSIONS: Purified staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility. The responses appear to be largely attributable to the generation of thromboxane and are even enhanced when the endogenous nitric oxide synthesis is blocked. Bacterial exotoxins, such as staphylococcal alpha-toxin, may thus be implicated in the loss of cardiac performance encountered in Gram-positive septic shock.     

Asymmetric scleroderma in a CVA patient

We describe a systemic sclerosis and cerebral vascular accident case in which the cutaneous manifestation and the distal acroosteolysis occurred in an asymmetrical way in the non-paretic limb. The subsequent sclerodermic alterations and the acroosteolysis acquired an asymmetric pattern, sparing the patient's hemiparetic side. Although a number of definitions of this protective effect may be found in other rheumatic diseases, such as rheumatoid arthritis and gout, we found in the literature only one previous case describing the protective effect of the hemiplegia in scleroderma.     

Allogeneic marrow transplantation for refractory anemia: a comparison of two preparative regimens and analysis of prognostic factors

From 1990 to 1993 we performed a prospective study of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) in 30 patients with refractory anemia (RA) undergoing related (n = 17) or unrelated (n = 13) donor marrow transplantation. Nineteen patients survive disease free (63% 3- year actuarial disease-free survival [DFS]) and no patient relapsed. These results were compared to those of 38 historical controls with RA treated with cyclophosphamide and total body irradiation, of whom 22 are disease-free survivors and 1 relapsed. After correcting for significant variables between the two treatment groups, we found no statistically significant difference in outcome based on preparative regimen. Combining data from these 68 patients plus 2 additional patients with RA treated before 1993 with busulfan and cyclophosphamide, we identified four variables independently associated with improved survival: younger age, shorter disease duration, lower neutrophil count pretransplant, and lower hematocrit pretransplant. We also found that 15 patients 40 to 55 years of age had a 46% 3-year actuarial DFS and 26 patients receiving unrelated or mismatched related donor marrow had a 50% 3-year actuarial DFS. We conclude that there does not appear to be any significant difference in outcome based on preparative regimen in this patient population. In addition, allogeneic bone marrow transplantation may be a reasonable approach to therapy of RA early after diagnosis. However, whether early intervention with transplantation prolongs survival over that expected without transplantation cannot be ascertained with certainty from available data.     

Protein C deficiency resulting from possible double heterozygosity and its response to danazol

A unique family with protein C (PC) deficiency is described. The proband had a history of renal vein thrombosis as a newborn and iliofemoral thrombosis at the age of 6 years. After 6 months of heparin treatment, discontinuation of anticoagulation therapy was accompanied by persistent hypofibrinogenemia with increased fibrinogen consumption. With continuous infusion of heparin, fibrinogen turnover normalized, and the child has remained free of thrombosis. Both the immunologic level of PC and the functional activity measured by amidolytic assay were moderately reduced (47% and 34%, respectively). Functional activity of PC measured by its anticoagulant activity was disproportionately lower (14%). A 3-year-old asymptomatic sibling had a similar disproportionate reduction of PC anticoagulant activity compared with the amidolytic activity or immunologic level. The mother demonstrated type I PC deficiency with a proportionate reduction in immunologic protein levels (59%), anticoagulant activity (52%), and amidolytic activity (46%), whereas the father had type II PC deficiency with normal immunologic protein levels (102%), normal amidolytic function (98%), but a low anticoagulant function (50%). An abnormal PC molecule was detected by two-dimensional immunoelectrophoresis in the father and two children. These data are consistent with the hypothesis that the children are doubly heterozygous for two different types of PC deficiency inherited from each of the parents. A 14-day trial of danazol in the proband resulted in a rise in the PC antigen concentration from 66% to 98% but no change in PC anticoagulant function.     

From the Cover: Monitoring war destruction from space using machine learning

Existing data on building destruction in conflict zones rely on eyewitness reports or manual detection, which makes it generally scarce, incomplete, and potentially biased. This lack of reliable data imposes severe limitations for media reporting, humanitarian relief efforts, human-rights monitoring, reconstruction initiatives, and academic studies of violent conflict. This article introduces an automated method of measuring destruction in high-resolution satellite images using deep-learning techniques combined with label augmentation and spatial and temporal smoothing, which exploit the underlying spatial and temporal structure of destruction. As a proof of concept, we apply this method to the Syrian civil war and reconstruct the evolution of damage in major cities across the country. Our approach allows generating destruction data with unprecedented scope, resolution, and frequency—and makes use of the ever-higher frequency at which satellite imagery becomes available.

Building destruction during war is a specific form of violence that is particularly harmful to civilians, commonly used to displace populations, and therefore warrants special attention. Yet, data from war-ridden areas are typically scarce, often incomplete, and highly contested, when available. The lack of such data from conflict zones severely limits media reporting, humanitarian relief efforts, human-rights monitoring, and reconstruction initiatives, as well as the study of violent conflict in academic research. A novel solution to this problem is to use remote sensing to identify destruction in satellite images (1–3). This approach is gaining momentum as high-resolution imagery is becoming readily available at ever-higher frequency, yielding weekly, or even daily, images. At the same time, recent methodological advances related to deep learning have provided sophisticated tools to extract data from these images (4–7).While seminal research has demonstrated the use of automated classifiers for destruction detection, practical applications have so far been hampered by severe problems with labeling, domain transfer, and class imbalance in real-world imagery from urban war zones. As a consequence, international organizations such as the United Nations, the World Bank, and Amnesty International use remote sensing with manual human classification to produce damage-assessment case studies (8–10). On the other hand, providers of conflict data for research purposes still rely heavily on news and eyewitness reports, which leads to large data-publishing lags and potential biases (11–17). An automated building-damage classifier for use with satellite imagery, which has a low rate of false positives in unbalanced samples and allows tracking on-the-ground destruction in close to real-time, would therefore be extremely valuable for the international community and academic researchers alike.In this article, we present a way of combining computer-vision techniques and publicly available high-resolution satellite images to produce building-destruction estimates that are of practical use to both practitioners and researchers. The standard architectures for this task are convolutional neural networks (CNNs),^* as they have achieved unprecedented success in large-scale visual image classification with error rates beating humans (18, 19). We train a CNN to spot destruction features from heavy weaponry attacks (i.e., artillery and bombing) in satellite images, such as the rubble from collapsed buildings or the presence of bomb craters.We make three relevant methodological contributions. First, we introduce a label-augmentation method for expanding destruction class labels by making reasonable assumptions about the data-generating process using contextual information. Second, we introduce a two-stage classification process to control for spatial and temporal noise where the results from the CNN are processed through a random-forest model that relies on spatial and temporal leads and lags to improve classification performance. Third, we apply our trained computer-vision model to repeated satellite images of the entire populated areas of major Syrian cities, including parks and highways, and produce longitudinal estimates of building destruction over the course of the recent civil war.We demonstrate that our method yields high performance in out-of-sample tests and validate its ability for destruction monitoring using a separate database of heavy weaponry attacks. Our results highlight the importance of repeated satellite imagery in combination with temporal filtering to improve monitoring performance. As a result, our approach can be applied to any populated area, provided that repeated, high-resolution (i.e., submeter) satellite imagery is available.