Search

We report a case of a 56-year-old woman with a history of idiopathic thrombocytopenic purpura (ITP) following splenectomy on mycophenolate mofetil (MMF), who developed moderate bleeding after stopping MMF. Her laboratory testing suggested the presence of an abnormal circulating heparin-like anticoagulant with demonstrable anti-Xa activity. She was initially treated with antifibrinolytic therapy and was subsequently started on MMF alongside intravenous immunoglobulin, which significantly improved her bleeding symptoms. The presence of abnormal circulating heparin-like anticoagulants is a rare cause of coagulopathy. Few cases exist in the literature, with nearly all occurring in the setting of hematologic or solid-organ malignancy. The mechanism by which these endogenous anticoagulants develop is unclear. Clinical manifestations range from mild bleeding and bruising to life-threatening hemorrhage refractory to conventional therapy. Diagnosis of a heparin-like anticoagulant is based on coagulation testing as well as exclusion of other exogenous anticoagulants, acquired inhibitors, and/or factor deficiencies.

Particulate matter (PM) is a huge environmental threat and is of major public concern. Oxidative stress and systemic inflammation are known factors that contribute to PM- related damage; however, a systematic understanding of the deleterious pulmonary effects of PM using multi-omics analysis is lacking. In this study, we performed transcriptomic, proteomic, and metabolomic analyses in a mouse model exposed to PM for three months to identify molecular changes in lung tissues. We identified 1690 genes, 326 proteins, and 67 metabolites exhibiting significant differences between PM-challenged and control mice (p0.05). Differentially expressed genes and proteins regulated in PM-challenged mice were involved in lipid metabolism and in the immune and inflammatory response processes. Moreover, a comprehensive analysis of transcript, protein, and metabolite datasets revealed that the genes, proteins, and metabolites in the PM-treated group were involved in lysosomal function and lipid metabolism. Specifically, Cathepsin D (Ctsd), Ferritin light chain (Ftl), Lactotransferrin (Ltf), Lipocalin 2 (Lcn2), and Prosaposin (Psap) were major proteins/genes associated with PM-induced pulmonary damage, while two lipid molecules PC (18:1(11Z)/16:0) and PA (16:0/18:1(11Z)) were major metabolites related to PM-induced pulmonary injury. In summary, lipid metabolism might be used as successful precautions and therapeutic targets in PM-induced pulmonary injury to maintain the stability of cellular lysosomal function.

This article has been retracted, and the online PDF has been watermarked “RETRACTION”. The retraction notice is available at http://doi.org/10.3233/MGC-220954.

Background: There has been growing interest in using theory-driven research to develop and evaluate continuing medical education (CME) activities. Within health professions education, testing has been shown to promote learning in a variety of different contexts, an effect referred to as test-enhanced learning (TEL). However, the extent to which TEL generalizes to CME remains unclear. The purpose of this study was to investigate whether physicians who received two intervening tests following a CME event would experience a TEL effect relative to physicians who received additional study material to review without testing. Methods: Forty-nine physicians were recruited during a local CME activity. Physicians were randomized to either a) the test group (n=26), where participants completed two 20 multiple-choice question (MCQ) quizzes related to the lecture content or b) the study group (n=23), where participants studied the same information without testing. Testing and studying occurred independently during the CME activity, and then four weeks later online. At eight weeks, participants completed a final 20-item MCQ online test. A between-subjects t-test was used to compare performance on the final test as a function of the initial educational activity (test group vs. study group).Results: Performance on the final MCQ test was equivalent for both test (Mean (SD): 75% (9.9)) and study-only (77% (7.3)) conditions (t(47) = 0.94, p=0.35). Conclusion: The null findings in the present study are contrary to previous findings demonstrating TEL among novice learner populations. The lack of TEL highlights several programmatic considerations that should be factored in before implementing TEL as a part of CME.

A new fluorescent probe, L1 based on 8-aminoquinoline, was designed and synthesized. It exhibits high selectivity and sensitivity toward Zn2+ over other common metal ions (especially Cd2+). Under physiological conditions (pH 7.0), the probe displays an 8-fold fluorescence turn-on response to Zn2+. Furthermore, using laser scanning confocal techniques, it can be used to effectively monitor and distinguish Zn2+ from Cd2+ in living cells and plant tissues.

We present the case of a 42-year-old man with a history of mitral valve prolapse (MVP) presenting with subacute native valve endocarditis secondary to Cardiobacterium hominis infection. He presented with non-specific symptoms of generalized fatigue and malaise subsequent to a complication-free dental cleaning. He was treated initially with 4 weeks of ceftriaxone, but ultimately required mitral valve replacement due to severe valvular degeneration. This case provides a review of the pathophysiology and presentations of infective endocarditis (IE) secondary to HACEK organisms. We will review risk factors, as well as the evidence and current guidelines for pre-procedural IE prophylaxis.RésuméIl s’agit du cas d’un homme âgé de 42 ans ayant des antécédents de prolapsus valvulaire mitral (PVM) lié à une endocardite sur valve native subaiguë attribuable à une infection causée par Cardiobacterium hominis. Le patient présente des symptômes non-spécifiques de fatigue générale et de malaise à la suite d’un nettoyage dentaire s’étant déroulé sans complications. Après 4 semaines de traitement à la ceftriaxone, il a finalement dû subir le remplacement de la valvule mitrale en raison d’une grave dégradation valvulaire. L’étude de ce cas fournit une rétrospective de la physiopathologie et des différentes présentations d’une endocardite infectieuse (EI) secondaire aux organismes HACEK. Nous passons en revue différents facteurs de risque, ainsi que les données probantes et les lignes directrices actuelles concernant les mesures préventives de prophylaxie relative à l’EI.Case PresentationA 42-year old man with a history of mitral valve prolapse (MVP) presented to the emergency department in August 2015 following direct referral by his cardiologist. A transthoracic echocardiogram (TTE) showed thickening of his posterior mitral valve leaflet, suspicious for a vegetation. He endorsed a history of worsening generalized fatigue and malaise over months that were beginning to impair his day to day function, but otherwise, a review of systems was negative. Of note, he denied any history of fevers, chills, night sweats or weight loss, and had no shortness of breath or chest pain. Four months prior to the onset of his symptoms, he had a complication-free dental cleaning, but no other procedures. As per AHA/IDSA guidelines, he did not take any antimicrobial prophylaxis prior to his cleaning. His past medical history was unremarkable with no history of autoimmune disease, intravenous drug use or chronic indwelling devices such as catheters or lines. He was not taking any prescribed or over the counter medications and had no known allergies. On social history, there was no recent travel, he was a non-smoker, minimal alcohol drinker, and his family owned a dog, a gecko, and a new kitten that was a few weeks old and had recently given him a superficial bite on the arm that had not broken through his skin.On examination, he looked systemically well. His vital signs were stable and he was afebrile. Precordial exam was normal except for the presence of a grade III/VI holosystolic murmur best heard at the apex, radiating to the axilla. There was no evidence of congestive heart failure. There were no stigmata of infective endocarditis (IE). The remainder of the exam was unremarkable.Pertinent laboratory investigations included a white blood cell count of 13.4 (normal range 4.0–11.0 × 109/L) with an absolute neutrophil count of 11.4 (normal range 2.0–7.5 × 109/L) and an elevated C-reactive protein at 28.6 (normal < 5 mg/L). ESR was not ordered. The remainder of his bloodwork and a urinalysis was within normal limits. Serial ECGs showed transient sinus tachycardia without any signs of heart block. A chest radiograph showed no visible abnormalities. Three sequential sets of blood cultures were drawn. A transesophageal echocardiogram (TEE) revealed severe mitral regurgitation as well as thickening and possible myxomatous degeneration of the mitral valve (Figure 1). The presence of a vegetation on the mitral valve could not be ruled out. Figure 1. Transesophageal echocardiogram showing a lesion suspicious for a vegetation on the anterior leaflet of the mitral valve. Two days following the patient’s admission, two sets of blood cultures grew Gram-negative bacilli after 43.2 hours. The long incubation time was inconsistent with most Gram-negative organisms, and given the microbiology lab’s comment on the inconsistency of the Gram stain with areas of under-colourization, the patient was treated with vancomycin and ceftazidime for broad spectrum coverage. The following day, Cardiobacterium hominis was isolated. The strain was susceptible to beta-lactams. The patient remained clinically stable and was discharged with a PICC line and a 4-week course of ceftriaxone for C. hominis infective endocarditis (IE). Blood cultures drawn a day after the initiation of treatment were negative. The patient was provided with antimicrobial prophylaxis for future appropriate procedures.The patient began to experience symptoms of shortness of breath on exertion and palpitations in the months after his initial diagnosis. Repeat echocardiography continued to demonstrate severe degeneration and regurgitation of the mitral valve. His progressive symptoms prompted a referral to cardiac surgery and he underwent a mitral valve replacement in March 2016. Pathology from the surgical tissue sample showed chronic inflammation, fibrosis and myxomatous degeneration but was culture negative several months after his course of antimicrobials.DiscussionThe HACEK GroupIE has a diverse pathophysiology and is caused by a variety of mechanisms. The most common etiology is secondary to bacterial infection. Streptococcus and Staphylococcus species are responsible for approximately 70-80% of cases of IE (Table 1). A group of fastidious Gram-negative organisms referred to as the HACEK organisms ( Haemophilus parainfluenzae, Aggregatibacter species, Cardiobacterium species, Eikenella corrodens and Kingella kingae) are well-established, albeit infrequent causes of IE (1–3%). There have been recent changes to the nomenclature as certain several members of the Haemophilus species have been reclassified as Aggregatibacter species.1 Distinguishing features of HACEK IE, as identified in a large database review, include a younger patient population and a weaker association with health care associated infections.2 Major causes of IE are outlined in Table 1. 3,4Table 1. Major Causes of Infective EndocarditisThe long incubation time required to culture HACEK organisms has been well-documented, almost exclusively taking in excess of 2 days. Previous studies suggested that long incubation times of at least five to seven days were required to culture C. hominis; however, recently published cases and reviews have demonstrated consistent growth within five days. 5 Similarly, a review of laboratory incubations showed that all cases of HACEK IE were diagnosed within 5 days, and all incubations beyond 5 days yielded no growth.6 This is important given the ever-increasing demands on microbiology labs and the extra costs incurred from prolonged incubation with no evident benefit. Current IDSA guidelines recommend three sets (including 8–10 ml of blood each into both an aerobic and anaerobic culture bottles) of sequential blood cultures be drawn to increase the diagnostic yield when investigating for endocarditis.7 Our patient’s strain of C. hominis was susceptible to beta-lactams, as are approximately 93% of reported cases.8Cardiobacterium hominis This case highlights a few classic features of C. hominis IE. C. hominis is a Gram-negative bacterium which commonly colonizes the oropharynx. Of note, the bacteria are pleomorphic rods and parts of the cell may actually stain Gram-positive.9 A retrospective study of HACEK IE showed that C. hominis had a predominance for late disease presentation with the majority of reported cases (10/12) occurring three or more months following symptom onset.3 The common symptoms are constitutional, including fever, chills, fatigue and weight loss. Symptoms of congestive heart failure are more common in cases of C. hominis than other HACEK organisms, and approximately 40% of cases ultimately require surgery on the affected valve.8Risk Factors for C. hominis IE:Established risk factors for IE caused by HACEK organisms, and specifically C. hominis, include structural cardiac abnormalities as well as dental procedures, which is understandable given that the bacteria are oral commensals. However, in contrast to the Gram-positive bacteria commonly causing IE, intravenous drug use does not seem to be a risk factor for C. hominis IE likely due to its absence on the skin at points of vascular injury.5 Dental manipulation has been classically associated with the development of transient bacteremia even in immunocompetent hosts.10 More recently, even mild dental manipulation from brushing has been shown to cause transient bacteremia. 11 While transient bacteremia is typically innocuous, it serves as a risk factor for IE particularly in the setting of structural cardiac abnormalities.There are several cardiac structural lesions that predispose a patient to bacterial seeding leading to IE. Population-based studies in North America have shown that MVP has superseded rheumatic heart disease as the most common predisposing cardiac condition.11 As well in patients with IE and no prior cardiac diagnosis, mitral valve prolapse with or without valvular regurgitation is the most commonly diagnosed underlying cardiac structural abnormality on echocardiography.12 The pathophysiology of regurgitant valvular disease predisposing to IE involves turbulent flow through the valve leading to endothelial damage and the development of a vegetation through the aggregation of platelets, fibrin, and clotting factors at the site of the exposed endothelium.Antibiotic Prophylaxis for IE PreventionThe utility of antibiotic prophylaxis prior to dental procedures for the prevention of infective endocarditis in patients with MVP has long been debated. Current major guidelines do not recommend prophylaxis for patients with MVP based on the lack of robust evidence for the effectiveness of prophylactic antibiotics in preventing endocarditis.11,13 A Cochrane review of pre-procedural antibiotic prophylaxis, updated in 2013, only found one study suitable for inclusion in their analysis: a Dutch case-control study published in 1992.14 There was a non-significant increase in the risk of developing IE 180 days post procedure for patients who did not receive antibiotic prophylaxis compared to those who did (odds ratio 1.62 with a 95% CI of 0.57–4.57).14,15 To date, there have not been any randomized controlled trials examining the use of antibiotic prophylaxis in the prevention of IE. Such a study would be challenging to undertake as relatively low event rates would require large numbers of enrolled patients to ensure adequate power. It is clear that this is an area that would benefit from further study in order to further our understanding about the prevention of IE.Based on the lack of strong evidence supporting antimicrobial prophylaxis, the United Kingdom’s 2008 NICE guidelines for IE recommended no prophylaxis ahead of dental surgery for any indication. A subsequent temporal cohort study of the years before and after this guideline showed both a decrease in prescriptions for antimicrobial prophylaxis, as well as an increase in the incidence of IE after the guideline change.16 Although this result does not suggest causation, it prompted an amendment to the NICE guidelines in 2016 to recommend against routine antibiotic prophylaxis, but to consider a case-by-case approach.17 In comparison, the AHA/IDSA guidelines recommend prophylaxis only to patients at high risk of developing IE (Table 2).11 Although the utility and efficacy of prophylaxis is still somewhat unclear, studies have shown that modern methods of prophylaxis with amoxicillin are safe and well-tolerated.18 While our patient would not have previously met the 2007 AHA/IDSA criteria for pre-procedural prophylaxis prior to his dental cleaning, his episode of endocarditis would qualify him for future prophylaxis with amoxicillin.Table 2. Cardiac Conditions for which Pre-procedural Antibiotics are Recommended to Prevent IE as per the AHA/IDSA GuidelinesConclusion In summary, our case of native valve C. hominis IE represents a classic presentation of an uncommonly-occurring disease process. The case emphasizes the importance of a thorough history, physical exam, and laboratory investigations in the workup of potential IE. In patients presenting with fever of unknown origin or new-onset heart failure one should not neglect to ask about major risk factors for IE such as cardiac structural disease and IV drug use, but also enquire about other routes of bacterial exposure including dental procedures and ownership of pets. A review of the literature shows that there is minimal evidence regarding the efficacy of antibiotic prophylaxis prior to dental procedures for all-comers at risk of IE. Further research should focus on specific populations in which procedural prophylaxis would be effective.

The aim of this research was to investigate the antioxidant and anti-apoptotic activities of Potentilla anserina polysaccharide (PAP) on kidney damage induced by cadmium (Cd) in vitro and in vivo. PAP has been suggested to have anti-oxidation, anti-apoptosis, immunoregulation, antimicrobial, antitussive, and expectorant abilities. In this study, PAP was extracted and the major components of PAP were analyzed. It was shown that PAP pretreatment remarkably improved redox homeostasis, both in human embryonic kidney 293 (HEK293) cells and in BALB/c mice. Administration of PAP attenuated the mitochondrial dysfunction, degeneration, and fibrosis of kidney induced by Cd. Furthermore, PAP exhibited anti-apoptotic activity, which involved regulating both the mitochondria-mediated intrinsic apoptotic pathway and the death receptor-initiated extrinsic pathway. These results suggest that PAP is a potential therapeutic agent for Cd-induced nephrotoxicity.

Biomaterials that have the ability to augment angiogenesis are highly sought-after for applications in regenerative medicine, particularly for revascularization of ischemic and infarcted tissue. We evaluated the culture of human circulating angiogenic cells (CAC) on collagen type I-based matrices, and compared this to traditional selective-adhesion cultures on fibronectin. Culture on a collagen matrix supported the proliferation of CD133(+) and CD34(+)CD133(+) CACs. When subjected to serum starvation, the matrix conferred a resistance to cell death for CD34(+) and CD133(+) progenitors and increased phosphorylation of Akt. After 4days of culture, phenotypically enriched populations of endothelial cells (CD31(+)CD144(+)) and progenitor cells (CD34(+)CD133(+)) emerged. Culture on matrix upregulated the phosphorylation and activation of ERK1/2 pathway members, and matrix-cultured cells also had an enhanced functional capacity for adhesion and invasion. These functional improvements were abrogated when cultured in the presence of ERK inhibitors. The formation of vessel-like structures in an angiogenesis assay was augmented with matrix-cultured cells, which were also more likely to physically associate with such structures compared to CACs taken from culture on fibronectin. In vivo, treatment with matrix-cultured cells increased the size and density of arterioles, and was superior at restoring perfusion in a mouse model of hindlimb ischemia, compared to fibronectin-cultured cell treatment. This work suggests that a collagen-based matrix, as a novel substrate for CAC culture, possesses the ability to enrich endothelial and angiogenic populations and lead to clinically relevant functional enhancements.

Pluripotent stem cells possess a tremendous potential for the treatment of many diseases because of their capacity to differentiate into a variety of cell lineages. However, they provide little promise for muscle-related diseases, mainly because of the lack of small molecule inducers to efficiently direct myogenic conversion. Retinoic acid, acting through the retinoic acid receptor (RAR) and retinoid X receptor (RXR), affects stem cell fate determination in a concentration-dependent manner, but it only has a modest efficacy on the commitment of ES cells into skeletal muscle lineage. The RXR is very important for embryonic development but is generally considered to act as a silent partner of RAR in a non-permissive mode. In this study, we have examined whether activation of the RXR by rexinoid or RXR-specific signaling play a role in the specification of stem cells into muscle lineage. Our findings demonstrate that mouse ES cells generate skeletal myocytes effectively upon treatment with rexinoid at the early stage of differentiation and that on a molecular level, rexinoid-enhanced myogenesis simulates the sequential events observed in vivo. Moreover, RXR-mediated myogenic conversion requires the function of β-catenin but not RAR. Our studies establish the feasibility of applying the RXR agonist in cell-based therapies to treat muscle-related diseases. The aptitude of mouse ES cells to generate skeletal myocytes following rexinoid induction also provides a model system to study the convergence of different signaling pathways in myogenesis.

The addition of harmful adulterants to cocaine has become widespread in recent years and constitutes a novel etiological agent for disease. One agent in particular, the veterinary anthelmintic “levamisole,” has been increasingly used, owing to its potentiating effects of cocaine and its ability to pass crude methods of detection. Levamisole has been shown to cause a vasculitic syndrome of retiform purpura and skin necrosis, as well as leukopenia and autoantibody formation.

Introduction: In North America, there are a growing number of patients with hemoglobinopathies, including sickle cell disease and thalassemia. As previously identified in needs assessment surveys of Canadian hematology training program directors and fellows (Verhovsek et. al. 2014 - https://ash.confex.com/ash/2014/webprogram/Paper71742.html), hemoglobinopathy learning constitutes an integral component of the hematology residency curriculum, however there are significant differences in volume and case-mix of hemoglobinopathy exposure among training programs. Fellows and program directors expressed strong interest in online e-learning modules to address gaps in clinical and laboratory learning. As such, we developed a set of e-learning modules for hemoglobinopathies that were implemented as a pilot study. We hypothesized that the e-learning-based curriculum would enhance education and standardize curricular exposure between Canadian hematology programs. Methods: Based on the National Hemoglobinopathy Learning Objectives, a curriculum of 12 case-based modules was developed. Modules were implemented as a pilot study in four Canadian hematology training programs using a distributed practice model - two modules every two months over the 12-month academic year. Training programs were selected based on baseline hemoglobinopathy exposure in their curriculum (two programs with high baseline exposure and two programs with low baseline exposure). Fellows completed the modules independently. Learning was supplemented with bimonthly module review sessions facilitated by expert faculty. In programs where the program directors did not identify a local faculty member with content expertise, review sessions were run by web conference. Data were collected regarding the efficacy of the intervention through three main formats: in-person fellow focus groups, online fellow questionnaires, and sets of designated hemoglobinopathy-related questions at the annual National Hematology Online Practice Exam for all Canadian Hematology fellows. Results: From online graded survey responses (1 to 5, "strongly disagree" to "strongly agree"), 97% of respondents indicated the modules were relevant to their particular learning needs (Mean 4.39, SD = 0.55). All survey respondents indicated the case scenarios were realistic, and 95% felt that the e-learning software was easy to use, engaging and offered flexibility of computer-based learning. Responses in focus group feedback sessions mirrored the survey findings: modules were described as "very useful", "realistic", and of high production quality, with participants indicating they felt the issue of variability in case mix could be addressed with online cases. With respect to the expert-led case review sessions, the majority of focus group responses indicated they were valuable and enhanced the learning obtained from online modules, with review sessions being increasingly useful with later modules that were more challenging. In addition, both online survey responses and focus group feedback identified that participants would strongly recommend the modules to their colleagues (97% of survey responses, Mean 4.43, SD = 0.56). Finally, comparing results of the annual National Hematology Online Practice exam, programs that participated in the online hemoglobinopathy modules saw their fellows achieve a higher incremental change in their score from 2015 to 2016, as compared to their counterparts who did not participate in the online modules (increase of 18.5% vs. 14.8%). Conclusion/Implications: In this pilot implementation study, online hemoglobinopathy modules were shown to have high usability and user satisfaction with content. Fellows agreed that the e-learning modules addressed current gaps in curricula and variability in case-mix exposure. Among fellows who have completed the annual National Hematology Online Practice Exam, comparison of the 2015 and 2016 exam scores in participating and non-participating programs indicated improved performance on hemoglobinopathy-related questions. Taken together, our study has shown that our proposed e-learning-based curriculum has been a successful intervention in promoting, standardizing and enhancing education in hemoglobinopathies among Canadian hematology programs. Disclosures Bates: Eli Lilly Canada: Other: Partial salary support through Eli Lilly Canada/May Cohen Chair in Women's Health.

Correction for ‘New fluorescent probe for Zn2+ imaging in living cells and plants’ by Rong Shen et al., Anal. Methods, 2016, 8, 83–88.

In this research, the cement/activated-carbon solidification/stabilization (S/S) technology was used to treat contaminated soil with 500ppm phenol, choosing ordinary portland cement (30% or 50% w/w of contaminated soil) and activated carbon (0%-10% w/w of contaminated soil) as binder and additive respectively. The leaching test, long-term leaching test, and pore size distribution analysis of the solidified/stabilized samples were carried out to investigate the S/S effect. The results showed that under the natural curing conditions, the phenol- contaminated soil could be effectively treated by the cement/activated-carbon S/S technology; very low amounts of activated carbon (less than 3% w/w of contaminated soil) could significantly improve the fixation ratios of phenol; the cumulative leaching ratio of 28 days cured samples were much lower than that of 7 days cured samples in the long-term leaching test; the adding of activated carbon had a strong effect on the porosity of the solidified/stabilized samples, increasing the total porosity, which might lead to easily leaching out of phenol; and careful balancing between the adding amount of activated carbon and cement was necessary to obtain the minimum phenol release and better economic feasibility.

The addition of harmful adulterants to cocaine has become widespread in recent years and constitutes a novel etiological agent for disease. One agent in particular, the veterinary anthelmintic “levamisole,” has been increasingly used, owing to its potentiating effects of cocaine and its ability to pass crude methods of detection. Levamisole has been shown to cause a vasculitic syndrome of retiform purpura and skin necrosis, as well as leukopenia and autoantibody formation.