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The immunoregulatory cytokine TGF-β is pleiotropic due to the near-ubiquitous expression of the TGF-β receptors TβRI and TβRII on diverse cell types. The helminth parasite Heligmosomoides polygyrus has convergently evolved a family of TGF-β mimics (TGMs) that bind both these receptors through domains 1-3 of a 5-domain protein. One member of this family, TGM4, differs from TGF-β in acting in a cell-specific manner, failing to stimulate fibroblasts, but activating SMAD phosphorylation in macrophages. Primarily through domains 4 and 5, TGM4 interacts with multiple co-receptors, including CD44, CD49d (integrin α4) and CD206, and can up- and downmodulate macrophage responses to IL-4 and lipopolysaccharide (LPS), respectively. The dependence of TGM4 on combinatorial interactions with co-receptors is due to a moderated affinity for TβRII that is more than 100-fold lower than for TGF-β. Thus the parasite has elaborated TGF-β receptor interactions to establish cell specificity through combinatorial cis-signalling, an innovation absent from the mammalian cytokine., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

Liebold et al. recently revealed how the identity of dying cells drives distinct changes to the macrophages which engulf and clear them, a process known as efferocytosis. During infection with the helminth Schistosoma mansoni, liver macrophages recapitulate these phenotypes, mediated by Axl/MerTK receptors and regulating egg burdens., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Demyelination in the central nervous system (CNS) resulting from injury or disease can cause loss of nerve function and paralysis. Cell therapies intended to promote remyelination of axons are a promising avenue of treatment, with mesenchymal stromal cells (MSCs) a prominent candidate. We have previously demonstrated that MSCs derived from human olfactory mucosa (hOM-MSCs) promote myelination to a greater extent than bone marrow-derived MSCs (hBM-MSCs). However, hOM-MSCs were developed using methods and materials that were not good manufacturing practice (GMP)-compliant. Before considering these cells for clinical use, it is necessary to develop a method for their isolation and expansion that is readily adaptable to a GMP-compliant environment. We demonstrate here that hOM-MSCs can be derived without enzymatic tissue digestion or cell sorting and without culture antibiotics. They grow readily in GMP-compliant media and express typical MSC surface markers. They robustly produce CXCL12 (a key secretory factor in promoting myelination) and are pro-myelinating in in vitro rodent CNS cultures. GMP-compliant hOM-MSCs are comparable in this respect to those grown in non-GMP conditions. However, when assessed in an in vivo model of demyelinating disease (experimental autoimmune encephalitis, EAE), they do not significantly improve disease scores compared with controls, indicating further pre-clinical evaluation is necessary before their advancement to clinical trials.

During inflammation, haematopoietic stem cells (HSCs) in the bone marrow (BM) and periphery rapidly expand and preferentially differentiate into myeloid cells that mediate innate immune responses. HSCs can be directed into quiescence or differentiation by sensing alterations to the haematopoietic niche, including cytokines, chemokines, and pathogen-derived products. Most studies attempting to identify the mechanisms of haematopoiesis have focused on bacterial and viral infections. From intracellular protozoan infections to large multicellular worms, parasites are a global health burden and represent major immunological challenges that remain poorly defined in the context of haematopoiesis. Immune responses to parasites vary drastically, and parasites have developed sophisticated immunomodulatory mechanisms that allow development of chronic infections. Recent advances in imaging, genomic sequencing, and mouse models have shed new light on how parasites induce unique forms of emergency haematopoiesis. In addition, parasites can modify the haematopoiesis in the BM and periphery to improve their survival in the host. Parasites can also induce long-lasting modifications to HSCs, altering future immune responses to infection, inflammation or transplantation, a term sometimes referred to as central trained immunity. In this review, we highlight the current understanding of parasite-induced haematopoiesis and how parasites target this process to promote chronic infections., (© 2023 The Authors. Parasite Immunology published by John Wiley & Sons Ltd.)

Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus , down-modulates the host immune system through release of an immunosuppressive TGF-β mimic, TGM1, which is a divergent member of the CCP (Sushi) protein family. TGM1 comprises 5 domains, of which domains 1-3 (D1/2/3) bind mammalian TGF-β receptors, acting on T cells to induce Foxp3 + regulatory T cells; however, the roles of domains 4 and 5 (D4/5) remain unknown. We noted that truncated TGM1, lacking D4/5, showed reduced potency. Combination of D1/2/3 and D4/5 as separate proteins did not alter potency, suggesting that a physical linkage is required and that these domains do not deliver an independent signal. Coprecipitation from cells treated with biotinylated D4/5, followed by mass spectrometry, identified the cell surface protein CD44 as a coreceptor for TGM1. Both full-length and D4/5 bound strongly to a range of primary cells and cell lines, to a greater degree than D1/2/3 alone, although some cell lines did not respond to TGM1. Ectopic expression of CD44 in nonresponding cells conferred responsiveness, while genetic depletion of CD44 abolished enhancement by D4/5 and ablated the ability of full-length TGM1 to bind to cell surfaces. Moreover, CD44-deficient T cells showed attenuated induction of Foxp3 by full-length TGM1, to levels similar to those induced by D1/2/3. Hence, a parasite protein known to bind two host cytokine receptor subunits has evolved a third receptor specificity, which serves to raise the avidity and cell type-specific potency of TGF-β signaling in mammalian cells.

Although significant progress has been made to improve short-term survival of transplant patients, long-term acceptance of allografts in solid organ and hematopoietic stem cell (HSC) transplantation is still a significant challenge. Current therapeutics for preventing or treating allograft rejection rely on potent immunosuppressive drugs that primarily target T cells of the adaptive immune response. Promising advances in transplant immunology have highlighted the importance of innate immune responses in allograft acceptance and rejection. Recent studies have demonstrated that innate immune cells are capable of mediating memory-like responses during inflammation, a term known as trained innate immunity. In this process, innate immune cells, such as macrophages and monocytes, undergo metabolic and epigenetic changes in response to a primary stimulus with a pathogen or their products that result in faster and more robust responses to a secondary stimulus. There is also some evidence to suggest that innate immune cells or their progenitors may be more anti-inflammatory after initial stimulation with appropriate agents, such as helminth products. Although this phenomenon has primarily been studied in the context of infection, there is emerging evidence to suggest that it could play a vital role in transplantation rejection and tolerance. Mechanisms of training innate immune cells and their progenitors in the bone marrow are therefore attractive targets for mediating long-term solid organ and HSC transplant tolerance. In this review, we highlight the potential role of proinflammatory and anti-inflammatory mechanisms of trained innate immunity in solid organ and HSC transplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Certain proinflammatory stimuli can metabolically and epigenetically modify monocytes/macrophages or NK cells to be more responsive to secondary stimuli, a process known as trained innate immunity. However, the longevity of trained innate immunity is unclear. In this study, we report that Fasciola hepatica excretory-secretory products (FHES) can imprint an anti-inflammatory phenotype on long-term hematopoietic stem cells (HSCs) and monocyte precursor populations, enhancing their proliferation and differentiation into anti-inflammatory Ly6C low monocytes. These monocytes expand and populate multiple compartments within mice, conferring hyporesponsiveness to proinflammatory stimuli and reduced susceptibility to induction of experimental autoimmune encephalomyelitis. Mice treated with FHES had enhanced alternatively activated macrophages, reduced Th1 and Th17 responses, and attenuating effects on autoimmunity that persisted for 8 mo. Furthermore, transplantation of HSCs from FHES-treated mice transferred the anti-inflammatory phenotype to naive mice. Our findings demonstrate that helminth products can modulate HSCs to promote development of anti-inflammatory myeloid cells that attenuate T cell-mediated autoimmune disease., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Purpose Of the three currently recognized variants of primary progressive aphasia, behavioral differentiation between the nonfluent/agrammatic (nfvPPA) and logopenic (lvPPA) variants is particularly difficult. The challenge includes uncertainty regarding diagnosis of apraxia of speech, which is subsumed within criteria for variant classification. The purpose of this study was to determine the extent to which a variety of speech articulation and prosody metrics for apraxia of speech differentiate between nfvPPA and lvPPA across diverse speech samples. Method The study involved 25 participants with progressive aphasia (10 with nfvPPA, 10 with lvPPA, and five with the semantic variant). Speech samples included a word repetition task, a picture description task, and a story narrative task. We completed acoustic analyses of temporal prosody and quantitative perceptual analyses based on narrow phonetic transcription and then evaluated the degree of differentiation between nfvPPA and lvPPA participants (with the semantic variant serving as a reference point for minimal speech production impairment). Results Most, but not all, articulatory and prosodic metrics differentiated statistically between the nfvPPA and lvPPA groups. Measures of distortion frequency, syllable duration, syllable scanning, and-to a limited extent-syllable stress and phonemic accuracy showed greater impairment in the nfvPPA group. Contrary to expectations, classification was most accurate in connected speech samples. A customized connected speech metric-the narrative syllable duration-yielded excellent to perfect classification accuracy. Discussion Measures of average syllable duration in multisyllabic utterances are useful diagnostic tools for differentiating between nfvPPA and lvPPA, particularly when based on connected speech samples. As such, they are suitable candidates for automatization, large-scale study, and application to clinical practice. The observation that both speech rate and distortion frequency differentiated more effectively in connected speech than on a motor speech examination suggests that it will be important to evaluate interactions between speech and discourse production in future research.

Purpose: There is persistent uncertainty about whether sound error consistency is a valid criterion for differentiating between apraxia of speech (AOS) and aphasia with phonemic paraphasia. The purpose of this study was to determine whether speakers with a profile of aphasia and AOS differ in error consistency from speakers with aphasia who do not have AOS. By accounting for differences in overall severity and using a sample size well over three times that of the largest study on the topic to date, our ambition was to resolve the existing controversy., Method: We analyzed speech samples from 171 speakers with aphasia and completed error consistency analysis for 137 of them. The experimental task was to repeat four multisyllabic words five times successively. Phonetic transcriptions were coded for four consistency indices (two at the sound-level and two at the word-level). We then used quantitative metrics to assign participants to four diagnostic groups (one aphasia plus AOS group, one aphasia only group, and two groups with intermediate speech profiles). Potential consistency differences were examined with ANCOVA, with error frequency as a continuous covariate., Results: Error frequency was a strong predictor for three of the four consistency metrics. The magnitude of consistency for participants with AOS was either similar or lower compared to that of participants with aphasia only. Despite excellent transcription reliability and moderate to excellent coding reliability, three of the four consistency indices showed limited measurement reliability., Discussion: People with AOS and people with aphasia often produce inconsistent variants of errors when they are asked to repeat challenging words several times sequentially. The finding that error consistency is similar or lower in aphasia with AOS than in aphasia without AOS is incompatible with recommendations that high error consistency be used as a diagnostic criterion for AOS. At the same time, group differences in the opposite direction are not sufficiently systematic to warrant use for differential diagnosis between aphasia with AOS and aphasia with phonemic paraphasia. Greater attention should be given to error propagation when estimating reliability of derived measurements.

IL-33 is known to promote type 2 immune responses through ST2, a component of the IL-33R complex, expressed primarily on mast cells, Th2 cells, group 2 innate lymphoid cells and regulatory T cells, and to a lesser extent, on NK cells and Th1 cells. Consistent with previous studies, we found that IL-33 polarized alternatively activated macrophages (AAMΦ) in vivo. However, in vitro stimulation of murine bone marrow-derived or peritoneal macrophages with IL-33 failed to promote arginase activity or expression of YM-1 or Retnla , markers of AAMΦ. Furthermore, macrophages have low/no basal expression of ST2. This suggested that alternative activation of macrophages may involve an IL-33-responsive third-party cell. Because mast cells have the highest expression of ST2 relative to other leukocytes, we focused on this cell type. Coculture experiments showed that IL-33-stimulated mast cells polarized AAMΦ through production of soluble factors. IL-33-stimulated mast cells produced a range of cytokines, including IL-6 and IL-13. Mast cell-derived IL-13 was required for induction of AAMΦ, whereas mast cell-derived IL-6 enhanced macrophage responsiveness to IL-13 via upregulation of the IL-4Rα receptor. Furthermore, we found that AAMΦ polarized by IL-33-stimulated mast cells could suppress proliferation and IL-17 and IFN-γ production by T cells. Finally, we show that AAMΦ polarized by IL-33-stimulated mast cells attenuated the encephalitogenic function of T cells in the experimental autoimmune encephalomyelitis model. Our findings reveal that IL-33 can promote immunosuppressive responses by polarizing AAMΦ via mast cell-derived IL-6 and IL-13., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Engineering a pro-regenerative immune response following scaffold implantation is integral to functional tissue regeneration. The immune response to implanted biomaterials is determined by multiple factors, including biophysical cues such as material stiffness, topography and particle size. In this study we developed an immune modulating scaffold for bone defect healing containing bone mimetic nano hydroxyapatite particles (BMnP). We first demonstrate that, in contrast to commercially available micron-sized hydroxyapatite particles, in-house generated BMnP preferentially polarize human macrophages towards an M2 phenotype, activate the transcription factor cMaf and specifically enhance production of the anti-inflammatory cytokine, IL-10. Furthermore, nano-particle treated macrophages enhance mesenchymal stem cell (MSC) osteogenesis in vitro and this occurs in an IL-10 dependent manner, demonstrating a direct pro-osteogenic role for this cytokine. BMnPs were also capable of driving pro-angiogenic responses in human macrophages and HUVECs. Characterization of immune cell subsets following incorporation of functionalized scaffolds into a rat femoral defect model revealed a similar profile, with micron-sized hydroxyapatite functionalized scaffolds eliciting pro-inflammatory responses characterized by infiltrating T cells and elevated expression of M1 macrophages markers compared to BMnP functionalized scaffolds which promoted M2 macrophage polarization, tissue vascularization and increased bone volume. Taken together these results demonstrate that nano-sized Hydroxyapatite has immunomodulatory potential and is capable of directing anti-inflammatory innate immune-mediated responses that are associated with tissue repair and regeneration., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose The purpose of this study was to compare the utility of two automated indices of lexical diversity, the Moving-Average Type-Token Ratio (MATTR) and the Word Information Measure (WIM), in predicting aphasia diagnosis and responding to differences in severity and aphasia subtype. Method Transcripts of a single discourse task were analyzed for 478 speakers, 225 of whom had aphasia per an aphasia battery. We calculated the MATTR and the WIM for each participant. We compared the group means among speakers with aphasia, neurotypical controls, and left-hemisphere stroke survivors with mild aphasia not detected by an aphasia battery. We examined whether each measure distinguished levels of aphasia severity and subtypes of aphasia. We used each measure to classify aphasia versus neurotypical control and compared the areas under the curve. Results The WIM and the MATTR differentiated among people with aphasia, neurotypical controls, and people with mild aphasia. Both measures demonstrated moderately high predictive accuracy in classifying aphasia. The WIM demonstrated greater sensitivity to aphasia severity and subtype compared to the MATTR. Conclusions The WIM and the MATTR are promising measures that quantify lexical diversity in different and complementary ways. The WIM may be more useful for quantifying the effect of treatment or disease progression, whereas the MATTR may be more useful for discriminating discourse produced by people with very mild aphasia from discourse produced by neurotypical controls. Further validation is required.

Purpose Many communication disorders result in speech sound errors that listeners perceive as phonemic errors. Unfortunately, manual methods for calculating phonemic error frequency are prohibitively time consuming to use in large-scale research and busy clinical settings. The purpose of this study was to validate an automated analysis based on a string metric-the unweighted Levenshtein edit distance-to express phonemic error frequency after left hemisphere stroke. Method Audio-recorded speech samples from 65 speakers who repeated single words after a clinician were transcribed phonetically. By comparing these transcriptions to the target, we calculated the percent segments with a combination of phonemic substitutions, additions, and omissions and derived the phonemic edit distance ratio, which theoretically corresponds to percent segments with these phonemic errors. Results Convergent validity between the manually calculated error frequency and the automated edit distance ratio was excellent, as demonstrated by nearly perfect correlations and negligible mean differences. The results were replicated across 2 speech samples and 2 computation applications. Conclusions The phonemic edit distance ratio is well suited to estimate phonemic error rate and proves itself for immediate application to research and clinical practice. It can be calculated from any paired strings of transcription symbols and requires no additional steps, algorithms, or judgment concerning alignment between target and production. We recommend it as a valid, simple, and efficient substitute for manual calculation of error frequency.

Purpose Collaborative goal setting is at the heart of person-centered rehabilitation but can be challenging, particularly in the area of aphasia. The purpose of this clinical focus article is to present a step-by-step model for forming a collaborative partnership with clients to develop an intervention plan that follows the client's lead, addresses communicative participation, and integrates multiple treatment strategies. Method We introduce the rationale and core features of a 4-step and 4-pronged process (the FOURC model) and illustrate its application through 3 cases of people with aphasia who were treated in outpatient rehabilitation. Conclusions The model invites client initiative in a clinically feasible manner while supporting the clinician's role in guiding the intervention based on professional expertise and growing familiarity with the case. Outcomes observed in case studies include strengthened motivation and improved real-life communication.

Purpose: Diagnostic recommendations for acquired apraxia of speech (AOS) have been contradictory concerning whether speech sound errors are consistent or variable. Studies have reported divergent findings that, on face value, could argue either for or against error consistency as a diagnostic criterion. The purpose of this study was to explain discrepancies in error consistency results based on the unit of analysis (segment, syllable, or word) to help determine which diagnostic recommendation is most appropriate., Method: We analyzed speech samples from 14 left-hemisphere stroke survivors with clinical diagnoses of AOS and aphasia. Each participant produced 3 multisyllabic words 5 times in succession. Broad phonetic transcriptions of these productions were coded for consistency of error location and type using the word and its constituent syllables and sound segments as units of analysis., Results: Consistency of error type varied systematically with the unit of analysis, showing progressively greater consistency as the analysis unit changed from the word to the syllable and then to the sound segment. Consistency of error location varied considerably across participants and correlated positively with error frequency., Conclusions: Low to moderate consistency of error type at the word level confirms original diagnostic accounts of speech output and sound errors in AOS as variable in form. Moderate to high error type consistency at the syllable and sound levels indicate that phonetic error patterns are present. The results are complementary and logically compatible with each other and with the literature.

Purpose: This study was conducted to evaluate the clinical utility of error variability for differentiating between apraxia of speech (AOS) and aphasia with phonemic paraphasia., Method: Participants were 32 individuals with aphasia after left cerebral injury. Diagnostic groups were formed on the basis of operationalized measures of recognized articulatory and prosodic characteristics of AOS and phonemic paraphasia. Sequential repetitions of multisyllabic words were elicited as part of a motor speech evaluation and transcribed phonetically. Four metrics of variability at the syllable and word levels were derived from these transcripts., Results: The measures yielded different magnitudes of variability. There were no group differences between participants who displayed speech profiles consistent with AOS and participants who displayed speech profiles indicative of aphasia with phonemic paraphasia. Rather, correlation coefficients and analyses of covariance showed that the variability metrics were significantly mediated by overall error rate. Additionally, variability scores for individuals with salient diagnoses of AOS and conduction aphasia were inconsistent with current diagnostic guidelines., Conclusions: The results do not support diagnostic validity of error variability for differentiating between AOS and aphasia with phonemic paraphasia. Future research using error variability metrics should account for overall error rate in the analysis and matching of participant groups.

5-HT3 receptor antagonists, ondansetron, granisetron and tropisetron are highly specific for the 5-HT3 receptor and have a selectivity ratio of approximately 1000:1 compared with affinities for other receptors. Other 5-HT3 receptor antagonists, largely those having a benzamide structure, are non-selective. These include metoclopramide, renzapride and zacopride which stimulate gastric motility via activation of 5-HT4 receptors; metoclopramide is also a potent dopamine receptor antagonist. Selective 5-HT3 receptor antagonists are a major advance in the treatment of chemotherapy- and radiotherapy-induced emesis in cancer patients. These agents inhibit emesis by blocking 5-HT3 receptors on vagal afferent nerve terminals in the gastrointestinal mucosa and on terminals on the same vagal nerves in the vomiting system. Inhibition of acute emesis appears to be produced by blocking the initiation of the emetic reflex induced via 5-HT3 receptors and by 5-HT released from enterochromaffin cells in the small intestine, as well as by blocking 5-HT3 receptors in the hindbrain vomiting system.

7864 infants were examined within 48 h of birth by junior medical staff; 5 with dislocation, 16 with dislocatable hip, and 25 with joint laxity were referred for abduction splinting. 622 of the infants (7.9%) had minor signs (clicking or grating hip). When these 622 infants underwent clinical and radiological examination at 4 months of age, 34 had serious hip pathology (5 dislocation, 5 dislocatable hip, and 24 radiological abnormalities). Of the 7196 infants considered normal in the newborn period, 7 were referred for orthopaedic opinion (3 with dislocation and 4 with subluxation) at age 2-9 months by general practitioners and community health physicians. Thus, dislocated or dislocatable hips were 39 times more frequent in infants who had minor signs on examination within 48 h of birth than in infants considered normal. The implication of these findings is that clicking and grating of the hip are important signs which require systematic follow-up, with radiological examination at 4-6 months.