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Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel “cytotopic” agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.

Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel “cytotopic” agent, thrombalexin (TLN), combines a cell‐membrane‐bound (myristoyl tail) anti‐thrombin (hirudin‐like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r‐time) in both rhesus and human blood, comparing TLNversus HLL(without cytotopic tail) versus negative control. Both TLN‐ and HLL‐treated rhesus or human whole blood result in significantly prolonged r‐time compared to kaolin controls. Only TLN‐treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane‐bound TLNwas confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN‐supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLNsystemically. Histologically, TLNwas shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMAseverity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN‐treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated. Direct local treatment of the transplanted kidney with thrombalexin, a cytotopic antithrombin agent, reduces histological evidence of thrombotic microangiopathy in a sensitized model of nonhuman primate transplantation.

Costimulation blockade (CoB) via belatacept is a lower‐morbidity alternative to calcineurin inhibitor (CNI)‐based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)‐1. LFA‐1 exists in two forms: a commonly expressed, low‐affinity form and a transient, high‐affinity form, expressed only during activation. We have shown that antibodies reactive with LFA‐1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL‐579, each of which targets the high‐affinity form of LFA‐1, to determine whether this more precise targeting prevents belatacept‐resistant rejection. Despite evidence of ex vivoand in vivoligand‐specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL‐579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA‐1 blockade may not be a suitable adjuvant agent for CoB‐resistant rejection. This study examines the use of belatacept with either depletion or inhibition of the high‐affinity form of LFA‐1 in a nonhuman primate model of kidney transplantation.

Planarizing films of fine-grained silica embedded in polyimide have been prepared by a spincoating technique and their structure has been investigated by optical and electron microscopy. The films were found to be diphasic. A silica content near 9 vol% yields a well mixed silica/polyimide composite which is homogeneous down to nanometre scale and has good planarization characteristics. Films with contents of 3 and 6 vol% silica have rough surfaces and exhibit two forms of segregation. In the 3% case, elongated inclusions of such silica/polyimide material appear at ~ 100-µm islands in a pure polyimide matrix. In the 6% case, the pure polyimide appears as ~ 100-µm elongated lakes surrounded by silica/polyimide material.

A method which can be implemented in a routine organochlorine analysis laboratory equipped with a quadrupole GC/MS is presented for determination of tetrachloro-(T4-) to octachloro- (O8-) dibenzodioxins (CDDs) in animal tissues. Long chain-length biogenic compounds such as lipids are removed by gel-permeation chromatography (GPC), and the CDDs are separated from most interfering organochlorine compounds by a combination of alumina and Florisil chromatography. Recoveries from spiked samples were in the 87-97% range for T4CDDs-H7CDDs at the 5-100 ng/kg level except for 1,3,6,8- and 1,3,7,9,-T4CDD, which had variable losses in the alumina chromatography step (recoveries of 73-97%). O8CDD recoveries depended on level, 80% at 200 ng/kg, 52-59% at 30-40 ng/kg. Precision of replicate analysis was generally in the 2-7% range. Positive interferences not completely removed by the method were identified as methoxychloro-biphenyls and methoxychloro-diphenylethers. Examples of the application of the method are given.

N⁴-Hydroxy-1,4-benzodiazepines were synthesized in a single step from synthetically versatile acylnitroso-derived hetero-Diels−Alder cycloadducts. The efficiency of this transformation was found to be dependent on the NH pKa of the cycloadduct sulfonamide.

A thorough microstructural study of common ceramics requires analysis at various length scales. Yttrium doped, polycrystalline α-Al203 was studied using a broad selection of microscopy techniques over a scale range covering seven-orders of magnitude (i.e. from mm to Å).Yttrium doped, (1000 (Y/Al) atomic ppm) polycrystalline alumina samples were prepared by hot pressing at 1450°C at 50 MPa. Some were subsequently crept in tension. Microstructure of these samples was studied by optical microscopy, scanning electron/orientation imaging microscopy (OIM™), conventional and high resolution transmission electron microscopy. Analytical electron microscopy was performed on a VG HB501 FEG-STEM equipped with an EDS and PEELS.On a large scale, the microstructure often consisted of bimodal sized alumina grains and second phase YAG (Y3A15012) precipitates. YAG precipitates at grain boundaries (GB) and triple points caused clusters (50μm to 1mm) of small equi-axed alumina grains (0.5-2 μm) randomly distributed over 40 area% of the sample.

A thorough microstructural study of common ceramics requires analysis at various length scales. Yttrium doped, polycrystalline α-Al203 was studied using a broad selection of microscopy techniques over a scale range covering seven-orders of magnitude (i.e. from mm to Å).Yttrium doped, (1000 (Y/Al) atomic ppm) polycrystalline alumina samples were prepared by hot pressing at 1450°C at 50 MPa. Some were subsequently crept in tension. Microstructure of these samples was studied by optical microscopy, scanning electron/orientation imaging microscopy (OIM™), conventional and high resolution transmission electron microscopy. Analytical electron microscopy was performed on a VG HB501 FEG-STEM equipped with an EDS and PEELS.On a large scale, the microstructure often consisted of bimodal sized alumina grains and second phase YAG (Y3A15012) precipitates. YAG precipitates at grain boundaries (GB) and triple points caused clusters (50μm to 1mm) of small equi-axed alumina grains (0.5-2 μm) randomly distributed over 40 area% of the sample.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.