Anaesthesia for vascular emergencies - a state of the art review.

In this state-of-the-art review, we discuss the presenting symptoms and management strategies for vascular emergencies. Although vascular emergencies are best treated at a vascular surgical centre, patients may present to any emergency department and may require both immediate management and safe transport to a vascular centre. We describe the surgical and anaesthetic considerations for management of aortic dissection, aortic rupture, carotid endarterectomy, acute limb ischaemia and mesenteric ischaemia. Important issues to consider in aortic dissection are extent of the dissection and surgical need for bypasses in addition to endovascular repair. From an anaesthetist's perspective, aortic dissection requires infrastructure for massive transfusion, smooth management should an endovascular procedure require conversion to an open procedure, haemodynamic manipulation during stent deployment and prevention of spinal cord ischaemia. Principles in management of aortic rupture, whether open or endovascular treatment is chosen, include immediate transfer to a vascular care centre; minimising haemodynamic changes to reduce aortic shear stress; permissive hypotension in the pre-operative period; and initiation of massive transfusion protocol. Carotid endarterectomy for carotid stenosis is managed with general or regional techniques, and anaesthetists must be prepared to manage haemodynamic, neurological and airway issues peri-operatively. Acute limb ischaemia is a result of embolism, thrombosis, dissection or trauma, and may be treated with open repair or embolectomy, under either general or local anaesthesia. Due to hypercoagulability, there may be higher numbers of acutely ischaemic limbs among patients with COVID-19, which is important to consider in the current pandemic. Mesenteric ischaemia is a rare vascular emergency, but it is challenging to diagnose and associated with high morbidity and mortality. Several peri-operative issues are common to all vascular emergencies: acute renal injury; management of transfusion; need for heparinisation and reversal; and challenging postoperative care. Finally, the important development of endovascular techniques for repair in many vascular emergencies has improved care, and the availability of transoesophageal echocardiography has improved monitoring as well as aids in surgical placement of endovascular grafts and for post-procedural evaluation.

Nociceptive pulmonary-cardiac reflexes are altered in the spontaneously hypertensive rat.

KEY POINTS: We investigated the cardiovascular and respiratory responses of the normotensive Wistar-Kyoto (WKY) rat and the spontaneously hypertensive (SH) rat to inhalation and intravenous injection of the noxious stimuli allyl isothiocyanate (AITC). AITC inhalation evoked atropine-sensitive bradycardia in conscious WKY rats, and evoked atropine-sensitive bradycardia and atenolol-sensitive tachycardia with premature ventricular contractions (PVCs) in conscious SH rats. Intravenous injection of AITC evoked bradycardia but no tachycardia/PVCs in conscious SHs, while inhalation and injection of AITC caused similar bradypnoea in conscious SH and WKY rats. Anaesthesia (inhaled isoflurane) inhibited the cardiac reflexes evoked by inhaled AITC but not injected AITC. Data indicate the presence of a de novo nociceptive pulmonary-cardiac reflex triggering sympathoexcitation in SH rats, and this reflex is dependent on vagal afferents but is not due to steady state blood pressure or due to remodelling of vagal efferent function. ABSTRACT: Inhalation of noxious irritants/pollutants activates airway nociceptive afferents resulting in reflex bradycardia in healthy animals. Nevertheless, noxious pollutants evoke sympathoexcitation (tachycardia, hypertension) in cardiovascular disease patients. We hypothesize that cardiovascular disease alters nociceptive pulmonary-cardiac reflexes. Here, we studied reflex responses to irritants in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive (SH) rats. Inhaled allyl isothiocyanate (AITC) evoked atropine-sensitive bradycardia with atrial-ventricular (AV) block in conscious WKY rats, thus indicating a parasympathetic reflex. Conversely, inhaled AITC in conscious SH rats evoked complex brady-tachycardia with both AV block and premature ventricular contractions (PVCs). Atropine abolished the bradycardia and AV block, but the atropine-insensitive tachycardia and PVCs were abolished by the ß1 -adrenoceptor antagonist atenolol. The aberrant AITC-evoked reflex in SH rats was not reduced by acute blood pressure reduction by captopril. Surprisingly, intravenous AITC only evoked bradycardia in conscious SH and WKY rats. Furthermore, anaesthesia reduced the cardiac reflexes evoked by inhaled but not injected AITC. Nevertheless, anaesthesia had little effect on AITC-evoked respiratory reflexes. Such data suggest distinct differences in nociceptive reflex pathways dependent on cardiovascular disease, administration route and downstream effector. AITC-evoked tachycardia in decerebrate SH rats was abolished by vagotomy. Finally, there was no difference in the cardiac responses of WKY and SH rats to vagal efferent electrical stimulation. Our data suggest that AITC inhalation in SH rats evokes de novo adrenergic reflexes following vagal afferent activation. This aberrant reflex is independent of steady state hypertension and is not evoked by intravenous AITC. We conclude that pre-existing hypertension aberrantly shifts nociceptive pulmonary-cardiac reflexes towards sympathoexcitation.

Patients' understanding of cellulitis and views about how best to prevent recurrent episodes: mixed-methods study in primary and secondary care.

BACKGROUND: Cellulitis is a common painful infection of the skin and underlying tissues that recurs in approximately one-third of cases. The only proven strategy to reduce the risk of recurrence is long-term, low-dose antibiotics. Given current concerns about antibiotic resistance and the pressure to reduce antibiotic prescribing, other prevention strategies are needed. OBJECTIVES: To explore patients' views about cellulitis and different ways of preventing recurrent episodes. METHODS: Adults aged ≥ 18 years with a history of first-episode or recurrent cellulitis were invited through primary care, hospitals and advertising to complete a survey, take part in an interview or both. RESULTS: Thirty interviews were conducted between August 2016 and July 2017. Two hundred and forty surveys were completed (response rate 17%). Triangulation of quantitative and qualitative data showed that people who have had cellulitis have wide-ranging beliefs about what can cause cellulitis and are often unaware of risk of recurrence or potential strategies to prevent recurrence. Enhanced foot hygiene, applying emollients daily, exercise and losing weight were more popular potential strategies than the use of compression stockings or long-term antibiotics. Participants expressed caution about long-term oral antibiotics, particularly those who had experienced only one episode of cellulitis. CONCLUSIONS: People who have had cellulitis are keen to know about possible ways to prevent further episodes. Enhanced foot hygiene, applying emollients daily, exercise and losing weight were generally viewed to be more acceptable, feasible strategies than compression or antibiotics, but further research is needed to explore uptake and effectiveness in practice.

Understanding transport mechanisms in ionic liquid/carbonate solvent electrolyte blends.

To unravel mechanistic details of the ion transport in liquid electrolytes, blends of the ionic liquid (IL) 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (Pyr14TFSI), ethylene carbonate (EC) and dimethyl carbonate (DMC) with the conducting salts lithium hexafluorophosphate (LiPF6) and lithium bis(trifluoromethylsulfonyl)imide (LiTFSI) were investigated as a function of the IL concentration. Electrochemical impedance, Pulsed Field Gradient Nuclear Magnetic Resonance (PFG NMR) and Raman spectroscopy supported by Molecular Dynamics (MD) simulations allowed the structural and dynamic correlations of the ion motions to be probed. Remarkably, we identified that though the individual correlations among different ion types exhibit a clear concentration dependence, their net effect is nearly constant throughout the entire concentration range, resulting in approximately equal transport and transference numbers, despite a monitored cross-over from carbonate-based lithium coordination to a TFSI-based ion coordination. In addition, though dynamical ion correlation could be found, the absolute values of the ionic conductivity are essentially determined by the overall viscosity of the electrolyte. The IL/carbonate blends with a Pyr14TFSI fraction of ∼10 wt% are found to be promising electrolyte solvents, with ionic conductivities and lithium ion transference numbers comparable to those of standard carbonate-based electrolytes while the thermal and electrochemical stabilities are considerably improved. In contrast, the choice of the conducting salt only marginally affects the transport properties.

Mapping transmembrane residues of proteinase activated receptor 2 (PAR2) that influence ligand-modulated calcium signaling.

Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor involved in metabolism, inflammation, and cancers. It is activated by proteolysis, which exposes a nascent N-terminal sequence that becomes a tethered agonist. Short synthetic peptides corresponding to this sequence also activate PAR2, while small organic molecules show promising PAR2 antagonism. Developing PAR2 ligands into pharmaceuticals is hindered by a lack of knowledge of how synthetic ligands interact with and differentially modulate PAR2. Guided by PAR2 homology modeling and ligand docking based on bovine rhodopsin, followed by cross-checking with newer PAR2 models based on ORL-1 and PAR1, site-directed mutagenesis of PAR2 was used to investigate the pharmacology of three agonists (two synthetic agonists and trypsin-exposed tethered ligand) and one antagonist for modulation of PAR2 signaling. Effects of 28 PAR2 mutations were examined for PAR2-mediated calcium mobilization and key mutants were selected for measuring ligand binding. Nineteen of twenty-eight PAR2 mutations reduced the potency of at least one ligand by >10-fold. Key residues mapped predominantly to a cluster in the transmembrane (TM) domains of PAR2, differentially influence intracellular Ca2+ induced by synthetic agonists versus a native agonist, and highlight subtly different TM residues involved in receptor activation. This is the first evidence highlighting the importance of the PAR2 TM regions for receptor activation by synthetic PAR2 agonists and antagonists. The trypsin-cleaved N-terminus that activates PAR2 was unaffected by residues that affected synthetic peptides, challenging the widespread practice of substituting peptides for proteases to characterize PAR2 physiology.

Serological and molecular evidence of a plausible transmission of hepatitis E virus through pooled plasma.

BACKGROUND AND OBJECTIVES: Recently, hepatitis E virus has been recognized as a new transfusion-associated risk; however, its efficiency of transmission through blood products requires further investigation. Asymptomatic viremia of short duration has been observed in blood donors from several European countries to the rate of <1:10,000 and HEV transmission in recipients of blood products has been documented in Japan and Europe. Although HEV RNA was detected in large plasma fractionation pools used for manufacturing of plasma derived products, HEV transmission has not been demonstrated so far. In this study, we investigated the possibility of HEV transmission in patients with thrombotic thrombocytopenic purpura whose treatment included up to 40 l of plasma exchange. MATERIALS AND METHODS: Thirty-six TTP patients received either solvent-detergent-treated plasma prepared by pooling of 2500 single-donor or cryosupernatant plasma. Three samples were collected from TTP patients at time 0, 1 and 6 months post-treatment and tested for anti-HEV antibodies. Patients with HEV seroconversion were also tested for viremia by PCR. RESULTS: Two of seventeen TTP patients treated with SDP showed serological evidence of HEV infection. The 1-month samples from these patients were also positive for HEV RNA. A distinct rise of anti-HEV IgG level was detected in two other TTP patients with weak pre-existing immunity to HEV; this observation is indicative of a possible immune response boost due to a breakthrough infection. CONCLUSION: This work provides, for the first time, indirect evidence of HEV transmission by pooled plasma and warrants further studies.

Ileorectal anastomosis in ulcerative colitis: what do surgeons and patients need to know? A systematic literature review.

INTRODUCTION: Ileal pouch-anal anastomosis (IPAA) is currently the gold standard for restoration of gastrointestinal continuity after colectomy for ulcerative colitis in the UK. However, with further experience of the risks relating to IPAA, the use of ileorectal anastomosis (IRA) is being revisited. Decisions regarding restorative surgery after colectomy are individual to every patient's circumstances, and this paper aims to provide a comprehensive review of the literature to guide a full discussion of the risks and benefits of IRA. METHODS: A systematic literature review was conducted of papers published from 2000 onwards relating to IRA and ulcerative colitis, in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. The papers were reviewed by two independent surgeons for information it was felt that patients and surgeons would want to know about the operation (cancer risk, bowel function, sexual and urinary function, fecundity/fertility and postoperative complications). RESULTS: Seventeen papers were identified for inclusion as they reported original data on one or more of the categories identified for discussion. The median ten-year cancer risk after IRA was 2.8% and the median failure rate at ten years was 21%. IRA was generally found to have lower postoperative complication rates and better bowel function than IPAA, with sexual function similar and fecundity not commented on in any paper. CONCLUSIONS: For some patients, IRA can offer restorative surgery in the short or long term, with acceptable cancer risk, failure rate and postoperative complications, while avoiding the higher risks associated with IPAA.

Stratum basale keratinocyte expression of the cell-surface glycoprotein CDCP1 during epidermogenesis and its role in keratinocyte migration.

BACKGROUND: Epidermogenesis and epidermal wound healing are tightly regulated processes during which keratinocytes must migrate, proliferate and differentiate. Cell-to-cell adhesion is crucial to the initiation and regulation of these processes. CUB-domain-containing protein (CDCP)1 is a transmembrane glycoprotein that is differentially tyrosine phosphorylated during changes in cell adhesion and survival signalling, and is expressed by keratinocytes in native human skin, as well as in primary cultures. OBJECTIVES: To investigate the expression of CDCP1 during epidermogenesis and its role in keratinocyte migration. METHODS: We examined both human skin tissue and an in vitro three-dimensional human skin equivalent model to examine the expression of CDCP1 during epidermogenesis. To examine the role of CDCP1 in keratinocyte migration we used a function-blocking anti-CDCP1 antibody and a real-time Transwell™ cell migration assay. RESULTS: Immunohistochemical analysis indicated that in native human skin CDCP1 is expressed in the stratum basale and stratum spinosum. In contrast, during epidermogenesis in a three-dimensional human skin equivalent model, CDCP1 was expressed only in the stratum basale, with localization restricted to the cell-cell membrane. No expression was detected in basal keratinocytes that were in contact with the basement membrane. Furthermore, an anti-CDCP1 function-blocking antibody was shown to disrupt keratinocyte chemotactic migration in vitro. CONCLUSIONS: These findings delineate the expression of CDCP1 in human epidermal keratinocytes during epidermogenesis and demonstrate that CDCP1 is involved in keratinocyte migration.

Irritant-evoked reflex tachyarrhythmia in spontaneously hypertensive rats is reduced by inhalation of TRPM8 agonists l-menthol and WS-12.

Inhalation of noxious irritants activates nociceptive sensory afferent nerves innervating the airways, inducing reflex regulation of autonomic networks and the modulation of respiratory drive and cardiovascular (CV) parameters such as heart rate and blood pressure. In healthy mammals, irritant-evoked pulmonary-cardiac reflexes cause parasympathetic-mediated bradycardia. However, in spontaneously hypertensive (SH) rats, irritant inhalation also increases sympathetic drive to the heart. This remodeled pulmonary-cardiac reflex may contribute to cardiovascular risk caused by inhalation of air pollutants/irritants in susceptible individuals with cardiovascular disease (CVD). Previous studies have shown that the cooling mimic l-menthol, an agonist for the cold-sensitive transient receptor potential melastatin 8 (TRPM8), can alleviate nasal inflammatory symptoms and respiratory reflexes evoked by irritants. Here, we investigated the impact of inhalation of TRPM8 agonists l-menthol and WS-12 on pulmonary-cardiac reflexes evoked by inhalation of the irritant allyl isothiocyanate (AITC) using radiotelemetry. l-Menthol, but not its inactive analog d-menthol, significantly reduced the AITC-evoked reflex tachycardia and premature ventricular contractions (PVCs) in SH rats but had no effect on the AITC-evoked bradycardia in either SH or normotensive Wistar-Kyoto (WKY) rats. WS-12 reduced AITC-evoked tachycardia and PVCs in SH rats, but this more potent TRPM8 agonist also reduced AITC-evoked bradycardia. l-Menthol had no effect on heart rate when given alone, whereas WS-12 evoked a minor bradycardia in WKY rats. We conclude that stimulation of TRPM8-expressing afferents within the airways reduces irritant-evoked pulmonary-cardiac reflexes, especially the aberrant reflex tachyarrhythmia in SH rats. Airway menthol treatment may be an effective therapy for reducing pollution-associated CV exacerbations.NEW & NOTEWORTHY Irritant-evoked pulmonary-cardiac reflexes are remodeled in spontaneously hypertensive (SH) rats-causing de novo sympathetic reflexes that drive tachyarrhythmia. This remodeling may contribute to air pollution-associated risk in susceptible individuals with cardiovascular disease. We found that inhalation of TRPM8 agonists, l-menthol and WS-12, but not the inactive analog d-menthol, selectively reduces the reflex tachyarrhythmia evoked by allyl isothiocyanate (AITC) inhalation in SH rats. Use of menthol may protect susceptible individuals from pollution-associated CV exacerbations.

Determination of tilt angle and its behavior in chiral smectic phases by exploring molecular conformations using complementary methods.

Density functional theory (DFT) calculations and x-ray diffraction techniques were employed to evaluate the value of the tilt angle in ferroelectric smectic C^{*} and antiferroelectric smectic C_{A}^{*} phases. Five homologues from the chiral series denoted as 3FmHPhF6(m=2,4,5,6,7), based on 4-(1-methylheptyloxycarbonyl) phenyl 4'-octyloxybiphenyl-4-carboxylate (MHPOBC), were studied. Two types of conformations for the nonchiral terminal chain (fully extended and gauche) and three types of deviation from the rodlike shape of the molecules (hockey stick, zigzag, and C shape) were computationally considered. The nonlinear shape of the molecules was accounted for by introducing a shape parameter δΘ. We observe that calculations of the tilt angle which consider the C-shaped structures, in both the fully extended or gauche conformations, lead to good agreement with the values of the tilt angle obtained from electro-optical measurements below the saturation temperature. The results allow us to conclude that such structures are adopted by molecules in the examined series of smectogens. Additionally, this study proves the presence of the standard orthogonal SmA^{*} phase for the homologues with m=6, 7, and the de Vries SmA^{*} phase for m=5.

NUMTs in the sponge genome reveal conserved transposition mechanisms in metazoans.

The transposition of parts of the mitochondrial (mt) genetic material into the nuclear genome (NUMTs) occurs in a wide range of eukaryotes. Here, we show that NUMTs exist for nearly all regions of the mt genome in the demosponge Amphimedon queenslandica, a representative of the oldest phyletic lineage of animals. Because the sponge NUMTs are small and noncoding, and transposed via a DNA intermediate, as in eumetazoans, we infer that the transpositonal processes underlying NUMT formation in contemporary animals existed in their most recent common ancestor. In contrast to most bilaterians, Amphimedon NUMTs are inserted into regions of high gene density. Given the common features of metazoan NUMTs, the reduction in animal mt genome sizes relative to other eukaryotes may be the product of the mt DNA transposition mechanisms that evolved along the metazoan stem.

Diversity and distribution of the bioactive actinobacterial genus Salinispora from sponges along the Great Barrier Reef.

Isolates from the marine actinobacterial genus Salinispora were cultured from marine sponges collected from along the length of the Great Barrier Reef (GBR), Queensland, Australia. Strains of two species of Salinispora, Salinispora arenicola and "Salinispora pacifica", were isolated from GBR sponges Dercitus xanthus, Cinachyrella australiensis and Hyattella intestinalis. Phylogenetic analysis of the 16S rRNA gene sequences of representative strains, selected via BOX-PCR screening, identified previously unreported phylotypes of the species "S. pacifica". The classification of these microdiverse 16S rRNA groups was further confirmed by analysis of the ribonuclease P RNA (RNase P RNA) gene through both phylogenetic and secondary structure analysis. The use of RNase P RNA sequences combined with 16S rRNA sequences allowed distinction of six new intraspecies phylotypes of "S. pacifica" within the geographical area of the GBR alone. One of these new phylotypes possessed a localised regional distribution within the GBR.

Irritant Inhalation Evokes P Wave Morphological Changes in Spontaneously Hypertensive Rats via Reflex Modulation of the Autonomic Nervous System.

Irritant inhalation is associated with increased incidence of atrial fibrillation (AF) and stroke. Irritant inhalation acutely regulates cardiac function via autonomic reflexes. Increases in parasympathetic and sympathetic reflexes may increase atrial susceptibility to ectopic activity and the initiation of arrhythmia such as AF. Both age and hypertension are risk factors for AF. We have shown that irritant-evoked pulmonary-cardiac reflexes are remodeled in spontaneously hypertensive (SH) rats to include a sympathetic component in addition to the parasympathetic reflex observed in normotensive Wistar-Kyoto (WKY) rats. Here, we analyzed P wave morphology in 15-week old WKY and SH rats during inhalation of the transient receptor potential ankyrin 1 agonist allyl isothiocyanate (AITC). P Wave morphology was normal during vehicle inhalation but was variably modulated by AITC. AITC increased RR intervals (RRi), PR intervals, and the P Wave duration. In SH rats only, AITC inhalation increased the occurrence of negative P waves. The incidence of AITC-evoked negative P waves in SH rats was dependent on RRi, increasing during bradycardic and tachycardic cardiac cycles. Inhibition of both parasympathetic (using atropine) and sympathetic (using atenolol) components of the pulmonary-cardiac reflex decreased the incidence of negative P waves. Lastly, the probability of evoking a negative P Wave was increased by the occurrence of preceding negative P waves. We conclude that the remodeled irritant-evoked pulmonary-cardiac reflex in SH rats provides a substrate for altered P Wave morphologies. These are likely ectopic atrial beats that could provide a trigger for AF initiation in structurally remodeled atria.

Protease-activated receptor-2 promotes osteogenesis in skeletal mesenchymal stem cells at the expense of adipogenesis: Involvement of interleukin-6.

Bone marrow mesenchymal stem cells (MSCs) give rise to osteoblasts and adipocytes, with an inverse relationship between the two. The MSCs from protease-activated receptor-2 knockout (PAR2 KO) mice have a reduced capacity to generate osteoblasts. Here we describe the observation that PAR2 KO osteoblastic cultures generate more adipocytes than wildtype (WT) cultures. Osteoblasts from PAR2 KO mice expressed lower levels of osteoblastic genes (Runx2, Col1a1 and Bglap), and higher levels of the adipocytic gene Pparg than WT osteoblasts. Bone marrow stromal cells from PAR2 KO mice generated fewer osteoblastic colonies (assessed by staining for alkaline phosphatase activity and mineral deposition) and more adipocytic (Oil Red-O positive) colonies than cultures from WT mice. Similarly, cultures of the bone marrow stromal cell line (Kusa 4b10) in which PAR2 was knocked down (F2rl1 KD), were less osteoblastic and more adipocytic than vector control cells. Putative regulators of PAR2-mediated osteogenesis and suppression of adipogenesis were identified in an RNA-sequencing (RNA-seq) investigation; these include C1qtnf3, Gpr35, Grem1, Snorc and Tcea3, which were more highly expressed, and Cnr1, Enpep, Hmgn5, Il6 and Ramp3 which were expressed at lower levels, in control than in F2rl1 KD cells. Interleukin-6 (IL-6) levels were higher in medium harvested from F2rl1 KD cells than from control cells, and a neutralising anti-IL-6 antibody reduced the number of adipocytes in F2rl1 KD cultures to that of control cultures. Thus, PAR2 appears to be a mediator of the reciprocal relationship between osteogenesis and adipogenesis, with IL-6 having a regulatory role in these PAR2-mediated effects.

Antibodies to synaptic vesicles purified from Narcine electric organ bind a subclass of mammalian nerve terminals.

Antibodies were raised in rabbits to synaptic vesicles purified to homogeneity from the electric organ of Narcine brasiliensis, a marine electric ray. These antibodies were shown by indirect immunofluorescence techniques to bind a wide variety of nerve terminals in the mammalian nervous system, both peripheral and central. The shared antigenic determinants are found in cholinergic terminals, including the neuromuscular junction, sympathetic ganglionic and parasympathetic postganglionic terminals, and in those synaptic areas of the hippocampus and cerebellum that stain with acetylcholinesterase. They are also found in some noncholinergic regions, including adrenergic sympathetic postganglionic terminals, the peptidergic terminals in the posterior pituitary, and adrenal chromaffin cells. They are, however, not found in many noncholinergic synapse-rich regions. Such regions include the molecular layer of the cerebellum and those laminae of the dentate gyrus that receive hippocampal associational and commissural input. We conclude that one or more of the relatively small number of antigenic determinants in pure electric fish synaptic vesicles have been conserved during evolution, and are found in some but not all nerve terminals of the mammalian nervous system. The pattern of antibody binding in the central nervous system suggests unexpected biochemical similarities between nerve terminals heretofore regarded as unrelated.

Feasibility of single-use 3D-printed instruments for total knee arthroplasty.

AIMS: This aim of this study was to assess the feasibility of designing and introducing generic 3D-printed instrumentation for routine use in total knee arthroplasty. MATERIALS AND METHODS: Instruments were designed to take advantage of 3D-printing technology, particularly ensuring that all parts were pre-assembled, to theoretically reduce the time and skill required during surgery. Concerning functionality, ranges of resection angle and distance were restricted within a safe zone, while accommodating either mechanical or anatomical alignment goals. To identify the most suitable biocompatible materials, typical instrument shapes and mating parts, such as dovetails and screws, were designed and produced. RESULTS: Before and after steam sterilization, dimensional analysis showed that acrylonitrile butadiene styrene could not withstand the temperatures without dimensional changes. Oscillating saw tests with slotted cutting blocks produced debris, fractures, or further dimensional changes in the shape of Nylon-12 and polymethylmethacrylate (MED610), but polyetherimide ULTEM 1010 was least affected. CONCLUSION: The study showed that 3D-printed instrumentation was technically feasible and had some advantages. However, other factors, such as whether all procedural steps can be accomplished with a set of 3D-printed instruments, the logistics of delivery, and the economic aspects, require further study. Cite this article: Bone Joint J 2019;101-B(7 Supple C):115-120.

A systematic review of McKittrick-Wheelock syndrome.

INTRODUCTION: McKittrick-Wheelock syndrome describes the condition of extreme electrolyte and fluid depletion caused by large distal colorectal tumours, usually the benign villous adenoma. Patients generally present critically unwell with severe hyponatraemia, hypokalaemia and/or acute kidney injury. METHODS: A structured literature review was undertaken to discover what is known about this condition, which is almost universally described as rare. Important features of the syndrome were identified, including common presenting symptoms, blood results, tumour location and size. FINDINGS: Our literature search identified 257 cases reported across all languages. The most remarkable features were the long duration of symptoms (median 24 months) and the significant electrolyte derangements (median sodium of 122mmol/l and median potassium of 2.7mmol/l at initial presentation). Five key recommendations are made to improve diagnosis, including aggressive fluid resuscitation to match rectal losses and surgical intervention on the index admission. The advantages and disadvantages of different treatment options are discussed, including minimally invasive alternatives to traditional resectional surgery. CONCLUSIONS: McKittrick-Wheelock syndrome describes a normally benign condition that can cause patients to become critically unwell and so it behoves all clinicians to be aware of it. By publishing recommendations based on a comprehensive literature review, we aim to improve diagnosis and management of this life threatening condition.

MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target.

MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-XL. MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+ CD44+ cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.