The compartmental distribution of knee osteoarthritis - a systematic review and meta-analysis.

OBJECTIVES: For a population with knee osteoarthritis (OA), determine: 1) the prevalence of single compartmental, bicompartmental and tricompartmental OA, 2) the prevalence of isolated medial tibiofemoral, lateral tibiofemoral, or patellofemoral OA, and combinations thereof. METHODS: PubMed and Web of Science databases, and reference lists of identified studies, were searched to find studies which reported on the compartmental distribution and prevalence of knee OA. Two independent reviewers assessed studies against pre-defined inclusion criteria and prevalence data were extracted along with subject characteristics. The methodological quality of each included study was assessed. A random-effects model meta-analysis was performed for each OA category to estimate the relative prevalence of OA in the knee compartments amongst people with knee OA. RESULTS: 16 studies (3,786 knees) met the inclusion criteria. High heterogeneity was measured. Normalised for knees with OA, estimated prevalence rates (95% CI) were: single compartmental 50% (31.5-58.3%), bicompartmental 33% (23.1-37.2%) and tricompartmental only 17% (8.8-24.8%). Isolated medial tibiofemoral OA, isolated patellofemoral OA, and combined medial tibiofemoral and patellofemoral OA were more common than tricompartmental disease, occurring in 27% (15.2-31.1%), 18% (9.9-22.7%) and 23% (14.1-27.3%) of people respectively. Single/bicompartmental patterns of disease involving the lateral tibiofemoral compartment were less common, summing to 15% (8.5-18.7%). CONCLUSION: Three-quarters of people with knee OA do not have tricompartmental disease. This is not reflected in the frequency with which partial and combined partial knee arthroplasties are currently used. TRIAL REGISTRATION NUMBER: PROSPERO systematic review protocol (CRD42019140345).

Neurite outgrowth inhibitory levels of organophosphates induce tissue transglutaminase activity in differentiating N2a cells: evidence for covalent adduct formation.

Organophosphate compounds (OPs) induce both acute and delayed neurotoxic effects, the latter of which is believed to involve their interaction with proteins other than acetylcholinesterase. However, few OP-binding proteins have been identified that may have a direct role in OP-induced delayed neurotoxicity. Given their ability to disrupt Ca2+ homeostasis, a key aim of the current work was to investigate the effects of sub-lethal neurite outgrowth inhibitory levels of OPs on the Ca2+-dependent enzyme tissue transglutaminase (TG2). At 1-10 µM, the OPs phenyl saligenin phosphate (PSP) and chlorpyrifos oxon (CPO) had no effect cell viability but induced concentration-dependent decreases in neurite outgrowth in differentiating N2a neuroblastoma cells. The activity of TG2 increased in cell lysates of differentiating cells exposed for 24 h to PSP and chlorpyrifos oxon CPO (10 µM), as determined by biotin-cadaverine incorporation assays. Exposure to both OPs (3 and/or 10 µM) also enhanced in situ incorporation of the membrane permeable substrate biotin-X-cadaverine, as indicated by Western blot analysis of treated cell lysates probed with ExtrAvidin peroxidase and fluorescence microscopy of cell monolayers incubated with FITC-streptavidin. Both OPs (10 µM) stimulated the activity of human and mouse recombinant TG2 and covalent labelling of TG2 with dansylamine-labelled PSP was demonstrated by fluorescence imaging following SDS-PAGE. A number of TG2 substrates were tentatively identified by mass spectrometry, including cytoskeletal proteins, chaperones and proteins involved protein synthesis and gene regulation. We propose that the elevated TG2 activity observed is due to the formation of a novel covalent adduct between TG2 and OPs.

Comparison of portable blood-warming devices under simulated pre-hospital conditions: a randomised in-vitro blood circuit study.

Pre-hospital transfusion of blood products is a vital component of many advanced pre-hospital systems. Portable fluid warmers may be utilised to help prevent hypothermia, but the limits defined by manufacturers often do not reflect their clinical use. The primary aim of this randomised in-vitro study was to assess the warming performance of four portable blood warming devices (Thermal Angel, Hypotherm X LG, °M Warmer, Buddy Lite) against control at different clinically-relevant flow rates. The secondary aim was to assess haemolysis rates between devices at different flow rates. We assessed each of the four devices and the control, at flow rates of 50 ml.min-1 , 100 ml.min-1 and 200 ml.min-1 , using a controlled perfusion circuit with multisite temperature monitoring. Free haemoglobin concentration, a marker of haemolysis, was measured at multiple points during each initial study run with spectrophotometry. At all flow rates, the four devices provided superior warming performance compared with the control (p < 0.001). Only the °M Warmer provided a substantial change in temperature at all flow rates (mean (95%CI) temperature change of 21.1 (19.8-22.4) °C, 20.4 (19.1-21.8) °C and 19.4 (17.7-21.1) °C at 50 ml.min-1 , 100 ml.min-1 and 200 ml.min-1 , respectively). There was no association between warming and haemolysis with any device (p = 0.949) or flow rate (p = 0.169). Practical issues, which may be relevant to clinical use, also emerged during testing. Our results suggest that there were significant differences in the performance of portable blood warming devices used at flow rates encountered in clinical practice.

Absolute Differential Positronium-Formation Cross Sections.

The first absolute experimental determinations of the differential cross sections for the formation of ground-state positronium are presented for He, Ar, H2, and CO2 near 0°. Results are compared with available theories. The ratio of the differential and integrated cross sections for the targets exposes the higher propensity for forward emission of positronium formed from He and H2.

Phenyl Saligenin Phosphate Induced Caspase-3 and c-Jun N-Terminal Kinase Activation in Cardiomyocyte-Like Cells.

At present, little is known about the effect(s) of organophosphorous compounds (OPs) on cardiomyocytes. In this study, we have investigated the effects of phenyl saligenin phosphate (PSP), two organophosphorothioate insecticides (diazinon and chlorpyrifos), and their acutely toxic metabolites (diazoxon and chlorpyrifos oxon) on mitotic and differentiated H9c2 cardiomyoblasts. OP-induced cytotoxicity was assessed by monitoring MTT reduction, LDH release, and caspase-3 activity. Cytotoxicity was not observed with diazinon, diazoxon, or chlorpyrifos oxon (48 h exposure; 200 µM). Chlorpyrifos-induced cytotoxicity was only evident at concentrations >100 µM. In marked contrast, PSP displayed pronounced cytotoxicity toward mitotic and differentiated H9c2 cells. PSP triggered the activation of JNK1/2 but not ERK1/2, p38 MAPK, or PKB, suggesting a role for this pro-apoptotic protein kinase in PSP-induced cell death. The JNK1/2 inhibitor SP 600125 attenuated PSP-induced caspase-3 and JNK1/2 activation, confirming the role of JNK1/2 in PSP-induced cytotoxicity. Fluorescently labeled PSP (dansylated PSP) was used to identify novel PSP binding proteins. Dansylated PSP displayed cytotoxicity toward differentiated H9c2 cells. 2D-gel electrophoresis profiles of cells treated with dansylated PSP (25 µM) were used to identify proteins fluorescently labeled with dansylated PSP. Proteomic analysis identified tropomyosin, heat shock protein ß-1, and nucleolar protein 58 as novel protein targets for PSP. In summary, PSP triggers cytotoxicity in differentiated H9c2 cardiomyoblasts via JNK1/2-mediated activation of caspase-3. Further studies are required to investigate whether the identified novel protein targets of PSP play a role in the cytotoxicity of this OP, which is usually associated with the development of OP-induced delayed neuropathy.

Evaluation of a service intervention to improve awareness and uptake of bowel cancer screening in ethnically-diverse areas.

BACKGROUND: Uptake of bowel cancer screening is lowest in London, in populations of lower socio-economic status, and in particular ethnic or religious groups. METHODS: We report on the evaluation of two interventions to improve uptake in an area including populations of low socio-economic status and considerable ethnic diversity. The interventions were face-to-face health promotion on bowel cancer screening at invitees' general practice and health promotion delivered by telephone only. Nine large general practices in East London were chosen at random to offer face-to-face health promotion, and nine other large practices to offer telephone health promotion, with 24 practices of similar size as comparators. Data at practice level were analysed by Mann-Whitney-Wilcoxon tests and grouped-logistic regression. RESULTS: There were 2034 invitees in the telephone intervention practices, 1852 in the face-to-face intervention practices and 5227 in the comparison practices. Median gFOBt kit uptake in the target population (aged 59-70) was 46.7% in the telephone practices, 43.8% in the face-to-face practices and 39.1% in the comparison practices. Significant improvements in the odds of uptake were observed following telephone intervention in both males (OR=1.39, 95% CI=1.20-1.61, P<0.001) and females (OR=1.49, 95% CI=1.29-1.73, P<0.001), while the face-to-face intervention mainly impacted uptake in males (OR=1.23, 95% CI=1.10-1.36), P<0.001) but did not lead to a significant increase in females (OR=1.12, 95% CI=0.96-1.29, P=0.2). CONCLUSIONS: Personally delivered health promotion improved uptake of bowel cancer screening in areas of low socio-economic status and high ethnic diversity. The intervention by telephone appears to be the most effective method.

Resilience following spinal cord injury: a phenomenological view.

STUDY DESIGN: Qualitative research design involving semi-structured focus groups. OBJECTIVES: To increase current understanding of how persons with spinal cord injuries (SCI) define resilience and what factors contribute to their resilience or the resilience of others. SETTING: Inpatient rehabilitation program in a large urban city in the Southwestern United States. METHODS: A convenience sample of 28 participants (14 current patients; 14 former patients) participated in semi-structured focus groups led by the research investigators. RESULTS: Through a constant comparative analysis of the data, six themes emerged in participants' responses regarding what they believed contributed to their own resilience in adapting to SCI. The six themes included psychological strength, social support, perspective, adaptive coping, spirituality or faith, and serving as a role model or inspiring others. CONCLUSION: Consistent with previous research findings, individuals with SCI identified positive thinking (for example, optimism, hope and positive attitude), perseverance and determination, and social support from friends and family as important contributors to their ability to adapt in spite of experiencing traumatic events that resulted in SCI. Findings provide richness and depth to current empirical conceptualizations of resilience.

Exploration of fs-laser ablation parameter space for 2D/3D imaging of soft and hard materials by tri-beam microscopy.

Tri-beam microscopes comprising a fs-laser beam, a Xe+ plasma focused ion beam (PFIB) and an electron beam all in one chamber open up exciting opportunities for site-specific correlative microscopy. They offer the possibility of rapid ablation and material removal by fs-laser, subsequent polishing by Xe-PFIB milling and electron imaging of the same area. While tri-beam systems are capable of probing large (mm) volumes providing high resolution microscopical characterisation of 2D and 3D images across exceptionally wide range of materials and biomaterials applications, presenting high quality/low damage surfaces to the electron beam can present a significant challenge, especially given the large parameter space for optimisation. Here the optimal conditions and artefacts associated with large scale volume milling, mini test piece manufacture, serial sectioning and surface polishing are investigated, both in terms of surface roughness and surface quality for metallic, ceramic, mixed complex phase, carbonaceous, and biological materials. This provides a good starting place for those wishing to examine large areas or volumes by tri-beam microscopy across a range of materials.

Determining the osmolality of over-concentrated and supplemented infant formulas.

BACKGROUND: Hyperosmolar infant feeds can cause osmotic diarrhoea and may be a risk factor for necrotising enterocolitis; the osmolality of infant formula is therefore usually <400 mOsm kg(-1) . However, in fluid-restricted infants and those needing nutritional support, formulas may be over-concentrated or supplemented. The present study aimed to determine the effect of these practices on osmolality. METHODS: A clinical laboratory osmometer was used to measure the osmolality of infant formulas. The effect of over-concentration and supplementation on osmolality was then determined using three and seven different infant formulas, respectively. Osmolalities were measured in triplicate. RESULTS: The effect of over-concentration was shown to be linear using Pepti Junior (Cow & Gate, Trowbridge, UK) at concentrations of 12.8% (standard), 17% and 19%. This linear relationship was also demonstrated with Enfamil A.R. (Mead Johnson Nutritionals, Uxbridge, UK) (15%) and Neocate (SHS International Ltd, Liverpool, UK) (21%). The effect of individual additives on osmolality was found to be similar for the seven infant formulas. All preparations of SMA High Energy (SMA Nutrition, Maidenhead, UK) and five of the 12 preparations of Nutriprem 1 (Cow & Gate) exceeded an osmolality of 400 mOsm kg(-1) . CONCLUSIONS: The effect of over-concentrating infant formulas was shown to be linear, meaning that the osmolality at different concentrations can be predicted accurately. The over-concentrated infant formulas that were measured in the present study did not exceed 400 mOsm kg(-1) , with the exception of 21% Neocate, which would not be used in practice. When supplemented, some infant formulas exceeded an osmolality of 400 mOsm kg(-1) ; this may be relevant in cases of feed intolerance or in those at risk of necrotising enterocolitis.

Feasibility of cerebral near-infrared spectroscopy monitoring in the pre-hospital environment.

BACKGROUND: Traumatic brain injury (TBI) is a significant cause of death and severe disability from trauma. Pre-hospital care of patients with TBI may be aided by non-invasive monitoring of cerebral tissue oxygenation. This pilot observational study was designed to assess if cerebral tissue oximetry using near-infrared spectroscopy (NIRS) is feasible in the pre-hospital and transport environment. METHODS: After ethics committee review, we undertook a feasibility trial in healthy volunteers, transported by road ambulance or helicopter, to assess if monitoring signals could be obtained in the outside environment and during patient transport. RESULTS: A total of 33 road ambulance transports and 32 helicopter transports were undertaken. For monitoring commenced outdoors, 33 of 66 probes applied (50%) provided adequate monitoring signal. For road transports, 33 out of 33 transports (100%) resulted in successful bilateral monitoring for more than 70% of the sampling period. For helicopter transports, four transports were cut short by battery failure during the mission and 24 of 28 transports (85.7%) resulted in successful bilateral monitoring for more than 70% of the sampling period. While patient and transport platform movement did not impact on monitoring signals, exposure to ambient light provided a challenge in obtaining monitoring signals that is nevertheless manageable with increased probe shielding. CONCLUSIONS: NIRS monitoring is feasible in the pre-hospital environment, opening up the possibility for further research of the role of this modality in this setting.

Lights, camera research! Short film and social media to recruit to HIV research in Indonesia.

Introduction: HIV prevalence among men who have sex with men has increased in Indonesia, amid reports of growing stigma against lesbian, gay, bisexual and transgender individuals and policies that have pushed back public health outreach to these groups. Methods: We assessed the utility of tailored short film and targeted social media engagement to recruit men who have sex with men in Indonesia to HIV social science research. A short HIV testing promotion film, anonymised short survey and invite to a wider research study was embedded on a website platform and disseminated using geo and social/community group targeting for 1 month via a social networking app and social media platforms. Results: From 3 January 2021 to 3 February 2021, there were over 2200 hits of the website within Indonesia. A total of 177 male web users who identified as men who have sex with men or preferred not to declare their sexuality, engaged by watching the short film and completing the survey, they were aged between 17 and 60 years old, of Indonesian nationality and living in Indonesia. Of these, 88% indicated having at least one HIV test in their lifetime, 66% had felt shame with respect to their sexuality and 53% indicated feeling afraid to have a HIV test. Ninety (51%) of the 177 validated using their email or mobile phone number demonstrating willingness to be contacted to join a further study. Twenty-three eligible men who have sex with men, aged 21-55 years old, joined a further social science research study. Participants were from diverse backgrounds and included men born in provinces outside Bali, of different socio-economic and employment backgrounds and diverse relationship contexts. Discussion: Engaging, empowering digital media involving key health messaging can provide health education in more effective ways, build trust and bring communities together. Targeted digital and social media approaches could reach increasingly marginalised and vulnerable communities to promote individual and public health and enable recruitment to valuable medical research.

Anti-cancer actions of carnosine and the restoration of normal cellular homeostasis.

Carnosine is a naturally occurring dipeptide found in meat. Alternatively it can be formed through synthesis from the amino acids, ß-alanine and L-histidine. Carnosine has long been advocated for use as an anti-oxidant and anti-glycating agent to facilitate healthy ageing, and there have also been reports of it having anti-proliferative effects that have beneficial actions against the development of a number of different cancers. Carnosine is able to undertake multiple molecular processes, and it's mechanism of action therefore remains controversial - both in healthy tissues and those associated with cancer or metabolic diseases. Here we review current understanding of its mechanistic role in different physiological contexts, and how this relates to cancer. Carnosine turns over rapidly in the body due to the presence of both serum and tissue carnosinase enzymes however, so its use as a dietary supplement would require ingestion of multiple daily doses. Strategies are therefore being developed that are based upon either resistance of carnosine analogs to enzymatic turnover, or else ß-alanine supplementation, and the development of these potential therapeutic agents is discussed.

ß2-Adrenergic Signalling Promotes Cell Migration by Upregulating Expression of the Metastasis-Associated Molecule LYPD3.

Metastasis is associated with poor prognosis in breast cancer. Although some studies suggest beta-blockers increase survival by delaying metastasis, others have been discordant. This study provides both insights into the anomalous findings and identifies potential biomarkers that may be treatment targets. Cell line models of basal-type and oestrogen receptor-positive breast cancer were profiled for basal levels of adrenoceptor gene/protein expression, and ß2-adrenoceptor mediated cell behaviour including migration, invasion, adhesion, and survival in response to adrenoceptor agonist/antagonist treatment. Protein profiling and histology identified biomarkers and drug targets. Baseline levels of adrenoceptor gene expression are higher in basal-type rather than oestrogen receptor-positive cancer cells. Norepinephrine (NE) treatment increased invasive capacity in all cell lines but did not increase proliferation/survival. Protein profiling revealed the upregulation of the pro-metastatic gene Ly6/PLAUR Domain-Containing Protein 3 (LYPD3) in norepinephrine-treated MDA-MB-468 cells. Histology confirmed selective LYPD3 expression in primary and metastatic breast tumour samples. These findings demonstrate that basal-type cancer cells show a more aggressive adrenoceptor-ß2-activated phenotype in the resting and stimulated state, which is attenuated by adrenoceptor-ß2 inhibition. This study also highlights the first association between ADRß2 signalling and LYPD3; its knockdown significantly reduced the basal and norepinephrine-induced activity of MCF-7 cells in vitro. The regulation of ADRß2 signalling by LYPD3 and its metastasis promoting activities, reveal LYPD3 as a promising therapeutic target in the treatment of breast and other cancers.

Doubly diastereoselective [3,3]-sigmatropic aza-Claisen rearrangements.

The doubly diastereoselective [3,3]-sigmatropic aza-Claisen rearrangement of silylketene aminals derived from 5-substituted (3S,4E,alphaR)-1-benzyloxy-3-[N-acyl-N-(alpha-methylbenzyl)amino]pent-4-enes furnishes 2,3-disubstituted (R)-N-alpha-methylbenzyl (2S,3R,4E)-7-benzyloxyhept-4-enamides in >90% de under the "matched" control of both stereogenic centres. Rearrangement of the "mismatched" diastereomeric (3R,4E,alphaR)-substrates proceeds with low diastereoselectivity. The substrate scope of the doubly diastereoselective rearrangement of the "matched" substrates in which two new stereogenic centres are created has been delineated.

Classification of combined partial knee arthroplasty.

AIMS: There has been a recent resurgence in interest in combined partial knee arthroplasty (PKA) as an alternative to total knee arthroplasty (TKA). The varied terminology used to describe these procedures leads to confusion and ambiguity in communication between surgeons, allied health professionals, and patients. A standardized classification system is required for patient safety, accurate clinical record-keeping, clear communication, correct coding for appropriate remuneration, and joint registry data collection. MATERIALS AND METHODS: An advanced PubMed search was conducted, using medical subject headings (MeSH) to identify terms and abbreviations used to describe knee arthroplasty procedures. The search related to TKA, unicompartmental (UKA), patellofemoral (PFA), and combined PKA procedures. Surveys were conducted of orthopaedic surgeons, trainees, and biomechanical engineers, who were asked which of the descriptive terms and abbreviations identified from the literature search they found most intuitive and appropriate to describe each procedure. The results were used to determine a popular consensus. RESULTS: Survey participants preferred "bi-unicondylar arthroplasty" (Bi-UKA) to describe ipsilateral medial and lateral unicompartmental arthroplasty; "medial bi-compartmental arthroplasty" (BCA-M) to describe ipsilateral medial unicompartmental arthroplasty with patellofemoral arthroplasty; "lateral bi-compartmental arthroplasty" (BCA-L) to describe ipsilateral lateral unicompartmental arthroplasty with patellofemoral arthroplasty; and tri-compartmental arthroplasty (TCA) to describe ipsilateral patellofemoral and medial and lateral unicompartmental arthroplasties. "Combined partial knee arthroplasty" (CPKA) was the favoured umbrella term. CONCLUSION: We recommend bi-unicondylar arthroplasty (Bi-UKA), medial bicompartmental arthroplasty (BCA-M), lateral bicompartmental arthroplasty (BCA-L), and tricompartmental arthroplasty (TCA) as the preferred terms to classify CPKA procedures. Cite this article: Bone Joint J 2019;101-B:922-928.

Isoforms of the avian TrkC receptor: a novel kinase insertion dissociates transformation and process outgrowth from survival.

TrkC receptor isoforms have been identified by cDNA cloning and RT-PCR analysis of embryonic chick brain RNA. An N-terminal truncation motif is missing from the signal sequence and first cysteine cluster of the extracellular domain. Within the cytoplasmic dimain, a kinase truncation motif retains part of the kinase domain, but appeared to lack activity. Finally, a kinase insert (KI) motif introduces a 25 amino acid sequence distinct from the known mammalian inserts. KI receptors, like full-length receptors, were tyrosine phosphorylated in response to NT-3 and mediated the transformation of chick embryo fibroblasts and process outgrowth from rat PC12 cells. However, KI receptors supported little, if any, survival of serum-deprived PC12 cells. These results indicate that alternative splicing of trkC transcripts is an important mechanism for regulating cellular responses to NT-3.

Piccolo, a presynaptic zinc finger protein structurally related to bassoon.

Piccolo is a novel component of the presynaptic cytoskeletal matrix (PCM) assembled at the active zone of neurotransmitter release. Analysis of its primary structure reveals that Piccolo is a multidomain zinc finger protein structurally related to Bassoon, another PCM protein. Both proteins were found to be shared components of glutamatergic and GABAergic CNS synapses but not of the cholinergic neuromuscular junction. The Piccolo zinc fingers were found to interact with the dual prenylated rab3A and VAMP2/Synaptobrevin II receptor PRA1. We show that PRA1 is a synaptic vesicle-associated protein that is colocalized with Piccolo in nerve terminals of hippocampal primary neurons. These data suggest that Piccolo plays a role in the trafficking of synaptic vesicles (SVs) at the active zone.

Implications of a simple mathematical model to cancer cell population dynamics.

Recent research in cancer progression and treatment indicates that many forms of cancer arise from the development of a small subpopulation of abnormal cancer stem cells (CSCs) that promote cancer growth and spread. Many potential treatments preferentially interact with cells at certain stages of the cell cycle by either selective killing or halting the cell cycle, such as intense, nanosecond-duration pulsed electric fields (nsPEFs). Simple mathematical models of unfed cancer cell populations at the plateau of their growth characteristics may estimate the long-term consequences of these treatments on proliferating and quiescent cell populations. Applying such a model with no transition from the quiescent to proliferating state shows that it is possible for the proliferating cell population to fall below 1 if the quiescent cell population obtains a sufficient competitive advantage with respect to nutrient consumption and/or survival rate. Introducing small, realistic transition rates did not appreciably alter short-term or long-term population behaviour, indicating that the predicted small cell population behaviour (< 1 cell) is not an artefact of the simpler model. Experimental observations of nsPEF-induced effects on the cell cycle suggest that such a model may serve as a first step in assessing the viability of a given cancer treatment in vitro prior to clinical application.

Lithium amide conjugate addition for the asymmetric synthesis of 3-aminopyrrolidines.

Conjugate addition of homochiral lithium amides to methyl 4-(N-benzyl-N-allylamino)but-2-enoate, chemoselective N-deprotection and concomitant cyclisation, followed by enolate functionalisation and deprotection allows access to syn- and anti-3,4-disubstituted aminopyrrolidines in > 98% d.e. and > 98% e.e.