Exploiting species specificity to understand the tropism of a human-specific toxin.

Many pathogens produce virulence factors that are specific toward their natural host. Clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) isolates are highly adapted to humans and produce an array of human-specific virulence factors. One such factor is LukAB, a recently identified pore-forming toxin that targets human phagocytes by binding to the integrin component CD11b. LukAB exhibits strong tropism toward human, but not murine, CD11b. Here, phylogenetics and biochemical studies lead to the identification of an 11-residue domain required for the specificity of LukAB toward human CD11b, which is sufficient to render murine CD11b compatible with toxin binding. CRISPR-mediated gene editing was used to replace this domain, resulting in a "humanized" mouse. In vivo studies revealed that the humanized mice exhibit enhanced susceptibility to MRSA bloodstream infection, a phenotype mediated by LukAB. Thus, these studies establish LukAB as an important toxin for MRSA bacteremia and describe a new mouse model to study MRSA pathobiology.

A novel airway management strategy for cervical necrotising fasciitis secondary to Bezold's abscess.

We describe a rare case of cervical necrotising fasciitis caused by mastoiditis and Bezold's abscess. This case was complicated by a tracheostomy delaying wound healing. A novel strategy to repair the tracheotomy defect using Permacol™, an acellular porcine dermal substitute, and a local muscle flap not previously reported in the literature is described to allow the use of negative pressure wound therapy dressing. This technique may be employed in similar applications for non-healing tracheotomy wounds.

Detection of N-glycolylneuraminic acid biomarkers in sera from patients with ovarian cancer using an engineered N-glycolylneuraminic acid-specific lectin SubB2M.

N-glycolylneuraminic acid (Neu5Gc)-containing glycans are a prominent form of aberrant glycosylation found in human tumor cells and have been proposed as cancer biomarkers. The B subunit of the subtilase cytotoxin (SubB) produced by Shiga toxigenic Escherichia coli recognises Neu5Gc containing glycans. We have previously engineered this lectin, SubB2M, for greater specificity and enhanced recognition of Neu5Gc-containing glycans. Here we further explore the utility of SubB2M to detect Neu5Gc tumor biomarkers in sera from patients with ovarian cancer. Using surface plasmon resonance (SPR) we show that SubB2M can detect the established ovarian cancer biomarker, CA125, in a highly sensitive and specific fashion in the context of human serum. These studies established conditions for screening serum samples from patients with ovarian cancer for Neu5Gc glycans. We found that serum from patients with all stages of ovarian cancer had significantly elevated mean levels of Neu5Gc glycans compared to normal controls. Serum from patients with late stage disease (stages IIIC, IV) had uniformly elevated levels of Neu5Gc glycans. Detection of Neu5Gc-glycans using SubB2M has the potential to be used as a diagnostic ovarian cancer biomarker, as well as a tool for monitoring treatment and disease progression in late stage disease.

A peculiar case of Campylobacter jejuni attenuated aspartate chemosensory mutant, able to cause pathology and inflammation in avian and murine model animals.

An attenuated Campylobacter jejuni aspartate chemoreceptor ccaA mutant caused gross pathological changes despite reduced colonisation ability in animal models. In chickens, the pathological changes included connective tissue and thickening of the mesenteric fat, as well as the disintegration of the villus tips in the large intestine, whereas in mice, hepatomegaly occurred between 48-72 hours post infection and persisted for the six days of the time course. In addition, there was a significant change in the levels of IL-12p70 in mice infected with the C. jejuni ccaA mutant. CcaA isogenic mutant was hyper-invasive in cell culture and microscopic examination revealed that it had a "run" bias in its "run-and-tumble" chemotactic behaviour. The mutant cells also exhibited lower level of binding to fucosylated and higher binding to sialylated glycan structures in glycan array analysis. This study highlights the importance of investigating phenotypic changes in C. jejuni, as we have shown that specific mutants can cause pathological changes in the host, despite reduction in colonisation potential.

A naturalistic, randomized, controlled trial combining cognitive remediation with cognitive-behavioural therapy after first-episode non-affective psychosis.

BACKGROUND: Cognitive remediation (CR) preceding cognitive-behavioural therapy for psychosis (CBTp) was trialled within routine clinical services, with the hypothesis that following first-episode non-affective psychosis CR would enhance CBTp efficacy by improving neuropsychological performance. METHOD: A total of 61 patients with DSM-IV non-affective psychoses waiting for routine CBTp were randomized to computerized CR over 12 weeks, supported by a trained support worker, or time-matched social contact (SC). Primary outcome was the blind-rated Psychotic Symptoms Rating Scale (PSYRATS). Secondary outcomes included measures of CBTp progress, cognition, symptoms, insight and self-esteem: all at baseline, after CR (12 weeks) and after CBTp (42 weeks). PSYRATS and global neuropsychological efficacy were tested using mixed-effects models with a group × time interaction term. Measures of CBTp progress and some neuropsychological measures were modelled by regression. RESULTS: There was no significant difference between the CR and SC groups in PSYRATS (group × time coefficient 0.3, 95% confidence interval -0.4 to 1.1, p = 0.39). However, after CR CBTp was shorter [median 7 sessions, interquartile range (IQR) 2-12 after CR; median 13, IQR 4-18 after SC; model p = 0.011] and linked to better insight (p = 0.02). Global cognition did not improve significantly more after CR (p = 0.20) but executive function did (Wisconsin Card Sort, p = 0.012). CONCLUSIONS: CBTp courses preceded by CR were far shorter but achieved the same outcome as CBTp preceded by an active control, consistent with neuropsychological improvement enhancing CBTp. CR was delivered by staff with minimal training, offering the potential to reduce the costs of CBTp considerably.

Orthodontic therapists--the first Bristol cohort.

This paper outlines the development of the training of orthodontic therapists in the UK, the experiences of the first cohort to pass through the Bristol course, the roles and responsibilities of the therapist and possible issues with future orthodontic manpower planning.

New developments in the pathogenesis of ANCA-associated vasculitis.

In recent years there have been substantial developments in the understanding of the pathogenesis of ANCA-associated vasculitidies. Animal models have now been developed that finally prove a direct pathogenic role for ANCA, a subject fiercely debated since their original identification. We are also closer to understanding how ANCA exert their effects to cause disease. Progress has been made in elucidating how ANCA activate neutrophils, from how they bind antigen and where that antigen is located, to how antigen binding is translated into intracellular activity. The effects of ANCA activation on the effector functions of neutrophils and monocytes are being further dissected and the flow-based assay is allowing interactions with endothelium to be studied in more detail. Knowledge of the role of T cells has been enhanced by examining contributions to disease by differing subsets and their cytokine secretions. Defects in apoptosis playing a role in the initiation of other autoimmune diseases has prompted investigations into whether a similar pathogenesis is relevant in vasculitis, and various genetic polymorphisms have been discovered to be important in determining in whom vasculitis develops. This article reviews how recent research has helped in the understanding of the pathogenesis of small vessel vasculitis.

Visible and occult blood contamination of laryngeal mask airways and tracheal tubes used in adult anaesthesia.

The purpose of this study was to compare visible and occult blood contamination of 50 laryngeal mask airways and 50 tracheal tubes following routine anaesthesia for procedures not involving the oropharyngeal or nasal cavities. All airway devices were examined visually for the presence of blood before washing in 100 ml of water. A semiquantitative dipstick was used to test for the presence of blood in the washings. Laryngeal mask airways were examined visually by both authors to test agreement. The results show that occult blood contamination occurred in 78% of tracheal tubes and 76% of laryngeal mask airways, while visible blood contamination was 16% and 12%, respectively. Other studies reporting visible blood contamination of airway devices probably underestimate the true incidence of blood contamination. Oral secretions following the use of these devices should be considered as high risk for transmission of blood-born viruses. Anaesthetic and recovery staff should be protected against the risks of occupational exposure to oral secretions following the use of airway devices.

The impact of percutaneous tracheostomy on intensive care unit practice and training.

We studied the impact of introducing percutaneous tracheostomy to our intensive care unit on the incidence and timing of tracheostomy and on the implications for surgical training. The proportion of patients receiving intensive care who underwent tracheostomy doubled from a median of 8.5% to 16.8% (p < 0.01) following the introduction of the percutaneous technique with the procedure being undertaken significantly earlier during the intensive care stay. The opportunity for surgical trainees to gain experience in open surgical tracheostomy has been virtually lost. The increase in tracheostomy rate may reflect a previous under-utilisation caused by the logistic problems of transferring a critically ill patient to theatre, or alternatively a relaxation of the indications for tracheostomy caused by a perceived benefit for the patient. An increased workload may also have contributed to the rise. Surgical trainees should be encouraged to learn percutaneous techniques and training opportunities in open surgical techniques should be maximised.

Hospital mortality after urgent and emergency laparotomy in patients aged 65 yr and over. Risk and prediction of risk using multiple logistic regression analysis.

We studied 107 patients aged over 65 years undergoing urgent or emergency laparotomy. Aspects of preoperative assessment, perioperative management and postoperative care were analysed by multiple logistic regression to determine the factors that predicted hospital survival. We determined which factors influenced anaesthetists' prediction that patients would survive. These predictions were made both before and immediately after operation. The factors associated with the use of invasive cardiovascular monitoring were also studied. We obtained a model that accounted for 93% of the variability in the likelihood of survival. Age and ASA status were significant predictors of survival (P < 0.05), and of anaesthetists' prediction of mortality both before and after operation. Several other factors were significant determinants of survival but were not determinants of the anaesthetist's opinion regarding survival.

The effects of cardiopulmonary bypass temperature on neuropsychologic outcome after coronary artery operations: a prospective randomized trial.

UNLABELLED: The effect of systemic perfusion temperature on postoperative cognitive function was investigated in 96 adult patients undergoing elective coronary revascularization with cardiopulmonary bypass at 28 degrees C, 32 degrees C, or 37 degrees C. Neuropsychologic performance was assessed 1 day before the operation and 6 weeks after the operation. Five tests were adapted from the Wechsler Adult Intelligence Scale and two from the Wechsler Memory Scale. RESULTS: No patients had major neurologic complications. Ninety-three patients completed the five Wechsler Adult Intelligence Scale tests, but only 70 went on to complete the Wechsler Memory Scale tests as well. In these, there was an effect of cardiopulmonary bypass temperature on the number of neuropsychologic tests in which there was a preoperative to postoperative deterioration (p = 0.021), the number with bypass at 37 degrees C being significantly greater than the number with bypass at 32 degrees C (p = 0.015). Subsidiary analyses using a multivariate linear model examined the effect of cardiopulmonary bypass temperature on the magnitude of change, with or without allowing for other possible confounding influences. There was an adverse effect of normothermic (37 degrees C) versus moderately hypothermic (32 degrees C) perfusion---more convincingly displayed in the analyses of all seven scores rather than just the Wechsler Adult Intelligence Scale scores. Further cooling to 28 degrees C conferred no additional benefit in terms of cognitive function. The importance of the deterioration is open to question.

Auditory, ocular, and facial complications of central neural block. A review of possible mechanisms.

BACKGROUND AND OBJECTIVES: The purpose of this review is to draw together a collection of uncommon complications of central neural block that affect the cranial nerves. There have been a small number of case reports, some of which have included a possible mechanism of the nerve dysfunction, but there is no prior review that collected them together and discussed the possible mechanisms. METHODS: Published case reports were identified by searching Medline of the British Medical Association and the Silver Platter CD-ROM library. In addition, the Medical Defence Union and Medical Protection Society were contacted to find cases that were unpublished but the subject of medical negligence lawsuits. RESULTS: The authors collected these cases together to increase awareness of alarming complications. If such cases are recognized for what they are, then the prognosis is good; however, delayed diagnosis can make them a cause of great anxiety and possible litigation. CONCLUSIONS: Increased awareness of these complications can decrease the likelihood of litigation by early diagnosis and explanation. Their mechanisms are not fully understood but the likely possibilities have been discussed. Further work is needed to establish the incidence of these problems, as it is likely that many cases are not diagnosed and not reported.

Traumatic pneumomyelogram. Implications for the anaesthetist.

A 70-year-old man sustained a severe head injury following a fall downstairs, which resulted in him being found in a head down position. In the accident and emergency department he was noted to have subarachnoid air on a lateral cervical spine radiograph. This drew attention to the presence of fractures in the middle cranial fossa and nitrous oxide was immediately discontinued. The presence of a traumatic pneumomylogram implies a base of skull or middle cranial fossa fracture, and is almost certainly associated with intracranial subarachnoid air. Early recognition of the condition, and cessation of nitrous oxide, is essential to prevent dangerous increases in intracranial pressure secondary to the diffusion of gas into the air filled cavity.