Abstract
Anticoagulant-related nephropathy (ARN) is a clinical syndrome of acute kidney injury in patients taking vitamin K antagonists or direct oral anticoagulants. It is associated with increased ...mortality and there is no specific treatment. We report the case of a 78-year-old man on dabigatran who developed macroscopic haematuria and acute kidney injury 2 weeks after mitral valve repair, reaching a peak creatinine of 415 µmol/L from a normal baseline, which was successfully treated with one course of idarucizumab. This case illustrates the efficacy of an anticoagulant reversal agent for the treatment of ARN.
The majority of gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT, an HSP90 client protein. Further secondary resistance mutations within KIT limit clinical ...responses to tyrosine kinase inhibitors, such as imatinib. The dependence of KIT and its mutated forms on HSP90 suggests that HSP90 inhibition might be a valuable treatment option for GIST, which would be equally effective on imatinib-sensitive and -resistant clones. We investigated the activity of AT13387, a potent HSP90 inhibitor currently being evaluated in clinical trials, in both in vitro and in vivo GIST models. AT13387 inhibited the proliferation of imatinib-sensitive (GIST882, GIST-T1) and -resistant (GIST430, GIST48) cell lines, including those resistant to the geldanamycin analogue HSP90 inhibitor, 17-AAG. Treatment with AT13387 resulted in depletion of HSP90 client proteins, KIT and AKT, along with their phospho-forms in imatinib-sensitive and -resistant cell lines, irrespective of KIT mutation. KIT signaling was ablated, whereas HSP70, a marker of HSP90 inhibition, was induced. In vivo, antitumor activity of AT13387 was showed in both the imatinib-sensitive, GIST-PSW, xenograft model and a newly characterized imatinib-resistant, GIST430, xenograft model. Induction of HSP70, depletion of phospho-KIT and inhibition of KIT signaling were seen in tumors from both models after treatment with AT13387. A combination of imatinib and AT13387 treatment in the imatinib-resistant GIST430 model significantly enhanced tumor growth inhibition over either of the monotherapies. Importantly, the combination of AT13387 and imatinib was well tolerated. These results suggest AT13387 is an excellent candidate for clinical testing in GIST in combination with imatinib.
In many patients referred with significant bleeding phenotype, laboratory testing fails to define any hemostatic abnormalities. Clinical practice with respect to diagnosis and management of this ...patient cohort poses significant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool. Patients with increased bleeding assessment tool scores should progress to hemostasis laboratory testing. To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission aggregometry should be the minimum laboratory assessment. In some laboratories, additional specialized hemostasis testing may be performed to identify other rare causes of bleeding. We recommend that patients with a significant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology. Global hemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical significance remains uncertain. Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield. Underlying BDUC should be considered in patients with heavy menstrual bleeding since delays in diagnosis often extend to many years and negatively impact quality of life. Treatment options for BDUC patients include tranexamic acid, desmopressin, and platelet transfusions.
Some insects are infected with maternally inherited bacterial endosymbionts that protect them against pathogens or parasitoids. The weevil Sitona obsoletus (=Sitona lepidus) is invasive in New ...Zealand, and suspected to contain such defensive symbionts, because it is particularly resistant to a Moroccan strain of the parasitoid Microctonus aethiopoides (which successfully attacks many other weevil species), and shows geographic variation in susceptibility to an Irish strain of the same parasitoid. Using 454 pyrosequencing, we investigated the bacterial community associated with S. obsoletus, two other exotic weevils (Sitona discoideus and Listronotus bonariensis) and two endemic New Zealand weevils (Irenimus aequalis and Steriphus variabilis). We found that S. obsoletus was infected by one strain of Wolbachia and two strains of Rickettsia, none of which were found in any other weevil species examined. Using diagnostic PCR, we found that S. obsoletus in the Northland region, where parasitism is highly variable, were primarily infected with Wolbachia and Rickettsia strain 2, indicating that these two symbionts should be investigated for potential defensive properties. In comparison, S. discoideus lacked any apparent maternally inherited bacterial endosymbionts. In the other weevil species, we found a different strain of Wolbachia and two different strains of Spiroplasma. Two weevil species (St. variabilis and L. bonariensis) were infected with distinct strains of Nardonella, the ancestral endosymbiont of weevils, whereas three weevil species (S. obsoletus, S. discoideus, and I. aequalis) lacked evidence for Nardonella infection. However, I. aequalis was consistently infected with a novel Enterobacteriaceae strain, suggesting that a symbiont replacement may have taken place, similar to that described for other weevil clades.
Aims
Ankle arthropathy commonly affects persons with haemophilia (PWH). Joint damage causes loss of movement, pain and reduced function. Current treatments are limited. Viscosupplementation has been ...used to treat other patient groups with joint damage. Viscosupplements serve to augment or act as a substitute for synovial fluid and may ameliorate the effects of cartilage loss by cushioning joints and reducing pain. This study evaluated intra‐articular Ostenil Plus™ (HA) for ankle arthropathy in PWH. Reduction in pain was the primary outcome.
Methods
A single centre open label pilot study. PWH and significant ankle arthropathy, according to MRI scores, were recruited. Participants received intra‐articular HA injections at baseline and 6 months. Follow up assessments were completed three‐monthly for 1 year. Pain was assessed by the Visual Analogue Scale (VAS). Participant perceptions of overall changes to pain, function and quality of life were sought.
Results
Twenty‐four participants were recruited, three withdrew. Twenty‐six joints were injected. Twenty participants had severe haemophilia. Mean age 35 years. Participants reported significant reduction in pain over the study. VAS baseline: 5.62; 6 month 3.92; 12‐month 3.42, P < .0001. Joint function improved together with ankle HJHS. No change was seen for EQ‐5D‐5L. Sixteen participants reported reductions in ankle pain and stiffness and greater confidence in undertaking physical activities. No significant adverse reactions were reported.
Conclusion
Ostenil Plus™ treatment improves pain, function and patient perception of functional ability in PWH and ankle arthropathy. This study supports the use of HA as a safe treatment in PWH.
The choice of treatments for inherited, or acquired, fibrinogen deficient states is expanding and there are now several fibrinogen concentrate therapies commercially available. Patients with the rare ...inherited bleeding disorder, afibrinogenemia, commonly require life-long replacement therapy with fibrinogen concentrate to prevent hemorrhagic complications. Recent reports in the setting of acquired bleeding, namely trauma hemorrhage, have highlighted the potential importance of the different compositions of fibrinogen supplements, including cryoprecipitate and the various plasma- derived concentrates. Clot strength and the subsequent susceptibility of a clot to lysis is highly dependent on the amount of fibrinogen as well as its structural composition, the concentration of pro- and anti-coagulant factors, as well as fibrinolytic regulators, such as factor XIII (FXIII). This report details the effects of two commercially available fibrinogen concentrates (Riastap ® , CSL Behring and Fibryga ® , Octapharma) on important functional measures of clot formation and lysis in a patient with afibrinogenemia. Our report offers insights into the differential effects of these concentrates, at the clot level, according to the variable constituents of each product, thereby emphasizing that the choice of fibrinogen concentrate can influence the stability of a clot in vivo . Whether this alters clinical efficacy is yet to be understood.
Grassland bird species are declining more quickly than birds of any other biome in North America, but effects of the most widespread use of native mixed-grass prairies, livestock grazing, on nest ...survival of songbirds is not well understood. We used an adaptive management grazing experiment in southwestern Saskatchewan to evaluate effects of cattle grazing intensity and number of years grazed on nest survival of five songbird species in 2009 and 2010. Two 300-m2 plots were located in each of 12 pastures. Three pastures were ungrazed controls, while the remaining pastures had grazing intensities ranging from 0.23â0.83 Animal Unit Months (AUM) · haâ1 (very low to very high for this region), and were grazed for 2â3 or >15years. Analyses were conducted using logistic exposure regression. We found few effects of grazing on nest survival. Exceptions to this pattern were that the lowest nest survival rates occurred at low-moderate grazing intensities for Sprague's pipits (Anthus spragueii) in 2009, at low grazing intensities for chestnut-collared longspurs (Calcarius ornatus) in 2009, and at moderate grazing intensities for vesper sparrows (Pooecetes gramineus) in 2010. Increasing grazing duration lowered nest survival for Sprague's pipits and increased nest survival for chestnut-collared longspurs in 2009. Although low or moderate grazing intensities are generally recommended to promote wildlife conservation, this may not promote productivity of all species. Nonetheless, our results suggest that in the short term, a wide range of grazing intensities is consistent with conservation of grassland songbirds.
Major hemorrhage is a source of significant mortality and morbidity worldwide. Identification and characterization of coagulation impairment associated with major hemorrhage has suggested a key role ...for fibrinogen deficiency, however the optimum mode of replacement of fibrinogen remains unclear, and standardized major hemorrhage protocols may overlook context-dependent variations in individual patients' clotting derangement. Areas covered: This paper examines the current practice and evidence regarding the role of different modes of fibrinogen replacement in major hemorrhage in 3 distinct clinical settings: trauma, obstetric hemorrhage, and gastrointestinal hemorrhage with associated liver disease. A literature search was carried out electronically using Athens access to the National Health Service evidence health information resources, primarily PubMed and Google Scholar. Expert commentary: Two key questions need to be addressed. First, what is the role of concentrated fibrinogen (by comparison to no fibrinogen), and second, which concentrated source or product is more effective (or cost-effective)? Current practice and concept is derived largely from small pilot trials in the trauma setting, but results from larger studies are awaited. More comparative data on changes to clotting profiles in different groups of bleeding patients are needed to help delineate differences and guide interventional treatment studies.
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