Mucus, with its burden of inspired particulates and pathogens, is cleared from mucosal surfaces of the airways by cilia beating within the periciliary layer (PCL). The PCL is held to be "watery" and ...free of mucus by thixotropic-like forces arising from beating cilia. With radii of gyration ~250 nm, however, polymeric mucins should reptate readily into the PCL, so we assessed the glycocalyx for barrier functions. The PCL stained negative for MUC5AC and MUC5B, but it was positive for keratan sulfate (KS), a glycosaminoglycan commonly associated with glycoconjugates. Shotgun proteomics showed KS-rich fractions from mucus containing abundant tethered mucins, MUC1, MUC4, and MUC16, but no proteoglycans. Immuno-histology by light and electron microscopy localized MUC1 to microvilli, MUC4 and MUC20 to cilia, and MUC16 to goblet cells. Electron and atomic force microscopy revealed molecular lengths of 190-1,500 nm for tethered mucins, and a finely textured glycocalyx matrix filling interciliary spaces. Adenoviral particles were excluded from glycocalyx of the microvilli, whereas the smaller adenoassociated virus penetrated, but were trapped within. Hence, tethered mucins organized as a space-filling glycocalyx function as a selective barrier for the PCL, broadening their role in innate lung defense and offering new molecular targets for conventional and gene therapies.
Counter‐wildlife crime (CWC) interventions—those that directly protect target wildlife from illegal harvest/persecution, detect and sanction rule‐breakers, and interdict and control illegal wildlife ...commodities—are widely applied to address biodiversity loss. This systematic map provides an overview of the literature on the effectiveness of CWC interventions for conserving African, Asian and Latin American wildlife directly threatened by exploitation, including human–wildlife conflicts that trigger poaching.
Following our systematic map protocol (Rytwinski, Öckerman, et al., 2021), we compiled peer‐reviewed and grey literature and screened articles using pre‐defined inclusion criteria. Included studies were coded for key variables of interest, from which we produced a searchable database, interactive map and structured heatmaps.
A total of 530 studies from 477 articles were included in the systematic map. Most studies were from Africa and Asia (81% of studies) and focused on African and Asian elephants (16%), felids (14%) and turtles and tortoises (11%). Most evaluations of CWC interventions targeted wildlife products (rather than species) and the transfer of those products along the wildlife crime continuum (40% of cases). Population/species outcomes were most commonly measured via indicators of threat reduction (65% of cases) and intermediate outcomes (25%).
We identified knowledge clusters where studies investigated the links between (1) patrols and other preventative actions to increase detection and population abundance and (2) information analysis and sharing and wildlife crime/trade levels. However, the effectiveness of most interventions was not rigorously evaluated. Most investigations used post‐implementation monitoring only (e.g. lacking a comparator), and no experimental designs were found. We identified several key knowledge gaps including a paucity of studies by geography (Latin America), taxonomy (plants, birds and reptiles), interventions (non‐patrol‐based CWC interventions) and outcomes (biological and the combination of biological and human well‐being outcomes).
Our map reveals an opportunity to improve the rigour and documentation of CWC intervention evaluations, which would enable the evidence‐based selection of effective approaches to improve wildlife conservation and national security.
Results of our systematic map indicate that despite a relatively large evidence base on the effectiveness of counter‐wildlife crime (CWC) interventions for conserving wildlife, most interventions have not been rigorously evaluated. Studies often lacked comparators and experimental designs. We also identify several knowledge gaps that deserve further study, including further investigations in Latin America, on plants, birds and reptiles, for non‐patrol‐based CWC interventions, and in relation to biological, and the combination of biological and human well‐being outcomes. Our assessment of the evidence base provides important first steps towards improving our understanding of CWC intervention effectiveness and making evidence‐informed management and funding decisions.
The coxsackievirus and adenovirus receptor (CAR) mediates viral attachment and infection, but its physiologic functions have not been described. In nonpolarized cells, CAR localized to homotypic ...intercellular contacts, mediated homotypic cell aggregation, and recruited the tight junction protein ZO-1 to sites of cell-cell contact. In polarized epithelial cells, CAR and ZO-1 colocalized to tight junctions and could be coprecipitated from cell lysates. CAR expression led to reduced passage of macromolecules and ions across cell monolayers, and soluble CAR inhibited the formation of functional tight junctions. Virus entry into polarized epithelium required disruption of tight junctions. These results indicate that CAR is a component of the tight junction and of the functional barrier to paracellular solute movement. Sequestration of CAR in tight junctions may limit virus infection across epithelial surfaces.
BACKGROUND: Idiopathic headshaking (HSK) in horses is a distressing disorder in which the etiology and pathophysiology are unknown. HYPOTHESIS: Differences in sensory function of the trigeminal nerve ...exist between healthy and affected horses. ANIMALS: Six healthy mature geldings and 6 mature geldings with idiopathic HSK. METHODS: Prospective study. Sensory nerve action and somatosensory evoked potentials studies were performed. The stimulus site comprised the gingival mucosa dorsal to the maxillary canine. A pair of recording electrodes was placed along the sensory pathway of the trigeminal complex at the infraorbital nerve (R1), maxillary nerve (R2), spinal tract of trigeminal (R3), and somatosensory cortex (R4). Sensory nerve action potential latency (ms), amplitude (μV), duration (ms), area under the curve (μVms), and conduction velocity (m/s) were calculated. RESULTS: Threshold for activation of the infraorbital branch of the trigeminal nerve was significantly different between 5 affected (≤5 mA) and 6 control horses (≥10 mA). After initiation of an action potential, there were no differences in all parameters measured and no differences between left and right sides. A horse with seasonal HSK tested during a time of no clinical manifestations showed a threshold for activation similar to control horses. CONCLUSIONS AND CLINICAL IMPORTANCE: This study confirms involvement of the trigeminal nerve hyperexcitability in the pathophysiology of disease. Further, results might support a functional rather than a structural alteration in the sensory pathway of the trigeminal complex that can be seasonal. The horse could serve as a natural animal model for humans with idiopathic trigeminal neuralgia.
Summary
Fumaric acid esters (FAEs) are licensed for the treatment of moderate‐to‐severe psoriasis in Germany but are also used off‐label in many other countries. We conducted this systematic review ...to synthesize the highest‐quality evidence for the benefits and risks of FAEs for psoriasis. Our primary outcomes were change in Psoriasis Area and Severity Index score and dropout rates due to adverse effects. Randomized controlled trials (RCTs) of FAEs or dimethylfumarate were included, with no restriction on age or psoriasis subtype. We searched the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library, Medline, Embase, LILACS and five trials registers, and hand searched six conference proceedings. Six RCTs with a total of 544 participants were included, four of which were published only as s or brief reports, limiting study reporting. Five RCTs compared FAEs with placebo, and all demonstrated benefit in favour of FAEs. However, meta‐analysis was possible only for PASI 50 response after 12–16 weeks, which was achieved by 64% of participants on FAEs compared with 14% on placebo: risk ratio (RR) 4·55, 95% confidence interval (CI) 2·80–7·40; two studies; 247 participants; low‐quality evidence). There was no difference in dropout rates due to adverse effects (RR 5·36, 95% CI 0·28–102·12; one study; 27 participants; very low‐quality evidence and wide CI). More participants experienced nuisance adverse effects with FAEs (76%) than with placebo (16%) (RR 4·72, 95% CI 2·45–9·08; one study; 99 participants; moderate‐quality evidence), mainly abdominal pain, diarrhoea and flushing. One head‐to‐head study of very low‐quality evidence comparing FAEs with methotrexate reported comparable efficacy and dropout rates, although FAEs caused more flushing. The evidence in this review was limited and must be interpreted with caution; studies with better design and outcome reporting are needed.
What's already known about this topic?
Fumaric acid esters (FAEs) are licensed for the treatment of moderate‐to‐severe psoriasis in Germany, and are used off‐label in many other countries.
Non‐Cochrane systematic reviews previously examined the effect of FAEs in psoriasis, but have not rigorously assessed the quality of the evidence.
What does this study add?
Six randomized controlled trials with 544 participants were included, four of which were published only as s or brief reports, resulting in low‐ or very low‐quality evidence.
Results suggest that FAEs are superior to placebo, but their efficacy in comparison with methotrexate is uncertain due to very low‐quality evidence.
The relative risk of nuisance adverse effects with FAEs is about five times greater than with placebo; however, there is insufficient evidence available to give an accurate figure for dropout rates due to adverse effects.
Linked Comment: Egeberg. Br J Dermatol 2016; 175:857.
Audio Commentary
How insight, paranoia and depression evolve in relation to each other during and after the first episode of schizophrenia is poorly understood but of clinical importance.
Serial assessments over 18 ...months were made using multiple instruments in a consecutive sample of 257 patients with first episode DSM-IV non-affective psychosis. Repeated measures of paranoia, insight, depression and self-esteem were analysed using structural equation modelling, to examine the direction of relationships over time after controlling for confounds.
Depression was predicted directly by greater insight, particularly at baseline, and by greater paranoia at every stage of follow-up. Neither relationship was mediated by self-esteem, although there was a weak association of lower self-esteem with greater depression and better insight. Paranoia was not strongly associated with insight. Duration of untreated psychosis and substance use at baseline predicted depression at 18 months.
In first-episode psychosis, good insight predicts depression. Subsequently, paranoia is the strongest predictor. Neither effect is mediated by low self-esteem. Effective treatment of positive symptoms is important in preventing and treating low mood in early schizophrenia.
Lentivirus-based gene transfer has the potential to efficiently deliver DNA-based therapies into non-dividing epithelial cells of the airway for the treatment of lung diseases such as cystic ...fibrosis. However, significant barriers both to lung-specific gene transfer and to production of lentivirus vectors must be overcome before these vectors can be routinely used for applications to the lung. In this study, we investigated whether the ability to produce lentiviral vectors pseudotyped with fowl plague virus hemagglutinin (HA) could be improved by co-expression of influenza virus M2 in vector-producing cells. We found that M2 expression led to a 10-30-fold increase in production of HA-pseudotyped lentivirus vectors based upon equine infectious anemia virus (EIAV) or human immunodeficiency virus type 1 (HIV-1). Experiments using the M2 inhibitor amantadine and a drug-resistant mutant of M2 established that the ion channel activity of M2 was important for M2-dependent augmentation of vector production. Furthermore, the neuraminidase activity necessary for particle release from producer cells could also be incorporated into producer cells by co-expression of influenza NA cDNA. Lentiviral vectors pseudotyped with influenza envelope proteins were able to efficiently transduce via the apical membrane of polarized mouse tracheal cultures in vitro as well as mouse tracheal epithelia in vivo.
Aims
Deciding if a diabetic foot ulcer is infected in a community setting is challenging without validated point‐of‐care tests. Four inflammatory biomarkers were investigated to develop a composite ...algorithm for mildly infected diabetic foot ulcers: venous white cell count, C‐reactive protein (CRP) and procalcitonin, and a novel wound exudate calprotectin assay. Calprotectin is a marker of neutrophilic inflammation.
Methods
In a prospective study, people with uninfected or mildly infected diabetic foot ulcers who had not received oral antibiotics in the preceding 2 weeks were recruited from community podiatry clinics for measurement of inflammatory biomarkers. Antibiotic prescribing decisions were based on clinicians’ baseline assessments and participants were reviewed 1 week later; ulcer infection was defined by clinicians’ overall impression from their two assessments.
Results
Some 363 potential participants were screened, of whom 67 were recruited, 29 with mildly infected diabetic foot ulcers and 38 with no infection. One participant withdrew early in each group. Ulcer area was 1.32 cm2 interquartile range (IQR) 0.32–3.61 cm2 in infected ulcers and 0.22 cm2 (IQR 0.09–1.46 cm2) in uninfected ulcers. Baseline CRP for mild infection was 9.00 mg/ml and 6.00 mg/ml for uninfected ulcers; most procalcitonin levels were undetectable. Median calprotectin level in infected diabetic foot ulcers was 1437 ng/ml and 879 ng/ml in uninfected diabetic foot ulcers. Area under the receiver operating characteristic curve for a composite algorithm incorporating calprotectin, CRP, white cell count and ulcer area was 0.68 (95% confidence intervals 0.52–0.82), sensitivity 0.64, specificity 0.81.
Conclusions
A composite algorithm including CRP, calprotectin, white cell count and ulcer area may help to distinguish uninfected from mildly infected diabetic foot ulcers. Venous procalcitonin is unhelpful for mild diabetic foot ulcer infection.
What's new?
Distinguishing between mild infection and no infection in diabetic foot ulcers, a frequent position of equipoise in antibiotic prescribing, is challenging in the absence of objective evidence available at point of care.
We developed a novel wound exudate calprotectin assay which, when combined with venous C‐reactive protein, white cell count and ulcer area, provided a diagnostic algorithm for diabetic foot ulcer infection.
The combined algorithm has a specificity of 0.81 in distinguishing mild infection from no infection in a diabetic foot ulcer.
Autism spectrum disorder (ASD) has its origins in the atypical development of brain networks. Infants who are at high familial risk for, and later diagnosed with ASD, show atypical activity in ...multiple electroencephalography (EEG) oscillatory measures. However, infant‐sibling studies are often constrained by small sample sizes. We used the International Infant EEG Data Integration Platform, a multi‐site dataset with 432 participants, including 222 at high‐risk for ASD, from whom repeated measurements of EEG were collected between the ages of 3–36 months. We applied a latent growth curve model to test whether familial risk status predicts developmental trajectories of spectral power across the first 3 years of life, and whether these trajectories predict ASD outcome. Change in spectral EEG power in all frequency bands occurred during the first 3 years of life. Familial risk, but not a later diagnosis of ASD, was associated with reduced power at 3 months, and a steeper developmental change between 3 and 36 months in nearly all absolute power bands. ASD outcome was not associated with absolute power intercept or slope. No associations were found between risk or outcome and relative power. This study applied an analytic approach not used in previous prospective biomarker studies of ASD, which was modeled to reflect the temporal relationship between genetic susceptibility, brain development, and ASD diagnosis. Trajectories of spectral power appear to be predicted by familial risk; however, spectral power does not predict diagnostic outcome above and beyond familial risk status. Discrepancies between current results and previous studies are discussed.
Lay Summary
Infants with an older sibling who is diagnosed with ASD are at increased risk of developing ASD themselves. This article tested whether EEG spectral power in the first year of life can predict whether these infants did or did not develop ASD.
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