Neuropeptide regulation of non-redundant ILC2 responses at barrier surfaces.

Emerging studies indicate that cooperation between neurons and immune cells regulates antimicrobial immunity, inflammation and tissue homeostasis. For example, a neuronal rheostat provides excitatory or inhibitory signals that control the functions of tissue-resident group 2 innate lymphoid cells (ILC2s) at mucosal barrier surfaces1-4. ILC2s express NMUR1, a receptor for neuromedin U (NMU), which is a prominent cholinergic neuropeptide that promotes ILC2 responses5-7. However, many functions of ILC2s are shared with adaptive lymphocytes, including the production of type 2 cytokines8,9 and the release of tissue-protective amphiregulin (AREG)10-12. Consequently, there is controversy regarding whether innate lymphoid cells and adaptive lymphocytes perform redundant or non-redundant functions13-15. Here we generate a new genetic tool to target ILC2s for depletion or gene deletion in the presence of an intact adaptive immune system. Transgenic expression of iCre recombinase under the control of the mouse Nmur1 promoter enabled ILC2-specific deletion of AREG. This revealed that ILC2-derived AREG promotes non-redundant functions in the context of antiparasite immunity and tissue protection following intestinal damage and inflammation. Notably, NMU expression levels increased in inflamed intestinal tissues from both mice and humans, and NMU induced AREG production in mouse and human ILC2s. These results indicate that neuropeptide-mediated regulation of non-redundant functions of ILC2s is an evolutionarily conserved mechanism that integrates immunity and tissue protection.

Criteria for the diagnosis of extranodal extension detected on radiological imaging in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Extranodal extension of tumour on histopathology is known to be a negative prognostic factor in head and neck cancer. Compelling evidence suggests that extranodal extension detected on radiological imaging is also a negative prognostic factor. Furthermore, if imaging detected extranodal extension could be identified reliably before the start of treatment, it could be used to guide treatment selection, as patients might be better managed with non-surgical approaches to avoid the toxicity and cost of trimodality therapy (surgery, chemotherapy, and radiotherapy together). There are many aspects of imaging detected extranodal extension that remain unresolved or are without consensus, such as the criteria to best diagnose them and the associated terminology. The Head and Neck Cancer International Group conducted a five-round modified Delphi process with a group of 18 international radiology experts, representing 14 national clinical research groups. We generated consensus recommendations on the terminology and diagnostic criteria for imaging detected extranodal extension to harmonise clinical practice and research. These recommendations have been endorsed by 19 national and international organisations, representing 34 countries. We propose a new classification system to aid diagnosis, which was supported by most of the participating experts over existing systems, and which will require validation in the future. Additionally, we have created an online educational resource for grading imaging detected extranodal extensions.

New supporting data to guide the use of evident toxicity in acute oral toxicity studies (OECD TG 420).

Currently there are three test guidelines (TG) for acute oral toxicity studies of substances or mixtures from the Organisation for Economic Co-operation and Development (OECD). TG 423 and TG 425 use lethality as an endpoint, while TG 420 replaces death with 'evident toxicity', defined as clear signs that exposure to a higher dose would result in death. However, the perceived subjectivity of 'evident toxicity' may be preventing wider use of TG 420. To address this, the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and the European Partnership for Alternative Approaches to Animal Testing (EPAA) collaborated to provide recommendations on the recognition of 'evident toxicity'. Historical data from acute oral toxicity studies were analysed for clinical signs at the lower dose that could have predicted death at the higher dose. Several signs including ataxia, laboured respiration, and eyes partially closed, alone or in combination, are highly predictive. Others such as lethargy, decreased respiration, and loose faeces have lower but still appreciable positive predictive value (PPV). The data has been used to develop recommendations to promote use of TG 420 and thus reduce the suffering and numbers of animals used in acute oral toxicity studies.

One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic ß-Lactone-Oxindoles and Double Ring-Opening.

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic ß-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the ß-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).

Description of Uniphylus gen. nov., a new genus of Carcharodini (Lepidoptera, Hesperiidae, Pyrginae) for Staphylus evemerus Godman & Salvin, 1896.

Staphylus evemerus Godman & Salvin, 1896 is a species with a unique set of morphological characters within Carcharodini. Also, mitochondrial cytochrome oxidase subunit 1 (COI) sequences analysis demonstrated a large genetic distance with other related genera of the tribe. Therefore, this paper aims to describe a new genus for this species, which is named as Uniphylus gen. nov. Besides the morphological redescription of the male of Uniphylus evemerus (Godman & Salvin, 1896) new comb., the description of the female is provided for the first time, as well as an updated distributional map with all records known so far for this species.

Moral distress in carers for people with an intellectual disability who died during the COVID-19 pandemic, a template analysis extending the Barlem and Ramos model of moral distress.

BACKGROUND: This article aims to understand moral distress in carers of people with an intellectual disability during the COVID-19 pandemic. METHOD: Nine staff carers of seven people with an intellectual disability, who had been participants of the IDS-TILDA study in Ireland, who died during the COVID-19 pandemic participated in in-depth, semi-structured telephone interviews. Template analysis was used to analyze the interviews. RESULTS: Obstructions in performing their duties left carers feeling powerless and experiencing moral conflict distress, moral constraint distress and moral uncertainty distress. Most managed to connect to the moral dimension in their work through peer support, understanding they fulfilled the wishes of the deceased, and/or thinking about how they or others did the best they could for the person they were caring for. CONCLUSIONS: This research demonstrates that while restrictions may have been effective in reducing the spread of COVID-19, they were potentially damaging to carer wellbeing.

Evaluating maternal health capacity building in rural and underserved areas: a research protocol.

INTRODUCTION: The US is currently experiencing a maternal health crisis. Maternal morbidity and mortality in the US are higher than in other developed nations and continue to rise. Infant mortality, likewise, is higher in the US than in other developed nations. Limited availability of maternal health services, particularly in rural areas, contributes to this crisis. Maternal health outcomes are poorer, and maternal care workforce shortages are more severe in rural areas of the US. In rural areas where obstetric specialists are rare, many patients rely on family medicine physicians for maternity care. However, the number of family medicine physicians who provide maternal care services is decreasing, aggravating shortages. Calls have been made to build maternal care capacity in rural areas. The role family medicine will play in addressing the maternal health crisis is not clear. Maternal care shortages are complex issues resulting from multiple factors; likewise, efforts to build maternal health capacity are challenging and require multifaceted approaches. METHODS: With funding from the Health Resources and Services Administration (HRSA), the University of Utah seeks to address the shortage of quality maternity care in rural and underserved areas of Utah by strengthening partnerships, enhancing maternal care training of family medicine residents and obstetrics fellows, and improving the transition from training to rural practice for residents and fellows. This protocol describes the evaluation of the HRSA-funded project. The evaluation includes three components. Component 1 consists of qualitative interviews with a diverse group of maternal health providers, administrators, educators and academics, patients, and others. Interviews will be analyzed using qualitative content analysis. Component 2 is a survey of family medicine residents and obstetrics fellows, which aims to increase understanding of the factors and circumstances influencing intention to practice in rural or underserved areas and to provide maternal health services. Component 3 involves surveying fellowship alumni and tracking graduates to assess effectiveness of training programs in producing physicians who provide maternal health services in rural and underserved areas. Surveys will be analyzed with descriptive statistics including means, frequencies, and cross-tabulations. If sample size and participation provide sufficient power, statistical tests will be included in analyses. RESULTS: Evaluation results will help to fill an important gap in research literature concerning outcomes of projects and initiatives designed to build maternal care capacity in rural areas of the US. In addition, results will provide valuable information regarding effective practices for building capacity, which can be adopted elsewhere to address maternal care shortages. Finally, results will help to define the role of family medicine in addressing the maternal health crisis. Amid maternal care shortages, fewer and fewer family medicine physicians are providing maternal care in their practice. Evaluation results will clarify the role of training and preparation of family medicine residents in addressing workforce shortages. CONCLUSION: This evaluation will provide important contributions, but additional research is needed, including research protocols and studies of project outcomes, to understand how best to resolve the maternal care crisis in the US.

Spontaneous motor-behavior abnormalities in two Drosophila models of neurodevelopmental disorders.

Mutations in hundreds of genes cause neurodevelopmental disorders with abnormal motor behavior alongside cognitive deficits. Boys with fragile X syndrome (FXS), a leading monogenic cause of intellectual disability, often display repetitive behaviors, a core feature of autism. By direct observation and manual analysis, we characterized spontaneous-motor-behavior phenotypes of Drosophila dfmr1 mutants, an established model for FXS. We recorded individual 1-day-old adult flies, with mature nervous systems and prior to the onset of aging, in small arenas. We scored behavior using open-source video-annotation software to generate continuous activity timelines, which were represented graphically and quantitatively. Young dfmr1 mutants spent excessive time grooming, with increased bout number and duration; both were rescued by transgenic wild-type dfmr1+. By two grooming-pattern measures, dfmr1-mutant flies showed elevated repetitions consistent with perseveration, which is common in FXS. In addition, the mutant flies display a preference for grooming posterior body structures, and an increased rate of grooming transitions from one site to another. We raise the possibility that courtship and circadian rhythm defects, previously reported for dfmr1 mutants, are complicated by excessive grooming. We also observed significantly increased grooming in CASK mutants, despite their dramatically decreased walking phenotype. The mutant flies, a model for human CASK-related neurodevelopmental disorders, displayed consistently elevated grooming indices throughout the assay, but transient locomotory activation immediately after placement in the arena. Based on published data identifying FMRP-target transcripts and functional analyses of mutations causing human genetic neurodevelopmental disorders, we propose the following proteins as candidate mediators of excessive repetitive behaviors in FXS: CaMKIIα, NMDA receptor subunits 2A and 2B, NLGN3, and SHANK3. Together, these fly-mutant phenotypes and mechanistic insights provide starting points for drug discovery to identify compounds that reduce dysfunctional repetitive behaviors.

Leveraging Multimedia Patient Engagement to Address Minority Cerebrovascular Health Needs: Prospective Observational Study.

BACKGROUND: Social inequities affecting minority populations after Hurricane Katrina led to an expansion of environmental justice literature. In August 2017, Hurricane Harvey rainfall was estimated as a 3000- to 20,000-year flood event, further affecting minority populations with disproportionate stroke prevalence. The Stomp Out Stroke initiative leveraged multimedia engagement, creating a patient-centered cerebrovascular health intervention. OBJECTIVE: This study aims to address social inequities in cerebrovascular health through the identification of race- or ethnicity-specific health needs and the provision of in-person stroke prevention screening during two community events (May 2018 and May 2019). METHODS: Stomp Out Stroke recruitment took place through internet-based channels (websites and social networking). Exclusively through web registration, Stomp Out Stroke participants (aged >18 years) detailed sociodemographic characteristics, family history of stroke, and stroke survivorship. Participant health interests were compared by race or ethnicity using Kruskal-Wallis or chi-square test at an α=.05. A Bonferroni-corrected P value of .0083 was used for multiple comparisons. RESULTS: Stomp Out Stroke registrants (N=1401) were 70% (973/1390) female (median age 45 years) and largely self-identified as members of minority groups: 32.05% (449/1401) Hispanic, 25.62% (359/1401) African American, 13.63% (191/1401) Asian compared with 23.63% (331/1401) non-Hispanic White. Stroke survivors comprised 11.55% (155/1401) of our population. A total of 124 stroke caregivers participated. Approximately 36.81% (493/1339) of participants had a family history of stroke. African American participants were most likely to have Medicare or Medicaid insurance (84/341, 24.6%), whereas Hispanic participants were most likely to be uninsured (127/435, 29.2%). Hispanic participants were more likely than non-Hispanic White participants to obtain health screenings (282/449, 62.8% vs 175/331, 52.9%; P=.03). Asian (105/191, 54.9%) and African American (201/359, 55.9%) participants were more likely to request stroke education than non-Hispanic White (138/331, 41.6%) or Hispanic participants (193/449, 42.9%). African American participants were more likely to seek overall health education than non-Hispanic White participants (166/359, 46.2% vs 108/331, 32.6%; P=.002). Non-Hispanic White participants (48/331, 14.5%) were less likely to speak to health care providers than African American (91/359, 25.3%) or Asian participants (54/191, 28.3%). During the 2018 and 2019 events, 2774 health screenings were completed across 12 hours, averaging four health screenings per minute. These included blood pressure (1031/2774, 37.16%), stroke risk assessment (496/2774, 17.88%), bone density (426/2774, 15.35%), carotid ultrasound (380/2774, 13.69%), BMI (182/2774, 6.56%), serum lipids (157/2774, 5.65%), and hemoglobin A1c (102/2774, 3.67%). Twenty multimedia placements using the Stomp Out Stroke webpage, social media, #stompoutstroke, television, iQ radio, and web-based news reached approximately 849,731 people in the Houston area. CONCLUSIONS: Using a combination of internet-based recruitment, registration, and in-person assessments, Stomp Out Stroke identified race- or ethnicity-specific health care needs and provided appropriate screenings to minority populations at increased risk of urban flooding and stroke. This protocol can be replicated in Southern US Stroke Belt cities with similar flood risks.

Not as simple as it seems: Front foot contact kinetics, muscle function and ball release speed in cricket pace bowlers.

This study investigated the relationship between front foot contact (FFC) ground reaction forces (GRF) during the delivery stride, lower-limb strength, eccentric dexterity and power, and ball release speed (BRS) among pace bowlers. Thirteen high-level male pace bowlers performed double and single leg drop landings; isometric mid-thigh pull; countermovement jump; and pace bowling (two-over bowling spell measuring BRS and FFC GRF). The relationship between assessed variables and BRS was determined via frequentist and Bayesian multiple linear regression. The model including peak braking force was the most probable given the data (Bayes Factor=1.713) but provided only weak evidence in comparison to the null model. The results of frequentist and Bayesian modelling were comparable with peak braking force explaining 23.3% of the variance in BRS (F(1, 11)=4.64, P=0.054). Results indicate pace bowlers with greater peak braking GRF during FFC generally elicit higher BRS. However, the weak relationship between peak braking force and BRS, and the lack of a linear relationship between BRS and other variables, highlights the complexities and inter-individual variability inherent to pace bowling at a high-level. A more individual-focused analysis revealed varied strategies within pace bowlers to deliver the outcome (e.g., BRS) and should be considered in future study designs.

Alternative polyadenylation in the regulation and dysregulation of gene expression.

Transcriptional control shapes a cell's transcriptome composition, but it is RNA processing that refines its expression. The untranslated regions (UTRs) of mRNA are hotspots for regulatory control. Features in these can impact mRNA stability, localisation and translation. Here we describe how alternative cleavage and polyadenylation can change mRNA fate by changing the length of its 3'UTR.

Synthesizing Multiple Stakeholder Perspectives on Using Virtual Reality to Improve the Periprocedural Experience in Children and Adolescents: Survey Study.

BACKGROUND: Virtual reality (VR) technology is a powerful tool for augmenting patient experience in pediatric settings. Incorporating the needs and values of stakeholders in the design of VR apps in health care can contribute to better outcomes and meaningful experiences for patients. OBJECTIVE: We used a multiperspective approach to investigate how VR apps can be designed to improve the periprocedural experiences of children and adolescents, particularly those with severe anxiety. METHODS: This study included a focus group (n=4) and a survey (n=56) of clinicians. Semistructured interviews were conducted with children and adolescents in an immunization clinic (n=3) and perioperative setting (n=65) and with parents and carers in an immunization clinic (n=3) and perioperative setting (n=35). RESULTS: Qualitative data were examined to determine the experience and psychological needs and intervention and design strategies that may contribute to better experiences for children in three age groups (4-7, 8-11, and 12-17 years). Quantitative data were used to identify areas of priority for future VR interventions. CONCLUSIONS: We propose a set of ten design considerations for the creation of future VR experiences for pediatric patients. Enhancing patient experience may be achieved by combining multiple VR solutions through a holistic approach considering the roles of clinicians and carers and the temporality of the patient's experience. These situations require personalized solutions to fulfill the needs of pediatric patients before and during the medical procedure. In particular, communication should be placed at the center of preprocedure solutions, while emotional goals can be embedded into a procedure-focused VR app to help patients shift their focus in a meaningful way to build skills to manage their anxiety.

Small-Scale Spatial Heterogeneity of Photosynthetic Fluorescence Associated with Biological Soil Crust Succession in the Tengger Desert, China.

In dryland regions, biological soil crusts (BSCs) have numerous important ecosystem functions. Crust species and functions are, however, highly spatially heterogeneous and remain poorly understood at a range of scales. In this study, chlorophyll fluorescence imaging was used to quantify millimeter-scale patterns in the distribution and activity of photosynthetic organisms in BSCs of different successional stages (including cyanobacterial, lichen, moss three main successional stages and three intermixed transitional stages) from the Tengger Desert, China. Chlorophyll fluorescence images derived from the Imaging PAM (Pulse Amplitude Modulation) showed that with the succession from cyanobacterial to lichen and to moss crusts, crust photosynthetic efficiency (including the maximum and effective photosynthetic efficiency, respectively) and fluorescence coverage increased significantly (P < 0.05), and that increasing photosynthetically active radiation (PAR) reduced the effective photosynthetic efficiency (Yield). The distribution of photosynthetic organisms in crusts determined Fv/Fm (ratio of variable fluorescence to maximum fluorescence) frequency pattern, although the photosynthetic heterogeneity (SHI index) was not significantly different (P > 0.05) between cyanobacterial and moss crusts, and showed a unimodal pattern of Fv/Fm values. In contrast, photosynthetic heterogeneity was significantly higher in lichen, cyanobacteria-moss and lichen-moss crusts (P < 0.05), with a bimodal pattern of Fv/Fm values. Point pattern analysis showed that the distribution pattern of chlorophyll fluorescence varied at different spatial scales and also among the different crust types. These new results provide a detailed (millimeter-scale) insight into crust photosynthetic mechanisms and spatial distribution patterns associated with their community types. Collectively, this information provides an improved theoretical basis for crust maintenance and management in dryland regions.

The feasibility of a novel limited field of view spiral cine DENSE sequence to assess myocardial strain in dilated cardiomyopathy.

OBJECTIVE: Develop an accelerated cine displacement encoding with stimulated echoes (DENSE) cardiovascular magnetic resonance (CMR) sequence to enable clinically feasible myocardial strain evaluation in patients with dilated cardiomyopathy (DCM). MATERIALS AND METHODS: A spiral cine DENSE sequence was modified by limiting the field of view in two dimensions using in-plane slice-selective pulses in the stimulated echo. This reduced breath hold duration from 20RR to 14RR intervals. Following phantom and pilot studies, the feasibility of the sequence to assess peak radial, circumferential, and longitudinal strain was tested in control subjects (n = 18) and then applied in DCM patients (n = 29). RESULTS: DENSE acquisition was possible in all participants. Elements of the data were not analysable in 1 control (6%) and 4 DCM r(14%) subjects due to off-resonance or susceptibility artefacts and low signal-to-noise ratio. Peak radial, circumferential, short-axis contour strain and longitudinal strain was reduced in DCM patients (p < 0.001 vs. controls) and strain measurements correlated with left ventricular ejection fraction (with circumferential strain r = - 0.79, p < 0.0001; with vertical long-axis strain r = - 0.76, p < 0.0001). All strain measurements had good inter-observer agreement (ICC > 0.80), except peak radial strain. DISCUSSION: We demonstrate the feasibility of CMR strain assessment in healthy controls and DCM patients using an accelerated cine DENSE technique. This may facilitate integration of strain assessment into routine CMR studies.

The Ethical and Responsible Development and Application of Advanced Brain Machine Interfaces.

Advanced brain machine interfaces provide potentially transformative approaches to treating neurological conditions and enhancing the performance of users. Yet, as technological capabilities continue to progress in leaps and bounds, there is a possibility that these capabilities outstrip our collective understanding of how to ensure brain machine interfaces are developed and used ethically and responsibly. In this case, there is an overt danger of rapid technological developments leading to unanticipated harm through a lack of foresight including threats to privacy, autonomy, self-identity, and other areas of personal and social value which, while hard to quantify, represent substantial risks. There is also a very real likelihood of such risks undermining value creation around the technologies and the associated enterprises, as key stakeholders push back against perceived and actual threats to what they, in turn, hold to be of value. In order to successfully traverse the resulting risk landscape, researchers and developers will need to become increasingly adept at integrating a sophisticated understanding of ethical and socially responsible innovation into their enterprises. Here, we illustrate how a "risk innovation" approach may provide novel insights into mapping out this landscape and revealing potentially blindsiding risks. We show how this approach can be used to illuminate challenges and opportunities to the successful, ethical, and responsible development of advanced brain machine interfaces. In addition, we emphasize how success will ultimately depend on the willingness of innovators and others to take ethical and responsible innovation seriously and to draw on the interdisciplinary and transdisciplinary expertise that is necessary to translate good intentions into positive outcomes.

A qualitative literature review exploring the role of the inguinal ligament in the context of inguinal disruption management.

PURPOSE: Groin injury, sportsman's groin and inguinal disruption (ID) refer to a diffuse chronic groin pain syndrome that has significant impact on athletes and is often unresponsive to conservative management. The ID aetiology is poorly understood but may involve weakness of the inguinal ligament attachments or the posterior inguinal canal wall or the tendons of adductor longus and rectus abdominis. We discuss the literature in which the inguinal ligament was directly targeted for ID management in athletic populations. Secondarily, we discuss the anatomical reclassification of the inguinal ligament to a tendon based on the above information. METHODS: This was a qualitative review of the published literature, in English, from January 2007 to February 2017. RESULTS: Five research papers, including 264 patients, were appraised. In patients with ID, tears were identified in the inguinal ligament, and to relieve pain, the surgical treatment of the ligament by tenotomy was shown to be beneficial. Techniques such as radiofrequency denervation involving the inguinal ligament and ilioinguinal nerve were also shown to relieve symptoms in athletes. CONCLUSIONS: This qualitative review has specifically focused on the literature directly targeting the inguinal ligament in ID which is a relatively unexplored management approach. When treated as a tendon, the inguinal ligament appears to be an appropriate ID therapeutic target. Integrated studies and randomised clinical trials will promote a better understanding of the role of the inguinal ligament and its tendinous properties in ID and provide a foundation for evidence-based management of chronic groin pain in athletes.

Loss of Neurokinin-1 Receptor Alters Ocular Surface Homeostasis and Promotes an Early Development of Herpes Stromal Keratitis.

Substance P neuropeptide and its receptor, neurokinin-1 receptor (NK1R), are reported to present on the ocular surface. In this study, mice lacking functional NK1R exhibited an excessive desquamation of apical corneal epithelial cells in association with an increased epithelial cell proliferation and increased epithelial cell density, but decreased epithelial cell size. The lack of NK1R also resulted in decreased density of corneal nerves, corneal epithelial dendritic cells (DCs), and a reduced volume of basal tears. Interestingly, massive accumulation of CD11c+CD11b+ conventional DCs was noted in the bulbar conjunctiva and near the limbal area of corneas from NK1R-/- mice. After ocular HSV-1 infection, the number of conventional DCs and neutrophils infiltrating the infected corneas was significantly higher in NK1R-/- than C57BL/6J mice. This was associated with an increased viral load in infected corneas of NK1R-/- mice. As a result, the number of IFN-γ-secreting virus-specific CD4 T cells in the draining lymph nodes of NK1R-/- mice was much higher than in infected C57BL/6J mice. An increased number of CD4 T cells and mature neutrophils (CD11b+Ly6ghigh) in the inflamed corneas of NK1R-/- mice was associated with an early development of severe herpes stromal keratitis. Collectively, our results show that the altered corneal biology of uninfected NK1R-/- mice along with an enhanced immunological response after ocular HSV-1 infection causes an early development of herpes stromal keratitis in NK1R-/- mice.

IL-2/anti-IL-2 antibody complex treatment inhibits the development but not the progression of herpetic stromal keratitis.

The IL-2/anti-IL-2 Ab immunocomplex has recently been shown to expand the naturally occurring pool of CD4(+)Foxp3(+) regulatory T cells (Tregs). In this study, we show that administration of the IL-2/anti-IL-2 Ab immunocomplex to C57BL/6 mice, prior to corneal HSV-1 infection, significantly increased the pool of Foxp3(+) Tregs when measured at early time points postinfection. Increased numbers of Foxp3(+) Tregs on days 2 and 4 postinfection resulted in a marked reduction in the development of severe herpetic stromal keratitis (HSK). When compared with corneas from the control group, corneas from the immunocomplex-treated group showed a significant reduction in the amount of infectious virus on day 2 but not on day 4 postinfection. Reduced viral load was associated with a 2-fold increase in NK cell numbers in corneas from the immunocomplex-treated group of mice. Moreover, a dramatic reduction in the influx of CD4 T cells in inflamed corneas was determined on days 7 and 16 postinfection in the immunocomplex-treated group of infected mice. Immunocomplex treatment given on days 5, 6, and 7 postinfection significantly increased Foxp3(+) Tregs in draining lymph nodes and in the spleen but failed to reduce the severity of HSK. In terms of the influx of CD4 T cells and granulocytes into inflamed corneas, no significant differences were noted between both groups of mice on day 16 postinfection. Our findings demonstrate that increasing Foxp3(+) Tregs early but not late postinfection in secondary lymphoid tissues is more efficacious in controlling the severity of HSK.

The added value of the 90-day repeated dose oral toxicity test for industrial chemicals with a low (sub)acute toxicity profile in a high quality dataset: An update.

A previous retrospective analysis of substances in the ECHA CHEM database concluded that, for industrial chemicals with a 'low (sub)acute toxicity profile', further testing in the 90-day study is unlikely to change this profile (Taylor et al., 2014). We have further tested this hypothesis by assessing the outcome of substances with testing proposals for which a prediction was made in that paper that the NOAEL based on the 90-day study would be 1000 mg/kg bw/d. Indeed, for seven out of ten substances for which data was available, the profile was shown to be held. For three substances, the reduced NOAEL was explained by renal effects in the rats, two of which had been seen in the 28-day study but had been dismissed by the study submitter. We conclude that the low toxicity profile will be even more protective if the NOEL is used from the 28-day study and an independent expert view is taken of the human relevance of any effects reported in the 28-day study.

Presentation of neurogenic shock within the emergency department.

BACKGROUND: Injury to the spinal cord can result in loss of sympathetic innervation causing a drop in BP and HR, this condition is known as neurogenic shock. There is debate among the literature on how and when neurogenic shock presents and what values of HR and BP should be used to define it. Previous studies do not take into account multiple prehospital and emergency department recordings. OBJECTIVE: To improve understanding of how neurogenic shock presents in humans, allowing better identification and treatment. METHODS: The Trauma Audit and Research Network database for an adult major trauma centre was used to isolate patients with a spinal cord injury. Qualifying patients had all available BPs and HRs collated into a database. Patients with neurogenic shock were isolated, allowing data analysis. RESULTS: Out of 3069 trauma patients, 33 met the inclusion criteria, of which 15 experienced neurogenic shock. 87% of the patients who had neurogenic shock experienced it within 2 hours of injury. Neurogenic shock below the T6 level was less common (p=0.009); however, there were still four cases in the cohort. More patients with complete spinal cord injury had neurogenic shock (p=0.039). CONCLUSIONS: Neurogenic shock is variable and unpredictable. It can present in the prehospital environment and without warning in a patient with previously normal vital signs. The medical team should be aware of it in all patients with spinal cord injury regardless of injury level.