Search results
Found 9279 matches for
Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation.
Expression of human leukocyte antigen (HLA)-B27 is strongly associated with predisposition toward ankylosing spondylitis (AS) and other spondyloarthropathies. However, the exact involvement of HLA-B27 in disease initiation and progression remains unclear. The homodimer theory, which proposes that HLA-B27 heavy chains aberrantly form homodimers, is a central hypothesis that attempts to explain the role of HLA-B27 in disease pathogenesis. Here, we examined the ability of the eight most prevalent HLA-B27 allotypes (HLA-B*27:02 to HLA-B*27:09) to form homodimers. We observed that HLA-B*27:03, a disease-associated HLA-B27 subtype, showed a significantly reduced ability to form homodimers compared with all other allotypes, including the non-disease-associated/protective allotypes HLA-B*27:06 and HLA-B*27:09. We used X-ray crystallography and site-directed mutagenesis to unravel the molecular and structural mechanisms in HLA-B*27:03 that are responsible for its compromised ability to form homodimers. We show that polymorphism at position 59, which differentiates HLA-B*27:03 from all other allotypes, is responsible for its compromised ability to form homodimers. Indeed, histidine 59 in HLA-B*27:03 leads to a series of local conformational changes that act in concert to reduce the accessibility of the nearby cysteine 67, an essential amino acid residue for the formation of HLA-B27 homodimers. Considered together, the ability of both protective and disease-associated HLA-B27 allotypes to form homodimers and the failure of HLA-B*27:03 to form homodimers challenge the role of HLA-B27 homodimers in AS pathoetiology. Rather, this work implicates other features, such as peptide binding and antigen presentation, as pivotal mechanisms for disease pathogenesis.
Current Understanding of Innate Immune Cell Dysfunction in Childhood Undernutrition.
Undernutrition affects millions of children in low- and middle-income countries (LMIC) and underlies almost half of all deaths among children under 5 years old. The growth deficits that characterize childhood undernutrition (stunting and wasting) result from simultaneous underlying defects in multiple physiological processes, and current treatment regimens do not completely normalize these pathways. Most deaths among undernourished children are due to infections, indicating that their anti-pathogen immune responses are impaired. Defects in the body's first-line-of-defense against pathogens, the innate immune system, is a plausible yet understudied pathway that could contribute to this increased infection risk. In this review, we discuss the evidence for innate immune cell dysfunction from cohort studies of childhood undernutrition in LMIC, highlighting knowledge gaps in almost all innate immune cell types. We supplement these gaps with insights from relevant experimental models and make recommendations for how human and animal studies could be improved. A better understanding of innate immune function could inform future tractable immune-targeted interventions for childhood undernutrition to reduce mortality and improve long-term health, growth and development.
Should first-line empiric treatment strategies cover coagulase-negative staphylococcal infections in severely malnourished or HIV-infected children in Kenya?
BACKGROUND: Bloodstream infection is a common cause of morbidity in children aged <5 years in developing countries. In studies reporting bacteremia in Africa, coagulase-negative Staphylococci (CoNS) are commonly isolated. However, it is currently unclear whether children who are highly susceptible to infection because of severe acute malnutrition (SAM) or HIV should be treated with antimicrobials specifically to cover CoNS. We aimed to determine the clinical significance of CoNS amongst children admitted to a rural hospital in Kenya in relation to nutritional and HIV status. METHODS: Systematically collected clinical and microbiological surveillance data from children aged 6-59 months admitted to Kilifi County Hospital (2007-2013) were analysed. Multivariable regression was used to test associations between CoNS isolation from blood cultures and SAM (MUAC <11.5cm or nutritional oedema (kwashiorkor)), and HIV serostatus; and among children with SAM or HIV, associations between CoNS isolation and mortality, duration of hospitalization and clinical features. RESULTS: CoNS were isolated from blood culture in 906/13,315 (6.8%) children, of whom 135/906 (14.9%) had SAM and 54/906 (6.0%) were HIV antibody positive. CoNS isolation was not associated with SAM (MUAC<11.5cm (aOR 1.11, 95% CI 0.88-1.40) or kwashiorkor (aOR 0.84, 95% CI 0.48-1.49)), or a positive HIV antibody test (aOR 1.25, 95% CI 0.92-1.71). Among children with SAM or a positive HIV antibody test, CoNS isolation was not associated with mortality or prolonged hospitalization. CONCLUSION: In a large, systematic study, there was no evidence that antimicrobial therapy should specifically target CoNS amongst children with SAM or HIV-infection or exposure.
Buried Versus Exposed Kirschner Wires Following Fixation of Hand Fractures: l Clinician and Patient Surveys.
Background: Fractures of the metacarpals and phalanges are common. Placement of Kirschner wires (K-wires) is the most common form of surgical fixation. After placement, a key decision is whether to bury the end of a K-wire or leave it protruding from the skin (exposed). A recent systematic review found no evidence to support either approach. The aim of study was to investigate current clinical practice, understand the key factors influencing clinician decision-making, and explore patient preferences to inform the design of a randomized clinical trial. Methods: The steering group developed surveys for hand surgeons, hand therapists, and patients. Following piloting, they were distributed across the United Kingdom hand surgery units using the Reconstructive Surgery Trials Network. Results: A total of 423 hand surgeons, 187 hand therapists, and 187 patients completed the surveys. Plastic surgeons and junior surgical trainees preferred to leave K-wires not buried. Ease of removal correlated with a decision to leave wires exposed, whereas perceived risk of infection correlated with burying wires. Cost did not affect the decision. Hand therapists were primarily concerned about infection and patient-related outcomes. Patients were most concerned about wire-related problems and pain. Conclusion: This national survey provides a new understanding of the use of K-wires to manage hand fractures in the United Kingdom. A number of nonevidence-based factors seem to influence the decision to bury or leave K-wires exposed. The choice has important clinical and health economic implications that justify a randomized controlled trial.
The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis.
BACKGROUND: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. METHODS: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. RESULTS: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32-0.77); P<0.01], but no difference in complication rates [OR 1.02 (0.88-1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62-0.92); P<0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61-0.88); P<0.01; I2=89%). CONCLUSIONS: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine.
[Eruptive epidermoid cysts after imiquimod treatment of recurrent basal cell carcinoma : A case report].
Eruptive epidermoid cysts are a rare adverse event of imiquimod treatment for basal cell carcinoma. Up to date, 8 cases have been described in the literature. We present the case of a 75-year-old Caucasian woman with recurrent basal cell carcinoma on the nose. After multiple excisions and treatment with vismodegib, imiquimod 5% cream was administered 5 times per week over 6 weeks. Two months after the end of treatment, the patient presented with eruptive epidermoid cysts.
Organotypic Culture of Bone-Like Structures Using Composite Ceramic-Fibrin Scaffolds.
We have developed an organotypic culture system that allows the production of bone tissue features on a centimeter scale. A composite, calcium phosphate-strained fibrin gel system is able to organize itself in the presence of osteoblastic cells, creating basic hierarchical units as seen in vivo, and can be modified to produce a range of other tissues that require such directional structuring. Constructs evolve over time into multi-compositional structures containing a high mineral content and terminally differentiated, osteocyte-like cells. These tissues can be cultured over extended durations (exceeding 1 year) and are responsive to a variety of chemical and biological agents. The platform can reduce the number of animals used in experimentation by acting as an intermediate stage in which more personalized research conditions can be generated. We provide a thorough description of the protocol used to successfully culture and modify this system, as well as guidance on compositional characterization. © 2019 by John Wiley & Sons, Inc.
Basal thumb osteoarthritis surgery improves health state utility irrespective of technique: a study of UK Hand Registry data.
We used UK Hand Registry data to study two aspects of basal thumb osteoarthritis surgery: first, whether health-related quality of life improves after surgery. Second, whether results from trials comparing simple trapeziectomy and trapeziectomy with ligament reconstruction and tendon interposition are reproducible in routine clinical practice. Prospectively collected EQ5D index and Patient Evaluation Measure part 2 data were compared at baseline and at 3, 6, and 12 months postoperatively in 1456 patients (median age 67 years; 78% female). A mixed-effects regression model was also used to determine the postoperative trajectory of these variables. There was a significant improvement in the EQ5D index (median + 0.15; (interquartile range 0 to 0.40)) and Patient Evaluation Measure (-22; (-33 to -10)) by 1 year postoperatively and with no meaningful difference between the two techniques. This study demonstrates health state utility gains after basal thumb osteoarthritis surgery regardless of surgical techniques used. Level of evidence: III.
Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication.
OBJECTIVE: Salmonella enterica infections can lead to Reactive Arthritis (ReA), which can exhibit an association with human leucocyte antigen (HLA)-B*27:05, a molecule prone to misfolding and initiation of the unfolded protein response (UPR). This study examined how HLA-B*27:05 expression and the UPR affect the Salmonella life-cycle within epithelial cells. METHODS: Isogenic epithelial cell lines expressing two copies of either HLA-B*27:05 and a control HLA-B*35:01 heavy chain (HC) were generated to determine the effect on the Salmonella infection life-cycle. A cell line expressing HLA-B*27:05.HC physically linked to the light chain beta-2-microglobulin and a specific peptide (referred to as a single chain trimer, SCT) was also generated to determine the effects of HLA-B27 folding status on S.enterica life-cycle. XBP-1 venus and AMP dependent Transcription Factor (ATF6)-FLAG reporters were used to monitor UPR activation in infected cells. Triacin C was used to inhibit de novo lipid synthesis during UPR, and confocal imaging of ER tracker stained membrane allowed quantification of glibenclamide-associated membrane. RESULTS: S.enterica demonstrated enhanced replication with an altered cellular localisation in the presence of HLA-B*27:05.HC but not in the presence of HLA-B*27:05.SCT or HLA-B*35:01. HLA-B*27:05.HC altered the threshold for UPR induction. Salmonella activated the UPR and required XBP-1 for replication, which was associated with endoreticular membrane expansion and lipid metabolism. CONCLUSIONS: HLA-B27 misfolding and a UPR cellular environment are associated with enhanced Salmonella replication, while Salmonella itself can activate XBP-1 and ATF6. These data provide a potential mechanism linking the life-cycle of Salmonella with the physicochemical properties of HLA-B27 and cellular events that may contribute to ReA pathogenesis. Our observations suggest that the UPR pathway maybe targeted for future therapeutic intervention.
Platelet-rich plasma injection for adults with acute Achilles tendon rupture: the PATH-2 RCT
BACKGROUND:Achilles tendon rupture (ATR) has a long healing period, which is challenging for patients and clinicians. Platelet-rich plasma (PRP) is an autologous concentration of platelets thought to improve tendon function recovery. Although preliminary research has indicated positive effects, there is, as yet, no evidence of clinical efficacy from adequately powered robust clinical trials. OBJECTIVES:The objectives were to determine the clinical efficacy of PRP in patients with acute ATR using an objective mechanical muscle–tendon function measure and patient-reported outcome measures (PROMs), and to determine which PRP components contribute to its mechanism. DESIGN:This was a multicentre, parallel-group, participant- and outcome assessor-blinded randomised controlled trial (RCT) comparing PRP with placebo. Two embedded substudies investigated the PRP’s quality and composition and its effects on healing tendon tissues. SETTING:This trial was set in trauma and orthopaedic surgery departments in 19 NHS hospitals in England and Wales. PARTICIPANTS:Adults with acute ATR presenting within 12 days of injury to be treated non-surgically were eligible. Patients with platelet dysfunction or leg functional deficiency were excluded. INTERVENTIONS:Participants were randomised 1 : 1 to the PRP injection group or the placebo group (dry needle in the rupture gap) by central computer-based randomisation using minimisation, stratified by centre and age. MAIN OUTCOME MEASURES:The primary outcome measure was the Limb Symmetry Index (LSI) of work during the heel-rise endurance test at 24 weeks. Secondary outcomes measures, collected at 4, 7, 13 and 24 weeks, were repetitions, maximum heel-rise height, Achilles tendon Total Rupture Score (ATRS), quality of life (as measured using the Short Form questionnaire-12 items version 2), pain and participant goal attainment. Needle biopsies of the affected tendon zone were taken under ultrasound guidance at 6 weeks from 16 participants from one centre. Whole blood was analysed for cell count. PRP was analysed for cell count, platelet activation and growth factor concentration. The primary analysis was intention to treat. RESULTS:A total of 230 participants were randomised: 114 to the PRP group (103 treated) and 116 to the placebo group (all treated). One participant withdrew after randomisation but before the intervention. At 24 weeks, 201 out of 230 participants (87.4%) completed the primary outcome and 216 out of 230 participants (93.9%) completed the PROMs. The treatment groups had similar participant characteristics. At 24 weeks, there was no difference in work LSI (mean difference –3.872; 95% confidence interval –10.454 to 2.710; p = 0.231), ATRS, pain or goal attainment between PRP- and placebo-injected participants. There were no differences between the groups in any PROM at any time point or in complication rates, including re-rupture and deep-vein thrombosis. There was no correlation between work LSI and platelet activation in PRP, or erythrocyte, leucocyte or platelet counts in whole blood or PRP. Biopsies showed similar cellularity and vascularity between groups. CONCLUSIONS:This trial design and standardised PRP preparation gives the first robust RCT evidence about PRP’s role in managing ATR, which suggests that PRP offers no patient benefit. Equally robust evidence to investigate PRP application in tendon and soft tissue injuries is required. The 24-month follow-up will be completed in April 2020. TRIAL REGISTRATION:Current Controlled Trials ISRCTN54992179. FUNDING:This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. The trial was supported by the NIHR Biomedical Research Centre, Oxford, and the NIHR Fellowship programme.
Regulating T-cell differentiation through the polyamine spermidine.
BACKGROUND: The cross-talk between the host and its microbiota plays a key role in the promotion of health. The production of metabolites such as polyamines by intestinal-resident bacteria is part of this symbiosis shaping host immunity. The polyamines putrescine, spermine, and spermidine are abundant within the gastrointestinal tract and might substantially contribute to gut immunity. OBJECTIVE: We aimed to characterize the polyamine spermidine as a modulator of T-cell differentiation and function. METHODS: Naive T cells were isolated from wild-type mice or cord blood from healthy donors and submitted to polarizing cytokines, with and without spermidine treatment, to evaluate CD4+ T-cell differentiation in vitro. Moreover, mice were subjected to oral supplementation of spermidine, or its precursor l-arginine, to assess the frequency and total numbers of regulatory T (Treg) cells in vivo. RESULTS: Spermidine modulates CD4+ T-cell differentiation in vitro, preferentially committing naive T cells to a regulatory phenotype. After spermidine treatment, activated T cells lacking the autophagy gene Atg5 fail to upregulate Foxp3 to the same extent as wild-type cells. These results indicate that spermidine's polarizing effect requires an intact autophagic machinery. Furthermore, dietary supplementation with spermidine promotes homeostatic differentiation of Treg cells within the gut and reduces pathology in a model of T-cell transfer-induced colitis. CONCLUSION: Altogether, our results highlight the beneficial effects of spermidine, or l-arginine, on gut immunity by promoting Treg cell development.
Severe acute malnutrition and infection.
Severe acute malnutrition (SAM) is associated with increased severity of common infectious diseases, and death amongst children with SAM is almost always as a result of infection. The diagnosis and management of infection are often different in malnourished versus well-nourished children. The objectives of this brief are to outline the evidence underpinning important practical questions relating to the management of infectious diseases in children with SAM and to highlight research gaps. Overall, the evidence base for many aspects covered in this brief is very poor. The brief addresses antimicrobials; antipyretics; tuberculosis; HIV; malaria; pneumonia; diarrhoea; sepsis; measles; urinary tract infection; nosocomial Infections; soil transmitted helminths; skin infections and pharmacology in the context of SAM. The brief is structured into sets of clinical questions, which we hope will maximise the relevance to contemporary practice.
Should First-line Empiric Treatment Strategies for Neonates Cover Coagulase-negative Staphylococcal Infections in Kenya?
BACKGROUND: Neonatal mortality remains high in sub-Saharan Africa, and a third of deaths are estimated to result from infection. While coagulase-negative staphylococci (CoNS) are leading neonatal pathogens in resource-rich settings, their role, and the need for early anti-Staphylococcal treatment in empiric antibiotic guidelines, is unknown in sub-Saharan Africa. METHODS: We examined systematic clinical and microbiologic surveillance data from all neonatal admissions to Kilifi County Hospital (1998-2013) to determine associated case fatality and/or prolonged duration of admission associated with CoNS in neonates treated according to standard World Health Organization guidelines. RESULTS: CoNS was isolated from blood culture in 995 of 9552 (10%) neonates. Case fatality among neonates with CoNS isolated from blood did not differ from other neonatal admissions (P = 0.2), and duration of admission was not prolonged [odds ratio (OR) = 0.9 (0.7-1.0), P = 0.040]. Neonates with CoNS were more likely to have convulsions [OR = 1.4 (1.0-1.8), P = 0.031] but less likely to have impaired consciousness or severe indrawing [OR = 0.8 (0.7-0.9), P = 0.025; OR = 0.9 (0.7-1.0), P = 0.065]. CONCLUSIONS: CoNS isolation in blood cultures at admission was not associated with adverse clinical outcomes in neonates treated according to standard World Health Organization guidelines for hospital care in this setting. There is no evidence that first-line antimicrobial treatment guidelines should be altered to increase cover for CoNS infections in neonates in this setting.