An international survey of clinicians regarding their management of venous thromboembolism following the initial 3-6 months of anticoagulation.

After an initial treatment period for venous thromboembolism (VTE), indefinite anticoagulation may be considered, depending upon individual risks. The aim of the study was to determine if there is consensus amongst clinicians that manage VTE regarding which patients require 3-6 months versus indefinite anticoagulation. The importance of VTE site and severity in decision making was also evaluated. An international survey of clinicians involved in VTE management was undertaken. Respondents were asked about long-term treatment of six patients that had completed 3-6 months initial anticoagulation. These included four cases of VTE not associated with a major reversible risk factor and two control cases; one unprovoked VTE and one VTE associated with a major reversible risk factor. For consensus, there was a pre-defined equivalence boundary whereby at least 70% of clinicians had to decide either to stop or consider indefinite anticoagulation for each case. 351 responses were collected. In the control cases, there was a ≥ 95% consensus on long-term management (stop versus indefinite anticoagulation). In three of the four test cases, there was no consensus about duration of anticoagulation. In case 3, 78% (99% confidence interval 73-84%) would stop anticoagulation after 3-6 months. When analysed by grade or specialty of doctor, a lack of consensus remained. Opinion on whether site or severity of VTE influenced decision making was variable. For patients with unprovoked VTE or VTE associated with a major transient risk factor there is treatment consensus. For the remainder, there is a lack consensus regarding the need for indefinite anticoagulation.

A Multicentre Study of Thromboprophylaxis in Pregnancy.

Venous thromboembolism (VTE) is a leading cause of maternal mortality. The risk increases with increasing maternal age, mode of delivery and medical co-morbidities. Thromboprophylaxis with low molecular weight heparin (LMWH) has been shown to be both safe and efficacious. The aim of this study was to prospectively investigate the incidence of maternal risk factors in pregnant women admitted to hospital, to calculate their VTE risk status and to investigate if they were receiving appropriate thromboprophylaxis. All patients admitted to the participating hospitals on the day of investigation were assessed for risk of VTE on the basis of hospital chart review. Five Hundred and forty women were recruited from 16 hospitals. Almost 32% (31.7%) were receiving thromboprophylaxis with LMWH. Just under 80% of patients were on the correct thromboprophylaxis strategy as defined by the RCOG guideline but 49% were under-dosed. The odds of receiving appropriate thromboprophylaxis were significantly increased if the woman was >35 years 0or with parity>3.

Ionizing radiation exposure as a result of diagnostic imaging in patients with lymphoma.

PURPOSE: Survival rates among patients with lymphoma continue to improve. Strategies aimed at reducing potential treatment-related toxicity are increasingly prioritized. While radiological procedures play an important role, ionizing radiation exposure has been linked to an increased risk of malignancy, particularly among individuals whose cumulative radiation exposure exceeds a specific threshold (75 millisieverts). METHODS: Within this retrospective study, the cumulative radiation exposure dose was quantified for 486 consecutive patients with lymphoma. RESULTS: The median estimated total cumulative effective dose (CED) of ionizing radiation per subject was 69 mSv (42-118). However, younger patients (under 40 years) had a median CED of 89 mSv (55-124). CONCLUSION: This study highlights the considerable radiation exposure occurring among patients with lymphoma as a result of diagnostic imaging. To limit the risk of secondary carcinogenesis, consideration should be given to monitoring cumulative radiation exposure in individual patients as well as considering imaging modalities, which do not impart an ionizing radiation dose.

Thromboprophylaxis in myeloma: what is happening outside of clinical trials?

Patients with myeloma are at high risk of venous thromboembolism (VTE). There is no consensus about what agent to use or what haematologists are doing in clinical practice. A survey was sent to haematologists treating patients with myeloma in Ireland. 32/45 (71%) responded. 13/28 (46%) felt that VTE affected < 5% of patients. However, 8/28 (29%) felt it affected 10-19%. Thromboprophylaxis was most commonly used in patients on lenalidomide; 25/28 (89%) and thalidomide; 23/28 (82%). 23/28 (82%) used LMWH and 20/28 (71%) used aspirin either very frequently or frequently. 3/28 (11%) had used dabigatran/rivaroxaban despite there being little evidence to support their use. Efficacy was the most important factor in choosing an agent for 25/28 (89%). Bleeding was not felt to be an issue 15/29 (52%) were not using thromboprophylaxis guidelines. This survey demonstrated wide variation in the beliefs and practices regarding the burden of VTE in patients with myeloma and the need for thromboprophylaxis.

Crystal structure of a gammadelta T cell receptor ligand T22: a truncated MHC-like fold.

Murine T10 and T22 are highly related nonclassical major histocompatibility complex (MHC) class Ib proteins that bind to certain gammadelta T cell receptors (TCRs) in the absence of other components. The crystal structure of T22b at 3.1 angstroms reveals similarities to MHC class I molecules, but one side of the normal peptide-binding groove is severely truncated, which allows direct access to the beta-sheet floor. Potential gammadelta TCR-binding sites can be inferred from functional mapping of T10 and T22 point mutants and allelic variants. Thus, T22 represents an unusual variant of the MHC-like fold and indicates that gammadelta and alphabeta TCRs interact differently with their respective MHC ligands.

A population of murine gammadelta T cells that recognize an inducible MHC class Ib molecule.

Although gammadelta T cells are implicated in regulating immune responses, gammadelta T cell-ligand pairs that could mediate such regulatory functions have not been identified. Here, the expression of the major histocompatibility complex (MHC) class Ib T22 and the closely related T10 molecules is shown to be activation-induced, and they confer specificity to about 0.4% of the gammadelta T cells in normal mice. Thus, the increased expression of T22 and/or T10 might trigger immunoregulatory gammadelta T cells during immune responses. Furthermore, the fast on-rates and slow off-rates that characterize this receptor/ligand interaction would compensate for the low ligand stability and suggest a high threshold for gammadelta T cell activation.

The specificity of a weak gamma delta TCR interaction can be modulated by the glycosylation of the ligand.

The gamma delta T cell clone LBK5 recognizes the MHC molecule IEk. Here, we demonstrate that the affinity of this interaction is weaker than those typically reported for alpha beta TCRs that recognize peptide/MHC complexes. Consistent with our previous finding that peptide bound to the IE molecule does not confer specificity, we show that the entire epitope for LBK5 is contained within the polypeptide chains of the molecule, centered around the polymorphic residues 67 and 70 of the IE beta-chain. However, LBK5 recognition is profoundly influenced by the N-linked glycosylation at residue 82 of the IE alpha-chain. Since infected, stressed, or transformed cells often change the posttranslational modifications of their surface glycoproteins, this finding suggests a new way in which gamma delta T cell Ag recognition can be regulated.

The recognition of the nonclassical major histocompatibility complex (MHC) class I molecule, T10, by the gammadelta T cell, G8.

Recent studies have shown that many nonclassical major histocompatibility complex (MHC) (class 1b) molecules have distinct antigen-binding capabilities, including the binding of nonpeptide moieties and the binding of peptides that are different from those bound to classical MHC molecules. Here, we show that one of the H-2T region-encoded molecules, T10, when produced in Escherichia coli, can be folded in vitro with beta2-microglobulin (beta2m) to form a stable heterodimer in the absence of peptide or nonpeptide moieties. This heterodimer can be recognized by specific antibodies and is stimulatory to the gammadelta T cell clone, G8. Circular dichroism analysis indicates that T10/beta2m has structural features distinct from those of classical MHC class I molecules. These results suggest a new way for MHC-like molecules to adopt a peptide-free structure and to function in the immune system.

Recognition by gamma/delta T cells.

In contrast with the study of alpha beta T cells, that of gamma delta T cells is relatively recent and stems from the discovery of their rearranged genes, rather than from any knowledge of their biological function. Thus, experiments designed to characterize their specificity and function have drawn heavily on our knowledge of alpha beta T cells. During the past few years, many studies, especially with mice lacking either alpha beta or gamma delta T cells, have demonstrated that gamma delta T cells can contribute to immune competence, but they do so in a way that is distinct from alpha beta T cells. It is also evident that gamma delta T cells may not recognize antigen the same way as do alpha beta T cells. Analysis of three protein antigens-the murine MHC class II IEk, the nonclassical MHC T10/T22, and the Herpes virus glycoprotein gI-indicates that gamma delta T cell recognition does not require antigen processing and that the proteins are recognized directly. In all three cases, recognition by these T cell clones involves neither peptides bound to these proteins nor peptides derived from them. Moreover, a group of small phosphate-containing nonpeptide compounds derived from mycobacterial extracts has been found to stimulate a major population of human peripheral gamma delta T cells in a T cell receptor (TCR)-dependent manner. This indicates that gamma delta T cells can respond to ligands that are different from those of alpha beta T cells. Analysis of complementarity determining region (CDR3) length distributions of gamma and delta chains indicates that they are more similar to those of immunoglobulins than to TCR alpha and beta. This further supports the idea that gamma delta and alpha beta T cells recognize antigens differently and suggests that gamma delta T cells may be more like immunoglobulins in their recognition properties. gamma delta T cells share many cell surface proteins with alpha beta T cells and are able to secrete lymphokines and express cytolytic activities in response to antigenic stimulation. These, together with the results cited above, indicate that gamma delta T cells can mediate cellular immune functions without a requirement for antigen processing. Thus, pathogens, damaged tissues, or even B and T cells can be recognized directly, and cellular immune responses can be initiated without a requirement for antigen degradation or specialized antigen-presenting cells. This would give gamma delta T cells greater flexibility than the more classical type of alpha beta T cell-mediated cellular immunity.

Effects of intratracheal endotoxin administration on hamster lung glycosaminoglycans.

Incorporation of [3H]glucosamine and 35S into glycosaminoglycan (GAG) was measured in hamster lung explant cultures at 0, 1, 4, and 24 h after a single endotracheal instillation of Escherichia coli endotoxin. Lung content of GAG was measured in a second group of treated animals over an 8-day period. Albumin was detected after endotoxin treatment in bronchoalveolar lavage fluid at 24 h but was not found in lavage fluid 7 days later or in lavage fluid of saline-treated animals. Over the initial 24 h, increasing amounts of radiolabeled precursor molecules were incorporated into all classes of GAG. Proportionally more radiolabel was incorporated into hyaluronic acid and chondroitin sulfate, and less was incorporated into heparan sulfate. The proportion of radiolabel incorporated into dermatan sulfate did not change. Total lung content of hyaluronate and chondroitin sulfate was elevated at 24 h but was returning to baseline by 8 days. The lung content of dermatan sulfate was increased at 8 days; lung content of heparan sulfate did not change over the 8-day study period. Elevations in the amount of explant heparan sulfate that bound to antithrombin III (AT III) were found at 1 h after both saline and endotoxin treatment. Radiosulfated heparan sulfates were found in blood from hamsters treated with endotoxin 1 h previously; these heparan sulfates did not bind to AT III. However, blood contained heparin-like activity. We conclude that endotoxin differentially alters the metabolism of each class of hamster lung glycosaminoglycans and that metabolic changes begin very rapidly after endotoxin exposure. The relation of pulmonary endothelial injury to the presence of heparin-like activity in blood is not yet clear.