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A countermovement jump (CMJ) performed on a force plate is commonly applied in soccer to quantify acute neuromuscular fatigue (NMF), which may manifest immediately following soccer match play. Jump height (JH) is the main outcome variable reported for this purpose; however, it is sensitive to alterations in movement strategy, which may act to mask JH and, therefore, mask any presence of NMF. Acute reductions in body mass (BM) during match play could also lead to the maintenance of JH, but this is yet to be explored. This study sought to explore soccer-match-induced alterations to JH, movement strategy, and BM to inform future variable selection for the study of acute NMF. Fourteen male English National League soccer players performed three CMJs on a dual-force plate system immediately before and after a competitive soccer match. Differences in jump height were non-significant and trivial (p = 0.924, g = 0.03) before and after soccer match play, but there was a large post-match decrease in BM (g = 1.66). Furthermore, moderate decreases in jump momentum (g = 0.56) and countermovement depth (g = 0.72) were noted. As JH was determined by the take-off velocity, reduced BM could have augmented it (less mass to accelerate); however, reduced countermovement depth seemingly counteracted this (less distance to attain velocity). It may, therefore, be beneficial to report these variables when monitoring acute NMF via the CMJ.

Particle image velocimetry is an important optical flow diagnostic tool due to its capacity for investigating a whole flow field without introducing disturbances. However, a significant drawback of PIV methods is their requirement for optical access, making capturing data in closed cavities and confined spaces extremely challenging. A potential approach to overcome this difficulty is miniaturising the system and placing the optical components inside the model. Conventional cross-correlation PIV methods do not allow this due to the size of current PIV cameras. In this study, a miniaturised autocorrelation-based stereo PIV system, which is volumetrically 1.2% of the conventional PIV cameras, was developed and tested. The miniature system is compared with a conventional stereo PIV in wind tunnel experiments up to 16 m/s free stream velocity and a 1.6% velocity difference is observed in the boundary layer flow. Despite a comparatively slow measurement rate of 4.5 Hz, the miniature PIV system demonstrates the ability to measure inside confined spaces and cavities and the ability to be mounted on board models and vehicles. However, limitations remain around conducting measurements with large velocity ranges and with regions of reversed flow due to the challenge of resolving a velocity of 0 m/s.

This review summarizes the current research and outlooks regarding the obstacles to diagnosing and treating early alpha-1-antitrypsin deficiency (AATD). It draws on prior systematic reviews and expert surveys to discover precisely what difficulties exist in early diagnosis and treatment of AATD and elucidate potential solutions to ease these difficulties. The perceived rarity of AATD may translate to a condition poorly understood by primary care physicians, and even many respiratory physicians, which results in opportunities for diagnosis being missed, especially in mild or asymptomatic patients. There are diagnostic techniques involving biomarkers and home testing methods which could improve the rate of early diagnosis. With respect to treatment, AATD involves treating two separate pathologies, lung disease and liver disease. The only specific AATD treatment, augmentation therapy, has proven ability in treating lung disease but not liver disease. Alpha-1-antitrypsin (AAT) synthesized in the liver can form damaging polymers that also result in reduced circulating AAT levels and, whilst liver transplantation is used to effectively treat AATD, it is inappropriate in early disease. Novel therapeutic areas such as gene editing and increasing autophagy are therefore being researched as future treatments. Ultimately, diagnosis and treatment are intrinsically linked in AATD, with earlier diagnosis leading to better treatment options and thus better patient outcomes.

The surgical approach for total hip arthroplasty (THA) has the potential to affect the immediate postoperative recovery; however, there is limited published data comparing the 3 most common surgical approaches. The purpose of the study was to investigate postoperative pain and subsequent opioid consumption between surgical approaches (anterior-AA, lateral-LA, and posterior-PA) in those undergoing primary elective THA.A retrospective cohort study assessed patient demographics (age, sex, and body mass index), American Society of Anesthesiologists grade, opioid naivety, operative details (anesthetic method, fixation method, and local infiltration analgesia), pain scores, and length of stay. Statistical analysis was performed with a 1-way analysis of variance 3 × 1 table with a P value.05.A total of 560 patients were included in the analysis (335 females and 225 males). The cohort consisted of 179 AA, 178 LA, and 203 PA patients. The average postoperative opioid usage was 63.05 (standard deviation [SD] = 42.97), 79.81 (SD = 56.10), and 77.50 (SD = 54.52) oral morphine equivalent daily dose (oMEDD) for the AA, LA, and PA, respectively. The mean difference was 16.8 oMEDD lower in the AA compared with the LA (P.01) and 14.5 oMEDD lower in the AA compared with the PA (P = .02).The direct anterior approach was associated with lower daily opioid usage and pain scores after elective THA in the early postoperative period. This represents a potential 21% reduction in daily opioid dosage when compared with LA patients and 18.7% reduction in PA patients.

Introduction The increasing incidence of acetabular fractures in the elderly and the fracture complexity seen in this cohort represents one of the greatest challenges faced by trauma orthopaedic surgeons today. There are no formal guidelines of best practice in the treatment of these patients. Management options vary from non-operative, acute ORIF, and/or total joint replacement. Although surgical intervention allows for earlier mobilization and avoidance of the complications of prolonged bedrest, the patients ability to tolerate what is often major surgery is always of concern. This is in stark contrast to intracapsular hip fractures, (a fracture within the same joint), where acute surgery is recommended in virtually all cases. Objectives This study was undertaken to evaluate the peri-operative outcomes for geriatric patients undergoing acetabular ORIF and hemiarthroplasty to assess if there is a significant difference in early outcome parameters. Design This is a retrospective case–control study. Setting This study was performed in the National Centre for Pelvic and Acetabular surgery. Patients 42 age- and sex-matched patients with comparable ASA grades were included in each arm of the study. Patient selection in the acetabular ORIF group was consecutive patients managed operatively in the centre during the period 2010–2015. The selection for the hemiarthroplasty group was by random selection of age- and sex-matched patients undergoing hemiarthroplasty during the same period. Main outcome measurements The primary outcomes that were proposed prior to the study being performed was perioperative mortality and post-op complications. Secondary outcomes were operating times, blood loss and need for ICU admission. Results A significant difference between the two cohorts was observed with operative times, blood loss, need for transfusion, and need for ICU admission, all higher in the acetabular ORIF group. There was no significant difference in mortality or post-op infection. Conclusions Our paper supports the concept that acute ORIF of acetabular fractures, with appropriate peri-operative support, can be undertaken safely. There is no difference in the major peri-operative outcomes of mortality or infection when compared with hip fracture patients requiring hemiarthroplasty.

We present a thermodynamics experiment suitable for first year undergraduate students employing Stirling Engines to create a demonstration of energy transformation and to measure the mechanical efficiency of such engines. Using an inexpensive transparent chambered Stirling Engine, students can connect concepts such as the theoretical pressure-volume diagram with the physical movements of the engine's pistons and the resultant useful output work of a spinning wheel. We found the majority of students successfully complete this experiment obtaining results similar to when performed by the authors. In addition to the core thermodynamics lesson, this experiment incorporates DC circuits, oscilloscopes, and data analysis so it can be integrated into a wider undergraduate physics course to combine the teaching of multiple subjects., 15 pages, 6 figures

This exploratory mixed method sub-study aimed to establish the impact of colour vision deficiency (CVD) on the usability of sputum colour charts in chronic obstructive pulmonary disease (COPD) patients. Participants with CVD and those with at risk of acquiring CVD were recruited for the study. Colour vision was tested using Chroma Test, which is a software program that analyses the tritan and protan colour contrast thresholds. Qualitative interviews (individual and focus groups) comprised of participants with COPD assessed for undiagnosed CVD, as well as a group with known CVD (with or without COPD). Interviews were analysed using the framework method. Refer to Protocol 1.In addition, a cross sectional study was conducted to determine the prevalence of CVD in The Health Improvement Network (THIN) using colour blind diagnostic read codes. A limitation of this could be failure of general practitioners to record CVD causing underreporting. Refer to Protocol 2.

Sputum colour may mark bacterial involvement in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, whether colour vision deficiency (CVD) in COPD patients could impact the use of sputum colour charts as part of a guide to antibiotic use in exacerbations is unknown. This study used an exploratory mixed-method approach to establish the likelihood that COPD patients will be colour blind and whether this would result in the sputum colour chart being unusable in the context of the patients’ self-management of their condition. CVD is under-reported in primary care and comorbidities in COPD patients increase the risk of acquiring CVD. Participants diagnosed with CVD and risk of acquiring CVD were able to use the sputum colour charts. Colour charts are likely to be usable even in the context of undiagnosed CVD in COPD patients.

The seminal observation of severe deficiency of alpha-1-antitrypsin (AAT) with premature emphysema over 50 years ago led to the elastase–antielastase hypothesis of lung disease. Subsequent research identified alpha-1-antitrypsin deficiency (AATD) as an inherited metabolic genetic condition caused by mutations on the SERPINA1 gene, resulting in a reduction in the serum concentration of AAT.1 The role of AAT is to act as an inhibitor to the enzyme neutrophil elastase, and it is crucial in the homeostasis of elastase–antielastase activity, with an imbalance in this activity causing lung disease via a cycle of inflammation and proteolytic damage leading to premature emphysema, disability and death. There are over 100 mutations of SERPINA1 described in the literature, some of which are associated with AATD. The normal genotype is designated PiMM; the most common genotype resulting in severe deficiency is designated PiZZ. AATD is an autosomal codominant condition so heterozygosity can also create in genotypes resulting in mild and intermediate deficiency, such as PiMZ and PiSZ. The prevalence of AATD worldwide is estimated between 0.02% and 0.05%. Normal AAT serum concentration would be in the range 20–53 µmol/L, while deficient genotypes express varying levels, from 55% for PiMZ to 40% for PiSZ and

Background: Graves’ disease is the commonest cause of thyrotoxicosis while thyrotropin producing pituitary adenomas (TSHoma) are very rare and represent 2-3.5% of all pituitary adenomas. Coexistence of a TSHoma and Graves’ disease has been very rarely reported. We present a case of a lady with a TSHoma initially presenting with primary thyrotoxicosis, likely Graves’ Disease. Case: A sixty-eight year old lady was referred to our department with thyrotoxicosis, a fT4 of 20.4pmol/L (7.0-16.0) and a TSH of

Acetabular fractures are associated with damage to the femoral head, acetabular cartilage and labrum and possible disruption of the femoral head blood supply. Treatment aims to provide the best opportunity for restoration of joint function and to prevent long-term complications. Surgical intervention, in the form of open reduction and internal fixation (ORIF), is often required. Where post-traumatic osteoarthritis develops after ORIF, total hip arthroplasty (THA) is often required. Our aim here has been to identify and highlight our experience with the key technical points associated with successful outcomes for THA in this setting. A single-centre retrospective review of patients with acetabular fractures treated with ORIF and subsequent THA over a 4-year period was undertaken. Demographics, mechanism of injury, complications, interval time between surgeries, intra-operative outcomes and post-operative outcomes were recorded. Particular emphasis is made to describe standard pre-operative and intra-operative protocols. Twenty-five patients were identified, with a mean age of 51.1 years at time of first ORIF. 60% presented following RTA. 80% of fractures involved the posterior wall or column. Meantime to eventual THA was 2.3 years. Mean THA duration was 1.52 h, with mean intra-operative blood loss and length of stay of 585 ml and 5 days, respectively. 24% required intra-operative removal of metal, with only one patient suffering a complication post-THA. Acceptable post-operative outcomes were demonstrated throughout the case series. In describing the pre-operative work up, intra-operative findings and intra-operative and post-operative complications encountered, common important technical points associated with a successful surgical strategy are described. Furthermore, potential pitfalls that may be encountered can be anticipated.

Introduction The objective of this non-interventional study was to investigate the long-term safety and effectiveness of certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA) in the UK and Ireland. Methods Patients were prescribed CZP at their physicians’ discretion and followed during routine clinical practice for up to 88 weeks. DAS28(ESR) response (defined as at least a 1.2-point reduction from baseline) was measured in the full analysis set (FAS) at week 12, and patients were categorized by week 12 responder status in all subsequent analyses. The primary outcome was DAS28(ESR) response at week 78. Secondary outcomes included change from baseline in DAS28(ESR), HAQ-DI, and RADAI scores at week 78, and EULAR response at week 78. Adverse drug reactions (ADRs) were recorded for all patients who received at least one dose of CZP. Results A total of 149 patients were enrolled, of whom 111 (74.5%) formed the FAS. At week 12, 80 patients (72.1%) were DAS28(ESR) responders and 31 (27.9%) non-responders. Compared to non-responders, a greater proportion of week 12 responders had a DAS28(ESR) response at week 78 (43.8% versus 22.6%). Improvements in DAS28(ESR), HAQ-DI, and RADAI scores were also greater on average among week 12 responders, as was the proportion of patients meeting EULAR criteria. Overall, 9 patients (6.1%) experienced 13 ADRs during the study. Conclusion These data demonstrate the safety and effectiveness of CZP in adult patients with RA treated during routine clinical practice in the UK and Ireland. Trial Registration ClinicalTrials.gov identifier, NCT01288287. Funding UCB Pharma. Electronic supplementary material The online version of this article (10.1007/s12325-018-0758-1) contains supplementary material, which is available to authorized users.

Traumatic brain injury (TBI) remains a major, global public health concern. Over the last 15 years, a significant body of evidence has emerged demonstrating that post-traumatic hypopituitarism (PTHP) is a common and clinically significant consequence of TBI. Non-specific symptomology and the lack of an agreed approach to screening for PTHP has led to significant under-diagnosis of this debilitating disease. In this review, we will discuss the frequency and clinical significance of acute and chronic PTHP as described in the current literature highlighting the evidence base for screening and hormone replacement in these patients. We will also offer a pragmatic approach to identifying relevant anterior pituitary dysfunction after TBI and a follow-up strategy for those patients. Specific controversies and remaining unanswered questions will be addressed.

The startup accelerators help nascent startups grow by providing funding and resources. This paper summarizes a data driven analysis of startup accelerators success and presents their growth trends. The goal of this paper was to assess the effectiveness of accelerators. The methodology was to use data to compare US startups that went through the accelerator program with the startups many of which according to Kauffman Foundation failed within 5-6 years, and the businesses that went through accelerator program outside of the US. Data for accelerators was collected from seed-db.com and was filtered for those that were established from 2005-2014. The data shows that the number of accelerators in the US is in the rise, although the growth has slowed down significantly after a very high rise in 2012. Startups that graduated from accelerator programs have approximately 23% higher survival rate than other new businesses.

\ud \ud Background\ud \ud Current methods for assessing concussion during rugby matches rely on rudimentary behavioural assessment, focusing on balance and gross motor function. Cognitive testing with the Sports Concussion Assessment Tool has recently been included, but there are a paucity of normative and baseline data for this test. This study examined the utility of the Trail Making Test (TMT), which is a neuropsychological test of executive function in two parts (TMT-A and TMT-B), to assist identification of cognitive impairments caused by impacts during rugby games.\ud \ud Methods\ud \ud 27 elite male rugby league players contracted to a professional rugby club were recruited towards the end of the season. Each player was tested on three occasions within a 2 week period with both TMT-A and TMT-B for baseline assessment. Each player was additionally assessed after full contact training on 2 consecutive days and during preseason training. Individual baseline data were calculated from the best of the baseline assessments, and time differences were examined with ANOVA.\ud \ud Findings\ud \ud No instances of concussion occurred during data collection. For TMT-A there was no significant difference (F(3, 24)=2·88, I2=0·27) between baseline (mean 13·79 s [SD 5·32], 95% CI 9·34–18·23), post-training day 1 (11·38 [2·63], 9·18–13·58), post-training day 2 (11·16 [1·94], 9·55–12·79), and preseason (11·79 [2·64], 9·58–13·99). For TMT-B there was no significant difference between baseline (31·50 [5·37], 27·01–35·99), post-training day 1 (28·07 [8·82], 20·70–35·44), post-training day 2 (26·18 [6·16], 21·03–31·33), and preseason (26·98 [4·89], 22·89–31·07).\ud \ud Interpretation\ud \ud These findings indicate that there were no significant differences in performance of these executive tasks from baseline to post-training (end of season and preseason). These data show stability of TMT-A and TMT-B data across a competitive rugby league season. Importantly, use of measures of variation such as CIs for these tasks can provide a metric for calculating minimally important clinical differences within cognition.\ud \ud Funding\ud \ud None.

Compared with the original approved biological drug on which it is based, a biosimilar has highly similar physicochemical characteristics and biological activity, as well as equivalent efficacy and no clinically meaningful differences in safety and immunogenicity. Before they are approved, biosimilars must undergo a rigorous development process using state-of-the-art technologies to establish biosimilarity to the reference biological product. After approval, biosimilars must comply with good pharmacological practices for biological drugs. Several biosimilar disease-modifying antirheumatic drugs (bsDMARDs) based on the tumour necrosis factor inhibitors adalimumab, etanercept and infliximab have been approved for use in patients with rheumatic diseases. Substantial cost savings can be made if biological-naive patients begin treatment with bsDMARDs, and patients receiving original biological DMARDs (bDMARDs) are switched to bsDMARDs. Despite the consistently similar efficacy, safety and immunogenicity of bsDMARDs relative to their respective original bDMARDs, switching from a reference bDMARD to a bsDMARD can result in nocebo responses, such as subjective increase of disease activity and pain-related adverse events. This may have a negative impact on adherence to bsDMARDs in clinical trials and clinical practice. To ensure optimal and rational integration of bsDMARDs into rheumatology practice and realise the full cost-saving efficacy of these drugs, rheumatologists must be aware that careful communication of the cost-saving efficacy and safety of bsDMARDs to their patients is the key to a successful long-term switch to bsDMARD therapy.

Objectives. Patients with RA have an increased prevalence of cardiovascular disease (CVD). This is due to traditional risk factors and the effects of chronic inflammation. MTX is the first-choice DMARD in RA. We performed a systematic literature review to determine whether MTX affects the risk of CVD in patients with RA. Methods. We searched Medline, Embase, Cochrane database, database of abstracts of reviews of effects, health technology assessment and Science Citation Index from 1980 to 2008. Conference proceedings (British Society of Rheumatology, ACR and EULAR) were searched from 2005 to 2008. Papers were included if they assessed the relationship between MTX use and CVD in patients with RA. Two reviewers independently assessed each title and abstract for relevance and quality. Results. A total of 2420 abstracts were identified, of which 18 fulfilled the inclusion criteria. Two studies assessed the relationship between MTX use and CVD mortality, one demonstrated a significant reduction in CVD mortality and the second a trend towards reduction. Five studies considered all-cause CVD morbidity. Four demonstrated a significant reduction in CVD morbidity and the fifth a trend towards reduction. MTX use in the year prior to the development of RA decreased the risk of CVD for 34 years. Four studies considered myocardial infarction, one demonstrated a decreased risk and three a trend towards decreased risk with MTX use. Conclusion. The current evidence suggests that MTX use is associated with a reduced risk of CVD events in patients with RA. This suggests that reducing the inflammation in RA using MTX not only improves disease-specific outcomes but may also reduce collateral damage such as atherosclerosis.

Background This study aimed to evaluate the effectiveness of the Parents Plus programme with families of pre-school children with developmental disabilities and significant behavioural problems in the Irish health service. The Parents Plus programme is a group-based parent training package involving video modelling, which was designed to be effective for children with conduct problems, but without developmental disabilities. Materials and methods Pre- and post-treatment assessments were conducted with 22 treated cases and 19 waiting-list controls with a protocol that included the Strengths and Difficulties Questionnaire, the Child Behaviour Checklist, the General Health Questionnaire-12, the Kansas Parental Satisfaction Scale, the Family Assessment Device, the Perceived Social Support Scale, the Family Inventory of Life Events and Changes, the Parenting Stress Index and the Questionnaire on Resources and Stress. Results Following the treatment, a comparison of treatment and control group means showed that the treated group showed better adjustment on the total difficulties scale of the Strengths and Difficulties Questionnaire. These gains were maintained at 10-month follow-up. Fifty per cent of treated cases showed clinically significant improvement and 14% showed reliable change on the Strengths and Difficulties Questionnaire. The treatment group reported a high level of satisfaction with the Parents Plus programme and showed significant goal attainment after treatment and at follow-up. Conclusions For some families of pre-school children with developmental disabilities and significant behavioural problems, the Parents Plus programme is an effective intervention and may be incorporated into routine early intervention clinics in the Irish health service.

The purpose of this systematic review and meta-analysis of randomised controlled trials is to assess the effectiveness of no drainage when compared to drainage in total knee arthroplasty, in terms of recovery of knee flexion, reduction in swelling, length of hospital stay and haemoglobin levels following TKA. Six randomised controlled trials were included. There is no significant difference between the individuals who receive a drain and those who do not across any of the measures examined (p

The last 3 decades have seen a wholesale change in the approach to the management of rheumatoid arthritis (RA). The emphasis has changed from symptom control, moderation of disease progression after structural damage had occurred, and accommodation of disability, to modern outcome-driven strategies. Rheumatologists now have treat to target1, remission induction2,3, damage prevention strategies4, and increasingly stretch targets of maintaining productivity5 and drug-free remission6. These management approaches and outcome targets demonstrate how much the treatment and our expectations have changed with advancing knowledge and new therapies in RA. It was not until cohort studies of the early 1980s demonstrated the true consequence of uncontrolled inflammation that attitudes to RA management began to change7. It was in 1987 that the American College of Rheumatology (ACR) revised the criteria for the classification of RA8. The criteria were developed to improve the homogeneity of patients entered into clinical trials with established disease. However, the pathognomonic features of RA such as classical clinical deformity, periarticular joint erosion, and nodules occur late in the disease process. The fact that the 1987 ACR criteria included the latter diminished their value in early disease, and several studies … Address correspondence to Dr. Quinn; E-mail: mark.quinn{at}york.nhs.uk

In 1967, in an article entitled, “The Literature of Exhaustion,” the novelist and critic John Barth suggested that the novel as traditionally conceived was facing a serious crisis. In his analysis of the state of contemporary fiction he noted an increased tendency and need on the part of many “serious” writers to engage in a kind of fiction that took writing as its subject. Barth saw this increasingly self-reflexive fiction as a tacit admission that traditional forms of narration were becoming outmoded and were perhaps on the verge of becoming obsolete. Citing Borges and Beckett as writers who had successfully responded to the literary legacies left by Eliot and Joyce, Barth’s essay effectively laid down a challenge to contemporary writers to find new ways of renewing the novelistic genre. Six years after Barth’s influential article, Thomas Pynchon published Gravity’s Rainbow, which, in its hugely complex encyclopedic nature, suggested not only that the novel as a form was alive and well, but equally that, in Pynchon, a highly original writer capable of creating new spaces and modes of narration had emerged. In the nearly four decades since its publication, Gravity’s Rainbow has consistently frustrated attempts by critics to provide totalized interpretations. The novel has fallen under the rubric of the postmodern and has come to be considered as an open text par excellence, a work whose magnitude and scope resists both traditional hermeneutic and poststructuralist modes of interpretation.

Objectives. RA is associated with early ischaemic heart disease. This appears to be driven largely by the presence of chronic inflammation. Studies suggest that treatment with disease-modifying drugs such as MTX may reduce the incidence of cardiovascular events in RA. Anti-TNF therapies significantly reduce inflammation in RA. However, the extent to which these agents also reduce cardiovascular disease (CVD) is uncertain. The purpose of this study was to explore the effect of anti-TNF agents on CVD in RA using a systematic literature review. Methods. We searched for studies of adults with RA treated with TNF antagonists where cardiovascular outcomes were recorded using MEDLINE, EMBASE, Cochrane Database, Database of Abstracts and Reviews of Effects, Health Technology Appraisal, Science Citation Index and Clinical Evidence from 1989 to 2010. Conference proceedings for the British Society of Rheumatology, ACR and EULAR between 2005 and 2009 were hand searched. Two reviewers assessed abstracts for inclusion and then quality of selected papers was assessed. Results. A total of 1840 abstracts were identified and 20 articles were suitable for inclusion. Information was obtained on the effect of TNF antagonists on overall CVD events, myocardial infarction, strokes and heart failure. Conclusion. In many studies, TNF antagonists appear to reduce the likelihood of CVD in individuals with RA. Reassuringly, there does not appear to be an increased risk of cardiac failure. However, the reduction in CVD is not as consistently seen as with studies of MTX.

A 51-year-old right-hand-dominant farmer fell 2.5 m off his roof, landing on his right shoulder. He had severe pain and gross deformity of the joint and was driven by his wife to the emergency department of our institution where he was diagnosed with an anterior dislocation of his right shoulder (figure 1A). This was reduced with great difficulty in the emergency department, requiring several sedations. At 3-week …

The effects of nutritional supplements on immunity are still not well understood. For example, although aging affects immune cell responsiveness, it is not well known if immune stimulation by some nutritional supplements is also affected by aging. We have previously shown that the ellagitannin oenothein B and Acai berry polysaccharides (AcaiPS) enhance IFNγ production by both bovine and human NK cells and T cells. We wanted to examine the effect age had on this activity. Studies comparing immune responses in immature individuals to those in adults are difficult to perform in humans and mice. As such, we utilized the bovine system to examine the responsiveness of T cells and NK cells from newborn calves, older calves, and adult cows to oenothein B and AcaiPS in vitro. Oenothein B induced greater IFNγ production by T cells from adults compared to calves. Within the responsive T cell population, we found that CD45RO+ T cells expressed more IFNγ in response to oenothein B than CD45RO- T cells. Similar responses were seen in a limited analysis with human cells. In contrast, AcaiPS, both alone and in combination with IL-18, induced greater IFNγ production by NK cells from calves, especially newborn calves, compared to adults. Our data suggest that immune stimulation of T cells and NK cells by oenothein B and AcaiPS is influenced by age. It also suggests that the bovine model may be very useful in examining the effect of age on immune stimulation by nutritional supplements.

Oenothein B is an ellagitannin isolated from the Epilobium angustifolium plant, which has been shown to have immunomodulatory properties. This compound is known to activate myeloid cells, αβ T cells, and innate lymphocytes, such as NK cells, NKT cells, and γδ T cells. Previous work from our laboratory showed that oenothein B primes and enhances the production of interferon-γ by human and bovine NK cells in response to secondary stimuli, including tumor cells and IL-18. Here, we examined whether oenothein B enhances the response of innate lymphocytes to various pathogen associated molecular patterns. We found that oenothein B enhanced interferon-γ production by bovine peripheral blood mononuclear cells in response to several pathogen associated molecular patterns, including the Toll-like receptor 3 agonist poly I:C. We have also found that intranasal administration of oenothein B to mice before infection with influenza can reduce the morbidity of the infection. Our preliminary results suggest that oenothein B is capable of enhancing innate immunity against viral infections, possibly through the enhanced production of interferon-γ by NK cells. The effect of oenothein B on the antiviral activity, including interferon-γ production, of innate lymphocytes during viral infection is currently under investigation in both human cells and mouse models. This work is funded by NIH NCCAM P01 AT004986 and P20 GM103500.

Extracts of leaves from different species of the genus Alchornea have been used for centuries to treat medical problems in tropical Africa; however, little is known about the active components conferring therapeutic properties to these extracts. We investigated the phagocyte immunomodulatory properties of water-soluble polysaccharides extracted from the leaves of Achornea cordifolia. Extracted polysaccharides were fractionated by DEAE-cellulose, Diaion HP-20 resin, and preparative Sepharose 6B size-exclusion chromatography and characterized. Fractions containing type II arabinogalactan had potent immunomodulatory activity. Specifically, the parent fraction AP-AU and its high-molecular weight sub-fraction AP-AU1 induced nitric oxide and cytokine (IL-1β, IL-6, IL-10, TNF-α, and GM-CSF) production by human peripheral blood mononuclear cells and human and murine monocyte/macrophages cell lines in vitro. We also evaluated the ability of selected fractions to activate mitogen activated phagocyte protein kinase (MAPK) pathways using a phospho-MAPK array and found that treatment of phagocytes with AP-AU1 induced phosphorylation of Akt2, p38δ/p38γ, p70S6K1, RSK2, and mTOR, as well as stimulation of NF-κB transcriptional activity. Thus, these results provide a molecular basis to explain a portion of the beneficial therapeutic properties of water extracts from A. cordifolia leaves in traditional folk medicine of Africa.

Mycobacterium avium subsp. paratuberculosis is an intracellular pathogen that has been implicated in Johne’s disease in cattle and possibly Crohn’s disease in humans. Cells expressing the NK cell activating receptor NKp46 have been shown to play an important role in mycobaterial infections in cattle by producing IFNγ and lysing infected monocytes. Therefore, compounds that enhance the activity of these cells may be useful in the treatment of these types of pathogens. Oenothein B is an immunomodulatory tannin isolated from Epilobium angustifolium plants and shown to have antitumor properties. This compound is known to activate myeloid cells, as well as NK cells, NKT cells, and γδ T cells. Previous work from our laboratory has shown that certain tannins have the ability to enhance the response of innate lymphocytes to secondary stimuli. Here, we report that oenothein B is capable of priming bovine peripheral blood mononuclear cells to produce increased levels of IFNγ in response to the IFNγ-inducing cytokine IL-18. This enhanced response is dependent upon the presence of cells expressing NKp46. Our preliminary results also suggest that oenothein B is able to enhance IFNγ production in response to M. avium subsp. paratuberculosis infected monocytes. This demonstrates that priming of innate lymphocytes by supplementation with specific polyphenols may be a useful strategy to enhance immunity to certain intracellular pathogens.

Oenothein B is an immunomodulatory tannin isolated from the Epilobium angustifolium plant. This compound is known to affect myeloid cells and these effects include enhanced chemotaxis, NF-κB activation, and production of proinflammatory cytokines, including TNFα and IL-6. Its effects on other innate immune cells have not been investigated. Previous studies have shown this compound to be beneficial in tumor models; therefore, it is of interest to determine what effect this compound may have on other innate immune cells known to be beneficial in anti-tumor responses, such as NK cells, NKT cells, and γδ T cells. Previous work from our lab has shown that certain tannins have the ability to directly stimulate γδ T cells, indicating oenothein B may also have immunomodulatory effects on this cell type. Our preliminary results show that oenothein B it is capable of stimulating γδ T cells and other lymphocytes. We also show that priming with oenothein B can enhance responses by these cells to secondary stimuli. This includes augmentation of IFNγ production, which may not be reliant upon oenothein B’s ability to stimulate both macrophages and γδ T cells. The molecular mechanisms, which facilitate these responses, are currently under investigation in both bovine and human cells. Funded by NIH Contract HHSN2662004000009/N01-AI40009, PO1 AT004986, and RR020185.