High-Resolution Free-Breathing Automated Quantitative Myocardial Perfusion by Cardiovascular Magnetic Resonance for the Detection of Functionally Significant Coronary Artery Disease.

AIMS: Current assessment of myocardial ischaemia from stress perfusion cardiovascular magnetic resonance (SP-CMR) largely relies on visual interpretation. This study investigated the use of high-resolution free-breathing SP-CMR with automated quantitative mapping in the diagnosis of coronary artery disease (CAD). Diagnostic performance was evaluated against invasive coronary angiography (ICA) with fractional flow reserve (FFR) measurement. METHODS & RESULTS: Seven-hundred and three patients were recruited for SP-CMR using the research sequence at 3 Tesla. Of those receiving ICA within 6 months, 80 patients either had FFR measurement, or identification of a chronic total occlusion (CTO) with inducible perfusion defects seen on SP-CMR. Myocardial blood flow (MBF) maps were automatically generated in-line on the scanner following image acquisition at hyperaemic stress and rest, allowing myocardial perfusion reserve (MPR) calculation. 75 coronary vessels assessed by FFR, and 28 vessels with CTO were evaluated at both segmental and coronary territory level. Coronary territory stress MBF and MPR were reduced in FFR-positive (≤ 0.80) regions (median stress MBF: 1.74 [0.90-2.17] ml/min/g; MPR: 1.67 [1.10-1.89]) compared with FFR-negative regions (stress MBF: 2.50 [2.15-2.95] ml/min/g; MPR 2.35 [2.06-2.54] p < 0.001 for both). Stress MBF ≤ 1.94 ml/min/g and MPR ≤ 1.97 accurately detected FFR-positive CAD on a per-vessel basis (area under the curve: 0.85 and 0.96 respectively; p < 0.001 for both). CONCLUSIONS: A novel scanner-integrated high-resolution free-breathing SP-CMR sequence with automated in-line perfusion mapping is presented which accurately detects functionally significant CAD.

Efficacy and Safety of Activated Prothrombin Complex Concentrate for Reversal of the Anticoagulant Effect of Apixaban and Rivaroxaban in Patients with Major Bleeding.

BACKGROUND: The use of activated prothrombin complex concentrate (aPCC) to treat direct oral anticoagulant (DOAC)-associated bleeding is off-label and clinical experience is limited. OBJECTIVES: We aimed to assess the efficacy and safety of aPCC in reversing the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding. METHODS: A retrospective cohort study of adult non-randomized patients was conducted at a tertiary referral medical center in the United States (US) to investigate the use of aPCC for the reversal of the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding. The primary outcome was achieving clinical hemostasis according to prespecified criteria. Safety outcomes included the occurrence of thrombotic events during hospitalization. RESULTS: A total of 217 patients were included in the study. Intracranial hemorrhage (ICH) was the most common site of bleeding (n = 100, 46.1%), followed by gastrointestinal bleed (n = 87, 40.1%). Clinical hemostasis was achieved in 170 patients (78.3%), and the risk of not achieving hemostasis with ICH-related bleeding was significantly higher than that of non-ICH-related bleeding (2.5, 95% confidence interval [CI] 1.44-4.34; p < 0.001). Eight patients not achieving hemostasis died during hospitalization, all of whom were suffering from ICH, and mortality associated with non-ICH-related bleeding was significantly lower compared with ICH-related bleeding (0.91, 95% CI 0.86-0.97; p < 0.001). Thromboembolic events during hospitalization occurred in one patient (0.5%). CONCLUSIONS: The use of aPCC for the management of apixaban- or rivaroxaban-related major bleeding is effective in most cases and is associated with a low risk of thromboembolism.

Efficacy and safety of activated prothrombin complex concentrate for the reversal of vitamin K antagonist major bleeding.

Data on the use of activated prothrombin complex concentrate (aPCC) for the management of warfarin associated major bleeding is sparse. The objective of the study was to assess the achievement of effective clinical hemostasis using aPCC in patients presenting with major bleeding while on warfarin. We also assessed the safety of the drug. This retrospective study was conducted at a tertiary care teaching center in the USA where patients with major bleeding while receiving warfarin, and received aPCC were included. Efficacy of aPCC in achieving effective hemostasis was assessed according to the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. Efficacy was also assessed by achieving INR < 1.5 after treatment. The primary safety endpoint was the occurrence of any thromboembolic complications. A total of 67 patients were included in the study. The most common site for bleeding was intracerebral hemorrhage (n = 37, 55.2%), followed by gastrointestinal bleed (n = 26, 38.8%). Clinical hemostasis was achieved in 46 (68.7%) patients and of the 21 (31.3%) patients who did not achieve clinical hemostasis, 16 died. Thirty nine (58.2%) patients achieved INR < 1.5. Five (7.5%) patients developed thromboembolic complications. This study suggests that the use of aPCCs is effective in achieving effective hemostasis in patients on warfarin presenting with major bleeding.

Prevention and Treatment of Bleeding with Direct Oral Anticoagulants.

Anticoagulant-related bleeding carries considerable morbidity and mortality. Major or life-threatening bleeding is among the most severe of these complications. As the number of patients treated with direct oral anticoagulants (DOACs) continues to increase, so does the number of DOAC-related bleeding events. The incidence of CRNM bleeding related to DOAC therapy ranges from 15 to 18% per 100-year patients, while the incidence of major bleeding ranges from 2.71 to 3.6%. Many of these bleeding events can be prevented with tailored dosing regimens or proper peri-procedural management. When unable to be prevented, DOAC-related bleeding can lead to significant long-term disability or death. Management with newer reversal agents such as andexanet alfa and idarucizumab, as well as prothrombin complex concentrates, may improve outcomes for patients with DOAC-related bleeding. The purpose of this review is to explore strategies for preventing and treating bleeding in patients receiving DOACs for anticoagulant therapy.

Reversal of Apixaban and Rivaroxaban Using Activated Prothrombin Complex Concentrates in Patients with Major Bleeding.

BACKGROUND: Clinical experience with using activated prothrombin complex concentrates (aPCCs) to reverse the effects of factor Xa inhibitors is limited. OBJECTIVES: Our objective was to assess the achievement of effective clinical hemostasis using aPCC in patients on chronic apixaban or rivaroxaban therapy presenting with major bleeding in whom a reversal agent is warranted. We also assessed the safety of the drug. METHODS: A retrospective medical records review was conducted at a tertiary referral medical center in the USA. Patients presenting with major bleeding while receiving apixaban or rivaroxaban and treated with aPCC were included. Clinical hemostasis was assessed using International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. RESULTS: A total of 35 patients were included in the study. The most common site of bleeding was intracerebral hemorrhage (ICH) (n = 18 [51.4%]), followed by gastrointestinal bleed (n = 10 [28.6%]). Clinical hemostasis was achieved in 24 (68.6%) patients; 11 patients (31.4%) did not achieve clinical hemostasis; nine of these patients had ICH. Seven of the patients who did not achieve hemostasis died during hospitalization. Three (8.6%) patients experienced thromboembolic events during hospitalization. In total, 21 (60%) patients were receiving concomitant medications that interact with anti-factor Xa inhibitors and can increase the risk of bleeding. CONCLUSIONS: Our study suggests that aPCC could be an option in patients with major bleeding associated with apixaban or rivaroxaban. It may be an alternative for patients who need anticoagulation reversal if the specific antidote, andexanet alfa, is unavailable.

Cognition in pregnancy and the first year post-partum.

A longitudinal study measured the performance of a group of 15 pregnant women on tests of verbal memory, divided attention, and focused attention on four occasions (second trimester, third trimester, 6 weeks post-partum, and 1 year post-partum) while at the same time obtaining self-assessment ratings of these cognitive functions. A group of 14 non-pregnant women was studied at equivalent intervals. The two groups of women did not differ in performance on the objective tests, and there was no change in performance over time except for an improvement in the measure of focused attention from the first to the final testing occasion. However, the self-assessment ratings showed that in the second trimester, the pregnant women rated themselves as more impaired than before compared with the non-pregnant women for all three cognitive abilities. To ensure that this difference was not due to the retrospective nature of the comparison of current with previous cognitive ability, a second longitudinal study compared 25 pregnant and 10 non-pregnant women using daily ratings over a period of 1 week on four occasions during pregnancy and the first year post-partum. Women in the third trimester of pregnancy reported mild impairments in their focused and divided attention ability and their ability to remember what they had read compared with the non-pregnant women. The results show that there are perceived cognitive impairments during pregnancy. It is suggested that these may be the result of mild impairments which are not revealed in objective tests because they can be overcome by conscious effort in short periods of testing. Alternatively, the perceptions may not be based on actual impairments but may result from depressed mood or expectations concerning the effect of pregnancy on cognition.

Childhood amnesia: on answering questions about very early life events.

Twenty five young adults were asked about the events surrounding the birth of a younger sibling which took place when they were under the age of 2 years. Approximately 40% of the participants claimed to have significant memories of the events. The mothers of our participants verified that a majority of their answers were accurate. Comparing the pattern of data with those previously collected (Eacott & Crawley, 1998) suggests that the memories of those who were aged below 2:0 are qualitatively similar to the memories of those who were older at the time of events and dissimilar in type to those who are basing their reports on reconstructions from family knowledge. This finding may be evidence that memories of events that occurred before the age of 2 years are genuine but rare. This conclusion may be useful in assessing theories of childhood amnesia.

The offset of childhood amnesia: memory for events that occurred before age 3.

Adult memory for the events surrounding the birth of a sibling was examined in 69 adults. The authors identified a steep offset for childhood amnesia for this event before the child reaches age 2 1/2 years. The authors also examined the accuracy of information recalled. Although the majority of the answers were accurate, false memories were a consistent feature of the data. Alternative explanations of the authors' data were considered by examining the amount of information an additional 57 adults had about a family birth for which they could have no memory. The pattern of results did not support the view that participants might be unable to differentiate between memories and knowledge about the event.

Virulence characteristics of oral treponemes in a murine model.

This study was designed to investigate the virulence characteristics of Treponema denticola, T. socranskii, T. pectinovorum, and T. vincentii following challenge infection of mice. These microorganisms induced well-demarcated, dose-dependent, raised subcutaneous (s.c.) abscesses which were similar in time of onset, lesion progression, and duration of healing. Only viable cells were capable of inducing these characteristic s.c. abscesses. Histological examination of the skin lesion 3 and 5 days postinfection revealed abscess formation in the s.c. tissues, and abundant spiral organisms were demonstrated to be present in the abscess. Host resistance modulation by dexamethasone (neutrophil alteration) and cyclophosphamide (neutrophil depletion) pretreatment had a minimal effect on the virulence expression by any of these treponemes. The T. denticola isolates demonstrated significant trypsin-like protease (TLPase) activity, while both T. socranskii and T. vincentii were devoid of this activity. Interestingly, T. pectinovorum strains were heterogeneous with respect to TLPase as high producers, low producers, and nonproducers. However, no differences in lesion formation were noted regardless of whether the species expressed this proteolytic activity or whether treatment with N alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) and dithiothreitol was performed. These results showed that (i) a murine model may be used to evaluate virulence expression by oral treponemes; (ii) while TLPase activity varies among the oral treponemes, this protease does not appear to participate in abscess induction in the mouse model; and (iii) T. pectinovorum strains show variation in TLPase activity.

Model for the neuromuscular complications of systemic lupus erythematosus.

The purpose of this study is to evaluate nerve and muscle physiology and histopathology in a murine lupus model. Muscle strength, compound muscle action potentials (distal latency and amplitude), proximal limb muscle, sciatic nerve and joint specimens were studied in MRL/lpr (lupus model) and MRL/++ (control) mice. MRL/lpr mice showed decreased muscle strength (P < 10(-6, Wilcoxon rank sum), lower compound muscle action potential mean amplitude and prolonged distal latency (P = 0.005 and 0.042. Mann-Whitney U-test), and muscle and nerve inflammation (P = 0.002 and P = 0.037, Fisher's exact test) compared with MRL/++ mice. The MRL/lpr strain evaluated in this study demonstrated muscle weakness, abnormal motor nerve conduction studies and inflammation of both muscle and nerve. These features make it an excellent model for studying the neuromuscular complications of lupus.

Molecular mimicry, anti-coxsackievirus B3 neutralizing monoclonal antibodies, and myocarditis.

Molecular mimicry has been suggested as one mechanism to explain chronic myocarditis in some murine strains in the postinfectious period following induction of acute myocarditis by coxsackievirus B3 (CVB3). To test this hypothesis, neutralizing mAbs were generated against a highly myocarditic CVB3 virus (CVB3m). These mAbs neutralized several myocarditic and amyocarditic CVB3 variants by cytopathic effects inhibition assays. Data from several experiments suggest that these mAbs recognize discontinuous epitopes on CVB3m capsid proteins. Several mAbs were found to induce cardiopathologic alterations subsequent to i.p. inoculation of normal adolescent male CD-1 or C3H/HeJ mice. Immunocytochemical assays demonstrated significant binding of two mAbs to the surface of normal cultured murine cardiac fibroblasts. Also, several mAbs were shown to participate in C-mediated lysis of normal cardiac fibroblasts, but this property did not correlate well with cardiopathogenic potential. The two properties of a mAb that were the best predictors for cardiopathogenic potential were the capacity for stimulation of normal murine fibroblasts to produce a chemoattractant activity for unelicted murine peritoneal macrophages, and the capacity for recognition of an epitopes(s) on murine or human cardiac myosins. These data show that some anti-CVB3m neutralizing mAbs can participate in proinflammatory reactions in vitro and induce cardiopathologic alterations in vivo, suggesting one mechanism by which CVB3-induced chronic inflammation in murine heart tissues can be sustained in the absence of continued virus replication.

Variability of a bacterial surface protein and disease expression in a possible mouse model of systemic Lyme borreliosis.

During persistent infection of scid mice with Borrelia turicatae, an agent of relapsing fever and neuroborreliosis, there was variation in the surface proteins the bacteria expressed and in disease manifestations over time. Two serotypes, A and B, were isolated from the mice, cloned by limiting dilution, and further characterized. The only discernible difference between the two variants was in the size of the major surface protein they expressed: serotype A had a variable major protein (Vmp) of 23,000, and serotype B had a Vmp of 20,000. When other scid mice were inoculated with clonal populations of A and B, the infections were similar with respect to onset and degree of spirochetemia, involvement of the eye and heart, and occurrence of a peripheral vestibular disorder. However, there were differences between the serotypes in other respects: (a) serotype B but not A caused reddened and significantly enlarged joints, markedly impaired performance on a walking bar, and severe arthritis by histologic examination; (b) serotype A but not B invaded the central nervous system during early infection; and (c) serotype A penetrated monolayers of human umbilical vein endothelial cells more readily than did serotype B. The combination of arthritis, myocarditis, and neurologic disease resembled human Lyme borreliosis. The findings indicate that differences in disease expression are determined by variable surface proteins of the bacterium and that scid mouse infections with B. turicatae provide a model for the study of the pathogenesis of Lyme borreliosis and other persistent spirochetal diseases.

Hepatic response to a very-low-energy diet and refeeding in rats.

Hepatic effects of very-low-energy diets (VLEDs) and refeeding were studied in dietary obese rats. Rats weighing 490-530 g (ages 72-119 d) were randomly assigned to control (C) and VLED groups. Control animals consumed a complete diet ad libitum whereas VLED animals consumed 20% of the energy intake of C animals for 7, 14, or 21 d, and some VLED animals were refed the C diet for 7 d. Hepatic weights, lipid, DNA, and total protein decreased in VLED animals. Observed hepatocytic lipid was high in C and progressively decreased in VLED rats. Hepatocytes from VLED rats lost cytoplasmic organelles, contained myelin figures, and became smaller. Decreased protein-DNA ratios and lipids in these same animals is consistent with atrophy. Other biochemical findings included reductions in blood urea nitrogen, albumin, triglycerides, total protein, and glucose, all of which are synthesized or metabolized by the liver. These observations suggest that attenuation of hepatic function is likely.

What lessons can be learned from animal model studies in viral heart disease?

Several well-defined coxsackievirus B3 (CVB3)-murine models of inflammatory heart disease are providing information about mechanisms which contribute to myocyte necrosis. Severity of disease induced and mechanisms responsible depend upon unresolved molecular activities of the viral genome, nonspecific defenses of the mouse at time of infection and immune responses of the mouse at the time of infection. Most important are the capabilities and directed responses of each mouse to infection which are determined by age and genetic background of the host. In addition to virus-induced contributions to tissue pathology during primary infection, persistence of viral genomes for week to months in some strains of mice forecast whether the acute disease will resolve or continue as chronic disease with sustained inflammatory reactions in the myocardium. Persistent infections can contribute to nascent cardiopathologic alterations by chronic induction of inflammatory events through expression of viral genes and altered expression of host genes during nonlytic infections. Products of these expressions include viral proteins and nonhomeostatic levels of cytokines and arachidonic acid cascade intermediates and final metabolites. Molecular mimicry via shared epitopes between virion capsid proteins and normal cell molecules/structures located on or within heart tissue cells may be the mechanism by which immune systems in certain strains of mice are persistently stimulated. The products of these immune responses, i.e. antibodies and cytotoxic T lymphocytes, may provide initial protection via termination of infection and virus clearance during acute disease but subsequently these autoreactive processes could contribute to chronic disease. The immune effector products (antibodies and T lymphocytes) have potential pro-inflammatory reactivities, capacity for exacerbating ongoing CVB3-induced disease and/or can induce disease in normal animals. In further support of the hypothesis that autoimmune reactions contribute to sustained inflammation of the heart, non-viral models of myocarditis have been developed. Cell constituents such as myosin and adenosine nucleotide translocator protein can induce cardiopathologic alterations in normal mice of strains known to develop CVB3-induced chronic disease. Thus host genetic background determines whether a mouse survives the initial infection, resolves the acute disease or inadvertently contributes to sustained inflammatory heart disease. Finally, shared epitopes among the enteroviruses may play a role in repeated episodes of disease during sequential infections by different serotypes.

Ig V kappa family repertoire of plasma cells derived from autoimmune MRL mice.

V kappa gene family usage was determined in the resident in vivo-activated plasma cells of individual diseased MRL mice by using in situ hybridization. In this way, the entire autoimmune repertoire could be analyzed. Autoantibody levels and extent of glomerulonephritis were also measured, so that the severity of disease could be assessed. It was found that V kappa expression was highly variable from mouse to mouse. Some animals displayed a V kappa family repertoire similar to mitogen-stimulated cells and consistent with the size of the families. These animals tended to have lower disease indices. Other animals, which had higher disease indices, displayed considerable over- or underutilization of individual V kappa families. However, no particular V kappa families were repeatedly biased in their expression, as was found at the VH level with J558. Importantly, in the 10% of animals that expressed VH J558 exclusively, four or more V kappa families were expressed and multiple antiself specificities were produced. The data are most consistent with a number of J558 genes being expanded in a variety of self-specificities. However, because only VH J558 is expressed in these sicker animals, nonspecific polyclonal activation is highly unlikely. These results underscore the continuing evolution of the autoimmune repertoire, with considerable diversity at early stages followed by a highly selected repertoire in which a potential role for nonspecific polyclonal activation is virtually excluded.

Virulence of Wolinella recta in a murine abscess model.

The virulence of Wolinella recta isolates was studied in an experimental animal model by using monoinfection of BALB/c mice. Infection with clinical isolates of W. recta 576 and W. recta 234 induced dry, flat, depressed gangrenous necrotic skin lesions, whereas W. recta ATCC 33238 failed to induce a similar lesion. Histological examination of the skin lesion 72 h postinfection revealed coagulation necrosis of the epidermis, subcutis and cutaneous truncus muscle, with marked exudation of serum proteins and neutrophils. Virulence-modulating agents such as dexamethasone, galactosamine, hydrazine sulfate, and dextran microcarrier beads were used in conjunction with W. recta infection. Dexamethasone, hydrazine sulfate, and dextran beads enhanced the infectivity and pathogenicity of W. recta for lesion formation and tissue destruction compared with what was found in untreated control mice. Galactosamine sensitization enhanced the virulence potential of W. recta to such an extent that a lethal outcome was observed. Laboratory passage of clinical isolates demonstrated a decreased virulence in high-passage strains, which correlated with the minimal virulence observed in the extensively passaged W. recta ATCC 33238. Serum immunoglobulin G (IgG) and IgM responses were detected in the serum of infected animals, and cross-reacting antibody indicated variation in the antigenic makeup of various W. recta strains. Enhanced IgG antibody responses were observed following the secondary challenge. Mice with acquired antibody response to initial infection remained susceptible to lesion formation with subsequent challenge, but the size of the lesion was significantly reduced, indicating partial protection. Serum IgG and IgM antibody levels were significantly increased by active immunization when compared with levels in mice which had recovered from infection. The immunization significantly decreased the lesion size; however, even these high levels of antibody failed to abrogate the lesion induction.

Anti-Coxsackievirus B3 neutralizing antibodies with pathological potential.

Adolescent CD-1 mice inoculated with coxsackievirus B3 (CVB3m) will develop acute myocarditis with focal lesions by 7 days post-inoculation (p.i.). Administration of murine sera containing anti-CVB3m-neutralizing antibodies into CVB3m-inoculated mice at 3 days p.i. will exacerbate myocarditis, suggesting the presence of pathological antibodies. To study potential pro-inflammatory properties of virus-induced antibodies, a panel of anti-CVB3m-neutralizing monoclonal antibodies (mAbs) was generated. Several studies demonstrated shared epitopes between CVB3m particles and cultured murine cardiac or neonatal skin fibroblasts: (1) one or more mAbs bound to cultured cardiac fibroblasts; (2) several mAbs can participate in complement-mediated lysis of neonatal skin fibroblasts; and (3) at least one mAbs stimulated synthesis of a macrophage chemoattractant from cultured neonatal skin fibroblasts. Injection of one mAb in three doses, each of about 5 micrograms, into adolescent male CD-1 mice induced focal myocarditic lesions which were similar to CVB3m-induced lesions. One mAb induced a diffuse interstitial hypercellularity in most mice and two mAbs did not induce detectable cardiopathology. These data suggest that some anti-CVB3m neutralizing idiotypes (antibodies) which initially can provide protection via virus clearance mechanisms can also bind to cross-reacting epitopes on normal tissues. Binding of antibodies to normal heart tissues could stimulate proinflammatory reactions by several mechanisms and sustain myocarditis.

The use of heuristic strategies in the interpretation of pronouns.

The aim of the two experiments reported here was to distinguish between two heuristic strategies that have been proposed to account for the assignment of pronouns: the subject assignment strategy and the parallel function strategy. According to the subject assignment strategy, a pronoun is assigned to a preceding subject noun phrase, whereas according to the parallel function strategy, a pronoun is assigned to a previous noun phrase in the same grammatical position as the pronoun. These two strategies were tested by examining the interpretation of single object pronouns, first in a reading task and second in an assignment task. In both experiments, there was a strong preference for assigning an object pronoun to the preceding subject noun phrase, thus supporting the subject assignment strategy. However, this was only the case for pronouns that were linguistically ambiguous. When assignment was constrained by gender, there was no effect of either strategy. It is suggested that heuristic strategies are only used in the absence of other strong cues to assignment.

Reference in single sentences and in texts.

This study investigated the comprehension and production of reference terms in both sentences (Experiments 1 and 2) and texts (Experiments 3 and 4) using a sentence completion task. In Experiments 1 and 2, the use of a sentence-level strategy (subject assignment) was investigated. In Experiments 3 and 4, the use of a text-level strategy (topic assignment) was also investigated. There was a clear preference for continuing the sentences by referring to the subjects of the sentences regardless of the availability of gender cues, in both single sentences and in texts. There was also an influence of the topic of each text on both the choice of referent and the type of reference term used. However, the choice of reference term was affected by the number of potential antecedents in the preceding text. Overall, the results suggest that the sentence subject is a salient item in working memory. This salience is increased if the sentence subject is also the textual topic. In addition, it appears that the presence of a pronoun in a text triggers a specific strategy to assign the pronoun to the (salient) sentence subject.