Task-based functional magnetic resonance imaging prediction of postsurgical cognitive outcomes in temporal lobe epilepsy: A systematic review, meta-analysis, and new data.

Task-based functional magnetic resonance imaging (tfMRI) has developed as a common alternative in epilepsy surgery to the intracarotid amobarbital procedure, also known as the Wada procedure. Prior studies have implicated tfMRI as a comparable predictor of postsurgical cognitive outcomes. However, the predictive validity of tfMRI has not been established. This preregistered systematic review and meta-analysis (CRD42020183563) synthesizes the literature predicting postsurgical cognitive outcomes in temporal lobe epilepsy (TLE) using tfMRI. The PubMed and PsycINFO literature databases were queried for English-language articles published between January 1, 2009 and December 31, 2020 associating tfMRI laterality indices or symmetry of task activation with outcomes in TLE. Their references were reviewed for additional relevant literature, and unpublished data from our center were incorporated. Nineteen studies were included in the meta-analysis. tfMRI studies predicted postsurgical cognitive outcomes in left TLE ( ρ ̂ = -.27, 95% confidence interval [CI] = -.32 to -.23) but not right TLE ( ρ ̂ = -.02, 95% CI = -.08 to .03). Among studies of left TLE, language tfMRI studies were more robustly predictive of postsurgical cognitive outcomes ( ρ ̂ = -.27, 95% CI = -.33 to -.20) than memory tfMRI studies ( ρ ̂ = -.27, 95% CI = -.43 to -.11). Further moderation by cognitive outcome domain indicated language tfMRI predicted confrontation naming ( ρ ̂ = -.32, 95% CI = -.41 to -.22) and verbal memory ( ρ ̂ = -.26, 95% CI = -.35 to -.17) outcomes, whereas memory tfMRI forecasted only verbal memory outcomes ( ρ ̂ = -.37, 95% CI = -.57 to -.18). Surgery type, birth sex, level of education, age at onset, disease duration, and hemispheric language dominance moderated study outcomes. Sensitivity analyses suggested the interval of postsurgical follow-up, and reporting and methodological practices influenced study outcomes as well. These findings intimate tfMRI is a modest predictor of outcomes in left TLE that should be considered in the context of a larger surgical workup.

A systematic review and meta-analysis of intellectual, neuropsychological, and psychoeducational functioning in neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a common genetic disorder frequently associated with cognitive deficits. Despite cognitive deficits being a key feature of NF1, the profile of such impairments in NF1 has been shown to be heterogeneous. Thus, we sought to quantitatively synthesize the extant literature on cognitive functioning in NF1. A random-effects meta-analysis of cross-sectional studies was carried out comparing cognitive functioning of patients with NF1 to typically developing or unaffected sibling comparison subjects of all ages. Analyses included 50 articles (Total NNF1 = 1,522; MAge = 15.70 years, range = 0.52-69.60), yielding 460 effect sizes. Overall moderate deficits were observed [g = -0.64, 95% CI = (-0.69, -0.60)] wherein impairments differed at the level of cognitive domain. Deficits ranged from large [general intelligence: g = -0.95, 95% CI = (-1.12, -0.79)] to small [emotion: g = -0.37, 95% CI = (-0.63, -0.11)]. Moderation analyses revealed nonsignificant contributions of age, sex, educational attainment, and parental level of education to outcomes. These results illustrate that cognitive impairments are diffuse and salient across the lifespan in NF1. Taken together, these results further demonstrate efforts should be made to evaluate and address cognitive morbidity in patients with NF1 in conjunction with existing best practices.

A scoping review of outcomes of operational success for nurse scientists in clinical practice settings.

BACKGROUND: The nurse scientist in the clinical setting is a role that has evolved over recent decades to encompass the concomitant development of personal research programs and the facilitation of staff and advanced practice nurse research in health care settings. However, the definition, operationalization, and measures of success are extremely variable. PURPOSE: To identify the defining features and characteristics of the nurse scientist role in clinical practice settings as represented in the existing literature. METHODS: We conducted a scoping review using PubMed and CINAHL databases. We initially identified a total of 3345 references from 1976 to June 2020, 217 of which were published from 2005-2020. We used the Joanna Briggs Institute (JBI) framework to explore the state of the science of the role of nurse scientists in practice settings. DISCUSSION: Approximately 100 articles met the criteria for full-text analysis, and the final review consisted of 20 descriptive analytic studies addressing the nurse scientist role definition, operationalization, and outcome measures. CONCLUSION: Findings suggest that nurse scientist roles serve to promote health system success through a host of research-focused activities that conceivably contribute to improved patient care outcomes. Work is needed to support the cost of requisite resources and infrastructure and to increase acceptance of the role as part of a tenure-earning track in academic settings that also stand to benefit.

Multiple-brain systems dynamically interact during tonic and phasic states to support language integrity in temporal lobe epilepsy.

An epileptogenic focus in the dominant temporal lobe can result in the reorganization of language systems in order to compensate for compromised functions. We studied the compensatory reorganization of language in the setting of left temporal lobe epilepsy (TLE), taking into account the interaction of language (L) with key non-language (NL) networks such as dorsal attention (DAN), fronto-parietal (FPN) and cingulo-opercular (COpN), with these systems providing cognitive resources helpful for successful language performance. We applied tools from dynamic network neuroscience to functional MRI data collected from 23 TLE patients and 23 matched healthy controls during the resting state (RS) and a sentence completion (SC) task to capture how the functional architecture of a language network dynamically changes and interacts with NL systems in these two contexts. We provided evidence that the brain areas in which core language functions reside dynamically interact with non-language functional networks to carry out linguistic functions. We demonstrated that abnormal integrations between the language and DAN existed in TLE, and were present both in tonic as well as phasic states. This integration was considered to reflect the entrainment of visual attention systems to the systems dedicated to lexical semantic processing. Our data made clear that the level of baseline integrations between the language subsystems and certain NL systems (e.g., DAN, FPN) had a crucial influence on the general level of task integrations between L/NL systems, with this a normative finding not unique to epilepsy. We also revealed that a broad set of task L/NL integrations in TLE are predictive of language competency, indicating that these integrations are compensatory for patients with lower overall language skills. We concluded that RS establishes the broad set of L/NL integrations available and primed for use during task, but that the actual use of those interactions in the setting of TLE depended on the level of language skill. We believe our analyses are the first to capture the potential compensatory role played by dynamic network reconfigurations between multiple brain systems during performance of a complex language task, in addition to testing for characteristics in both the phasic/task and tonic/resting state that are necessary to achieve language competency in the setting of temporal lobe pathology. Our analyses highlighted the intra- versus inter-system communications that form the basis of unique language processing in TLE, pointing to the dynamic reconfigurations that provided the broad multi-system support needed to maintain language skill and competency.

Computational support, not primacy, distinguishes compensatory memory reorganization in epilepsy.

Temporal lobe epilepsy is associated with impairment in episodic memory. A substantial subgroup, however, is able to maintain adequate memory despite temporal lobe pathology. Missing from prior work in cognitive reorganization is a direct comparison of temporal lobe epilepsy patients with intact status with those who are memory impaired. Little is known about the regional activations, functional connectivities and/or network reconfigurations that implement changes in primary computations or support functions that drive adaptive plasticity and compensated memory. We utilized task functional MRI on 54 unilateral temporal lobe epilepsy patients and 24 matched healthy controls during the performance of a paired-associate memory task to address three questions: (i) which regions implement paired-associate memory in temporal lobe epilepsy, and do they vary as a function of good versus poor performance, (ii) is there unique functional connectivity present during memory encoding that accounts for intact status by preservation of primary memory computations or the supportive computations that allow for intact memory responses and (iii) what features during memory encoding are most distinctive: is it the magnitude and location of regional activations, or the presence of enhanced functional connections to key structures such as the hippocampus? The study revealed non-dominant hemisphere regions (right posterior temporal regions) involving both increased regional activity and increased modulatory communication with the hippocampi as most important to intact memory in left temporal lobe epilepsy compared to impaired status. The profile involved areas that are neither contralateral homologues to left hemisphere memory areas, nor regions traditionally considered computationally primary for episodic memory. None of these areas of increased activation or functional connectivity were associated with advantaged memory in healthy controls. Our emphasis on different performance levels yielded insight into two forms of cognitive reorganization: computational primacy, where left temporal lobe epilepsy showed little change relative to healthy controls, and computational support where intact left temporal lobe epilepsy patients showed adaptive abnormalities. The analyses isolated the unique regional activations and mediating functional connectivity that implements truly compensatory reorganization in left temporal lobe epilepsy. The results provided a new perspective on memory deficits by making clear that they arise not just from the knockout of a functional hub, but from the failure to instantiate a complex set of reorganization responses. Such responses provided the computational support to ensure successful memory. We demonstrated that by keeping track of performance levels, we can increase understanding of adaptive brain responses and neuroplasticity in epilepsy.

Diminished reward responsiveness is associated with lower reward network GluCEST: an ultra-high field glutamate imaging study.

Low reward responsiveness (RR) is associated with poor psychological well-being, psychiatric disorder risk, and psychotropic treatment resistance. Functional MRI studies have reported decreased activity within the brain's reward network in individuals with RR deficits, however the neurochemistry underlying network hypofunction in those with low RR remains unclear. This study employed ultra-high field glutamate chemical exchange saturation transfer (GluCEST) imaging to investigate the hypothesis that glutamatergic deficits within the reward network contribute to low RR. GluCEST images were acquired at 7.0 T from 45 participants (ages 15-29, 30 females) including 15 healthy individuals, 11 with depression, and 19 with psychosis spectrum symptoms. The GluCEST contrast, a measure sensitive to local glutamate concentration, was quantified in a meta-analytically defined reward network comprised of cortical, subcortical, and brainstem regions. Associations between brain GluCEST contrast and Behavioral Activation System Scale RR scores were assessed using multiple linear regressions. Analyses revealed that reward network GluCEST contrast was positively and selectively associated with RR, but not other clinical features. Follow-up investigations identified that this association was driven by the subcortical reward network and network areas that encode the salience of valenced stimuli. We observed no association between RR and the GluCEST contrast within non-reward cortex. This study thus provides new evidence that reward network glutamate levels contribute to individual differences in RR. Decreased reward network excitatory neurotransmission or metabolism may be mechanisms driving reward network hypofunction and RR deficits. These findings provide a framework for understanding the efficacy of glutamate-modulating psychotropics such as ketamine for treating anhedonia.

Olfactory Dysfunction in Neurodevelopmental Disorders: A Meta-analytic Review of Autism Spectrum Disorders, Attention Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder.

Olfactory dysfunction is recognized in neurodevelopmental disorders and may serve as an early indicator of global dysfunction. The present meta-analysis measures olfaction effect sizes in attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), and obsessive-compulsive disorder (OCD). Meta-analysis included 320 ADHD, 346 ASD, and 208 OCD individuals as compared to 910 controls. Olfactory performance deficits were small-to-moderate and heterogeneous (d = - 0.42, 95% CI = - 0.59 < δ < - 0.25). Meta-analytic results indicate that olfactory dysfunction is evident in individuals with ASD and OCD, with small-to-negligible effects in ADHD. These findings imply olfactory dysfunction is related to clinical phenotype in ASD and OCD, but not ADHD, and warrant inclusion in clinical assessment and evaluation of certain neurodevelopmental disorders.

Treating murine inflammatory diseases with an anti-erythrocyte antibody.

Treatment of autoimmune and inflammatory diseases typically involves immune suppression. In an opposite strategy, we show that administration of the highly inflammatory erythrocyte-specific antibody Ter119 into mice remodels the monocyte cellular landscape, leading to resolution of inflammatory disease. Ter119 with intact Fc function was unexpectedly therapeutic in the K/BxN serum transfer model of arthritis. Similarly, it rapidly reversed clinical disease progression in collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis and completely corrected CAIA-induced increase in monocyte Fcγ receptor II/III expression. Ter119 dose-dependently induced plasma chemokines CCL2, CCL5, CXCL9, CXCL10, and CCL11 with corresponding alterations in monocyte percentages in the blood and liver within 24 hours. Ter119 attenuated chemokine production from the synovial fluid and prevented the accumulation of inflammatory cells and complement components in the synovium. Ter119 could also accelerate the resolution of hypothermia and pulmonary edema in an acute lung injury model. We conclude that this inflammatory anti-erythrocyte antibody simultaneously triggers a highly efficient anti-inflammatory effect with broad therapeutic potential.

Associations Between Neuroticism and Executive Function Outcomes: Response Inhibition and Sustained Attention on a Continuous Performance Test.

There are known relationships between psychopathology, personality, and executive function (EF), though the association between personality and EF, independent of psychopathology, remains understudied. The present study investigated relationships between Five Factor Model personality traits and indices of response inhibition, sustained attention, and response variability on a continuous performance test (CPT) among 50 healthy adults (male = 27, female = 23; Mage = 19.9 years, range 18-24 years) of primarily Caucasian descent (58.0%). Participants performed an open-source CPT, the Psychology Experiment Building Language Battery Test of Attentional Vigilance (TOAV), and completed self-ratings of conscientiousness, extraversion, and neuroticism on an inventory developed from the public-domain International Personality Item Pool. After controlling for the influences of age, gender, and other personality traits, neuroticism was significantly associated with faster error reaction time and a higher frequency of multiple responses. Neuroticism was also nominally predictive of more frequent commission errors and faster correct and mean reaction time. The present findings indicate that neuroticism is associated with error-prone behavioral performance on a CPT, suggesting that a propensity to experience negative emotions may manifest as impulsivity and hyperactivity on performance-based measures of EF.

A Quantitative Meta-analysis of Olfactory Dysfunction in Epilepsy.

Olfactory dysfunction in epilepsy is well-documented in several olfactory domains. However, the clinical specificity of these deficits remains unknown. The aim of this systematic meta-analysis was to determine which domains of olfactory ability were most impaired in individuals with epilepsy, and to assess moderating factors affecting olfactory ability. Extant peer-reviewed literature on olfaction in epilepsy were identified via a computerized literature search using PubMed, MEDLINE, PsycInfo, and Google Scholar databases. Twenty-one articles met inclusion criteria. These studies included a total of 912 patients with epilepsy and 794 healthy comparison subjects. Included studies measured olfaction using tests of odor identification, discrimination, memory, and detection threshold in patients with different types of epilepsy, including temporal lobe epilepsy (TLE), mixed frontal epilepsy (M-F), and mixed epilepsy (MIX). Olfactory deficits were robust in patients with epilepsy when compared to healthy individuals, with effect sizes in the moderate to large range for several olfactory domains, including odor identification (d = -1.59), memory (d = -1.10), discrimination (d = -1.04), and detection threshold (d = -0.58). Olfactory deficits were most prominent in patients with TLE and M-F epilepsy. Amongst patients with epilepsy, sex, age, smoking status, education, handedness, and age of illness onset were significantly related to olfactory performance. Overall, these meta-analytic findings indicate that the olfactory system is compromised in epilepsy and suggest that detailed neurobiological investigations of the olfactory system may provide further insight into this disorder.

The Effects of Electronic Cigarette (ECIG)-Generated Aerosol and Conventional Cigarette Smoke on the Mucociliary Transport Velocity (MTV) Using the Bullfrog (R. catesbiana) Palate Paradigm.

Background: While ECIGs are under scrutiny concerning safety, particularly in reference to the physiological impact that aerosolized ECIG liquid (E-liquid) may have on respiratory tissues, others believe that ECIGs are a "Harm Reduction" alternative to conventional cigarettes. Previous studies investigating ciliated respiratory epithelium indicate that smoking shortens cilia length, reduces cilia beat frequency and disrupts respiratory epithelium, which most likely contributes to the inhibition of mucocilliary clearance. Monitoring mucous clearance of respiratory tissues exposed to ECIG-generated aerosol or conventional cigarette smoke, as indexed by mucous transport velocity (MTV), is one way to gauge the impact aerosol and smoke have on the respiratory tract. Therefore, we designed an experiment to test the effect of ECIG-generated aerosol and smoke on MTV using the frog palate paradigm. Methods: Peristaltic pumps transport ECIG-generated aerosol and conventional cigarette smoke into custom-made chambers containing excised bullfrog palates. MTVs were determined before exposure, immediately after exposure and approximately 1 day following exposure. MTVs were also determined (at the same time points) for palates exposed to air (control). Surface and cross sectional SEM images of palates from all three groups were obtained to support MTV data. Results: The results indicate that ECIG-generated aerosol has a modest inhibitory effect (p < 0.05) on MTV 1 day post-exposure (0.09 ± 0.01) compared to control MTV (0.16 ± 0.03 mm/s). In contrast, smoke completely inhibits MTV from 0.14 ± 0.03 mm/s immediately before exposure to 0.00 mm/sec immediately after exposure and the MTV is unable to recover 1 day later. SEM images of control palates and palates exposed to ECIG-generated aerosol both show cilia throughout their epithelial surface, while some areas of palates exposed to smoke are completely devoid of cilia. Additionally, the epithelial thickness of aerosol-exposed palates appears thicker than control palates while smoke-exposed palates appear to be thinner due to epithelial disruption. Conclusions: These results indicate that ECIG-generated aerosol has only a modest effect on mucocilary clearance of bullfrog palates and aerosol sedimentation accounts for epithelial thickening. In accordance with the primary literature, conventional cigarette smoke dramatically inhibits mucociliary clearance and is, in part, due to decreased number of cilia and disruption of the smoke-exposed epithelium.

Mechanistic properties of intravenous immunoglobulin in murine immune thrombocytopenia: support for FcγRIIB falls by the wayside.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterised by platelet clearance resulting from the production of platelet-reactive autoantibodies. Platelet clearance appears to occur mainly via phagocytosis in the mononuclear phagocytic system, although T-cell-mediated platelet destruction, platelet apoptosis and dysregulation of platelet production can also play a role in disease pathogenesis. One of the most successful treatments for ITP is intravenous immunoglobulin (IVIg), and while it has been used in ITP for over 30 years, its mechanism(s) of action still remain unclear. Animal models of ITP have proven useful in understanding IVIg's immunomodulatory properties, providing a valuable tool to test new mechanistic theories as well as further explore the soundness of older ones. This model has also provided the key evidence that IVIg exerts its effects via activating receptors for IgG Fc, specifically FcγRIII, via formation of IgG dimers or immune complexes. Here, we discuss the validity of one prominent theory of IVIg function, anti-inflammatory activity mediated through the inhibitory Fcγ receptor FcγRIIB, and review evidence to suggest that this theory is not likely valid in the practical sense.

Trace Metals Derived from Electronic Cigarette (ECIG) Generated Aerosol: Potential Problem of ECIG Devices That Contain Nickel.

Introduction: ECIGs are currently under scrutiny concerning their safety, particularly in reference to the impact ECIG liquids (E-liquids) have on human health. One concern is that aerosolized E-liquids contain trace metals that could become trapped in respiratory tissues and induce pathology. Methods: To mimic this trapping, peristaltic pumps were used to generate and transport aerosol onto mixed cellulose ester (MCE) membranes where aluminum (Al), arsenic (As), cadmium (Cd), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), and zinc (Zn) were subsequently captured and quantified. The presence of trace metals on unexposed MCE membranes and on MCE membranes exposed to mainstream smoke served as control and comparison, respectively. The presence of these metals was also determined from the E-liquid before aerosolization and untouched by the ECIG device. All metals were quantified using ICP-MS. The ECIG core assembly was analyzed using scanning electron microscopy with elemental analysis capability. Results: The contents (µg) of Al, As, Cd, Cu, Fe, Mn, Ni, Pb, and Zn on control MCE membranes were 1.2 ± 0.2, 0.050 ± 0.002, 0.047 ± 0.003, 0.05 ± 0.01, 0.001 ± 0.001, 0.16 ± 0.04, 0.005 ± 0.003, 0.014 ± 0.006, and 0.09 ± 0.02, respectively. The contents of all trace metals on MCE membranes exposed to aerosol were similar to controls, except Ni which was significantly (p < 0.01) higher (0.024 ± 0.004 µg). In contrast, contents of Al, As, Fe, Mn, and Zn on MCE membranes exposed to smoke were significantly higher (p < 0.05) than controls. The contents of Al, As, Cu, Fe, and Mn on smoke-exposed MCE membranes were also significantly higher (p < 0.05) than their content on aerosol-exposed membranes. The contents per cigarette equivalent of metals in E-liquid before aerosolization were negligible compared to amounts of aerosolized E-liquid, except for Fe (0.002 µg before and 0.001 µg after). Elemental analysis of the core assembly reveals the presence of several of these trace metals, especially Al, Fe, Ni, and Zn. Conclusions: In general, from the single ECIG-device/E-liquid combination used, the amount of trace metals from ECIG-generated aerosol are lower than in traditional mainstream smoke, Only Ni in the ECIG-generated aerosol was higher than control. The most probable source of Ni in this aerosol is the core assembly.

CD44 antibody-mediated amelioration of murine immune thrombocytopenia (ITP): mouse background determines the effect of FcγRIIb genetic disruption.

BACKGROUND: Several monoclonal antibodies to CD44 can successfully ameliorate murine immune thrombocytopenia (ITP). As these antibodies may be a potential replacement for intravenous immune globulin (IVIG) in the treatment of ITP and other autoimmune diseases, an understanding of their mechanisms of action is important. The role of the inhibitory Fc receptor (FcγRIIb) in the mechanism of action of IVIG and therapeutic CD44 antibodies remains uncertain. To assess if FcγRIIb in splenic macrophages plays a critical role in the action of these two therapeutics, splenectomized mice and mice genetically deficient in FcγRIIb on different backgrounds were evaluated. STUDY DESIGN AND METHODS: Thrombocytopenia was induced in FcγRIIb-deficient mice on B6;129S, C57BL/6, and BALB/C backgrounds, as well as splenectomized mice and control mice by platelet (PLT) antibody. PLT counts were enumerated before and after treatment with anti-CD44, red blood cell antibodies, or IVIG. RESULTS: Anti-CD44 is ineffective at inhibiting thrombocytopenia in B6;129S FcγRIIb-deficient mice but, like IVIG, is effective in splenectomized mice and FcγRIIb-deficient mice on the BALB/C and C57BL/6 background. CONCLUSION: These data suggest that 1) the B6;129S background itself is unlikely to be the sole reason for anti-CD44's inability to function in B6;129S FcγRIIb-deficient mice, 2) the simple loss of macrophage FcγRIIb expression alone is insufficient to explain anti-CD44 ameliorative function, and 3) a combination of mouse background genes in addition to FcγRIIb genetic disruption may affect the ability of anti-CD44 to function therapeutically. Similarities between IVIG and anti-CD44 mechanisms suggest that patients responsive to IVIG may also potentially respond to anti-CD44 treatment.

Amelioration of murine passive immune thrombocytopenia by IVIg and a therapeutic monoclonal CD44 antibody does not require the Myd88 signaling pathway.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by a low platelet count and the production of anti-platelet antibodies. The majority of ITP patients have antibodies to platelet integrin α(IIb)ß3 (GPIIbIIIa) which can direct platelet phagocytosis by macrophages. One effective treatment for patients with ITP is intravenous immunoglobulin (IVIg) which rapidly reverses thrombocytopenia. The exact mechanism of IVIg action in human patients is unclear, although in mouse models of passive ITP, IVIg can rapidly increase platelet counts in the absence of adaptive immunity. Another antibody therapeutic that can similarly increase platelet counts independent of adaptive immunity are CD44 antibodies. Toll-like receptors (TLRs) are pattern recognition receptors which play a central role in helping direct the innate immune system. Dendritic cells, which are notable for their expression of TLRs, have been directly implicated in IVIg function as an initiator cell, while CD44 can associate with TLR2 and TLR4. We therefore questioned whether IVIg, or the therapeutic CD44 antibody KM114, mediate their ameliorative effects in a manner dependent upon normal TLR function. Here, we demonstrate that the TLR4 agonist LPS does not inhibit IVIg or KM114 amelioration of antibody-induced thrombocytopenia, and that these therapeutics do not ameliorate LPS-induced thrombocytopenia. IVIg was able to significantly ameliorate murine ITP in C3H/HeJ mice which have defective TLR4. All known murine TLRs except TLR3 utilize the Myd88 adapter protein to drive TLR signaling. Employing Myd88 deficient mice, we found that both IVIg and KM114 ameliorate murine ITP in Myd88 deficient mice to the same extent as normal mice. Thus both IVIg and anti-CD44 antibody can mediate their ameliorative effects in murine passive ITP independent of the Myd88 signaling pathway. These data help shed light on the mechanism of action of IVIg and KM114 in the amelioration of murine ITP.

The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody-mediated amelioration of murine immune thrombocytopenia.

To definitively determine whether the neonatal Fc receptor (FcRn) is required for the acute amelioration of immune thrombocytopenia (ITP) by IVIg, we used FcRn-deficient mice in a murine ITP model. Mice injected with antiplatelet antibody in the presence or absence of IVIg displayed no difference in platelet-associated IgG between FcRn deficient versus C57BL/6 mice. FcRn-deficient mice treated with high-dose (2 g/kg) IVIg or a low-dose (2 mg/kg) of an IVIg-mimetic CD44 antibody were, however, protected from thrombocytopenia to an equivalent extent as wild-type mice. To verify and substantiate the results found with FcRn-deficient mice, we used ß(2)-microglobulin-deficient mice (which do not express functional FcRn) and found that IVIg or CD44 antibody also protected them from thrombocytopenia. These data suggest that for both high-dose IVIg as well as low-dose CD44 antibody treatment in an acute ITP model, FcRn expression is neither necessary nor required.

Amelioration of murine immune thrombocytopenia by CD44 antibodies: a potential therapy for ITP?

To explore the potential for monoclonal antibodies as a treatment for immune thrombocytopenia (ITP) and to further explore their mechanisms of action, we tested 8 monoclonal CD44 antibodies in murine ITP and found 4 antibodies that could successfully ameliorate ITP; 2 of these antibodies function at a full 3-log fold lower dosage compared with IVIg. Further characterization of the 2 most successful antibodies (5035-41.1D and KM114) demonstrated that, similar to IVIg: (1) the presence of the inhibitory IgG receptor FcγRIIB was required for their ameliorative function, (2) complement-deficient mice responded to anti-CD44 treatment, and (3) human transgenic FcγRIIA-expressing mice also responded to the CD44 therapeutic modality. Dissimilar to IVIg, the Fc portion of the CD44 antibody was not required. These data demonstrate that CD44 antibodies can function therapeutically in murine ITP and that they could potentially provide a very-low-dose recombinant therapy for the amelioration of human ITP.

Transfusion of antibody-opsonized red blood cells results in a shift in the immune response from the red blood cell to the antibody in a murine model.

BACKGROUND: It is well known that infusion of immunoglobulin (Ig)G-coated cells results in an inhibited antigen-specific humoral immune response compared to the cells themselves, a phenomenon termed antibody-mediated immune suppression (AMIS). Although this AMIS effect has been well described with many different types of cells as well as vaccines and insoluble antigens, the mechanisms behind this effect remain unresolved. STUDY DESIGN AND METHODS: To study AMIS in a broad context, three different models of AMIS were studied. In the first, mice were transfused with sheep red blood cells (SRBCs) versus IgG-coated SRBCs. In the second, SRBCs expressing the antigen hen egg white lysozyme (HEL) were studied, and the third model consisted of the diphtheria/tetanus vaccine in the absence versus presence of anti-tetanus IgG. The antibody responses to the SRBCs and HEL-SRBCs, as well as the vaccine, were analyzed for up to 4 weeks after challenge. RESULTS: In these mouse models of immunization, the IgG-coated RBCs or HEL-RBCs induced an antibody response against the IgG, rather than against the RBCs. The decreased response to the RBCs was directly related to the increase of the response against the IgG. The inhibitory AMIS effect using the vaccine strategy again showed an immune response against the IgG, concurrent with a decrease in the immune response against the specific vaccine component targeted. CONCLUSIONS: This work demonstrates that, under AMIS conditions, the IgG itself becomes the focus of B cells in the immune system, suggesting a potential mechanism of B-cell regulation.

Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk.

To determine whether inhibition of Syk would be useful in FcgammaR-dependent cytopenias such as immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia, mouse models were used to evaluate efficacy of R406, an inhibitor of Syk function, in treating cytopenia. Both disease models responded favorably to treatment, with amelioration of ITP being more dramatic. Thus, phase 2 clinical trial was initiated to study the effects of Syk inhibition in humans with ITP. Sixteen adults with chronic ITP were entered into an open-label, single-arm cohort dose-escalation trial beginning with 75 mg and escalating as high as 175 mg twice daily. Doses were increased until a persistent response was seen, toxicity occurred, or 175 mg twice daily was reached. Eight patients achieved persistent responses with platelet counts greater than 50 x 10(9)/L (50 000 mm(3)) on more than 67% (actually 95%) of their study visits, including 3 who had not persistently responded to thrombopoietic agents. Four others had nonsustained responses. Mean peak platelet count exceeded 100 x 10(9)/L (100 000 mm(3)) in these 12 patients. Toxicity was primarily GI-related with diarrhea (urgency) and vomiting; 2 patients had transaminitis. In conclusion, inhibition of Syk was an efficacious means of increasing and maintaining the platelet count in half the patients with chronic refractory ITP. (ClinicalTrials.gov, no. NCT00706342).

Transfusion of IgG-opsonized foreign red blood cells mediates reduction of antigen-specific B cell priming in a murine model.

Hemolytic disease of the fetus and newborn can be effectively prevented by administration of anti-D to the mother. The administered IgG results in the attenuation of RBC-specific Ab production, a process termed Ab-mediated immune suppression (AMIS). Because in animal models of AMIS no major effect on T cell priming occurs, we hypothesized that the effect of the IgG on the immune system under AMIS conditions may involve a deficiency in B cell priming. We therefore challenged mice with either untreated RBCs or IgG-opsonized RBCs (AMIS) and assessed B cell priming. B cells from mice transfused with untreated RBCs, but not from mice treated under AMIS conditions, were primed as assessed by their ability to function as Ag-specific APCs to appropriate T cells. To our knowledge, this is the first report demonstrating that AMIS inhibits the appearance of Ag-primed RBC-specific B cells.