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Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing., CZI NIH grant ERC grant (Thdefine)

The precise mechanism of anaesthetic action on a neural level remains unclear. Recent approaches suggest that anaesthetics attenuate the complexity of interactions (connectivity) however evidence remains insufficient. We used tools from network and information theory to show that, during propofol-induced sedation, a collection of brain regions displayed decreased complexity in their connectivity patterns, especially so if they were sparsely connected. Strikingly, we found that, despite their low connectivity strengths, these regions exhibited an inordinate role in network integration. Their location and connectivity complexity delineated a specific pattern of sparse interactions mainly involving default mode regions while their connectivity complexity during the awake state also correlated with reaction times during sedation signifying its importance as a reliable indicator of the effects of sedation on individuals. Contrary to established views suggesting sedation affects only richly connected brain regions, we propose that suppressed complexity of sparsely connected regions should be considered a critical feature of any candidate mechanistic description for loss of consciousness.

Retrospective data from patients with severe traumatic brain injury (TBI) indicate that deviation from the continuously calculated pressure reactivity-based "optimal" cerebral perfusion pressure (CPPopt) is associated with worse patient outcome. The objective of this study was to assess the relationship between prospectively collected CPPopt data and patient outcome after TBI.We prospectively collected intracranial pressure (ICP) monitoring data from 231 patients with severe TBI at Addenbrooke's Hospital, UK. Uncleaned arterial blood pressure and ICP signals were recording using ICM+When ΔCPPopt was plotted against PRx and stratified by GOS groupings, data belonging to patients with a more unfavourable outcome had a U-shaped curve that shifted upwards. More time spent with a ΔCPPopt value below the LLR was positively associated with mortality (area under the receiver operating characteristic curve = 0.76 [0.68-0.84]).In a recent cohort of patients with severe TBI, the time spent with a CPP below the CPPopt-derived LLR is related to mortality. Despite aggressive CPP- and ICP-oriented therapies, TBI patients with a fatal outcome spend a significant amount of time with a CPP below their individualised CPPopt, indicating a possible therapeutic target.

Each year, approximately 2.5 million people experience some form of traumatic brain injury (TBI) in Europe. One million of these are admitted to hospital and 75 000 will die. TBI represents a major cause of death and disability, particularly among those of working age. Substantial investments have been made in an effort to improve diagnosis, management and survival in TBI, but with little success. The Collaborative European Neuro-Trauma Effectiveness Research in TBI (CENTER-TBI) study promises to use the natural variability seen in the management of TBI across Europe with the application of Comparative Effectiveness Research (CER). It will generate repositories of baseline and comprehensive TBI patient data, neuroimaging, neurogenetics and biomarkers, which aim to improve the diagnosis, stratification, management and prognostication of patients with TBI.

Traumatic brain injury (TBI) is a growing global problem, which is responsible for a substantial burden of disability and death, and which generates substantial healthcare costs. High-quality intensive care can save lives and improve the quality of outcome. TBI is extremely heterogeneous in terms of clinical presentation, pathophysiology, and outcome. Current approaches to the critical care management of TBI are not underpinned by high-quality evidence, and many of the current therapies in use have not shown benefit in randomized control trials. However, observational studies have informed the development of authoritative international guidelines, and the use of multimodality monitoring may facilitate rational approaches to optimizing acute physiology, allowing clinicians to optimize the balance between benefit and risk from these interventions in individual patients. Such approaches, along with the emerging impact of advanced neuroimaging, genomics, and protein biomarkers, could lead to the development of precision medicine approaches to the intensive care management of TBI.

The number of anaesthetists who are involved in magnetic resonance (MR) units is increasing. Magnetic resonance systems are becoming more powerful and interventional procedures are now possible. This paper updates information relating to safety terminology, occupational exposure, reactions to gadolinium-based contrast agents and the risk of nephrogenic systemic fibrosis. Magnetic resonance examinations of patients with pacemakers are still generally contra-indicated but have been carried out in specialist centres under strictly controlled conditions. As availability of MR increases, so the education of anaesthetists, who are occasionally required to provide a service, must be considered. Anaesthesia in MR units was first described in the 1980s. Guidelines on the provision of anaesthetic services in MR units were published by the Association of Anaesthetists of Great Britain and Ireland (AAGBI) in 2002 [1]. Since then, the number of hospitals with MR units, and hence the number of patients requiring anaesthesia for MR, has increased. While the issues relating to setting up anaesthetic services in MR have not changed, there have been a number of developments that warrant this update: Safety terminology and guidelines have changed. MR systems utilise higher magnetic-field strengths and more open designs are available. Interventional and intra-operative MR are now routine in some centres. Mobile MR scanners are increasingly used to reduce waiting lists. Although still generally contra-indicated, some patients with pacemakers have been scanned under strictly controlled conditions in specialist centres. ‘MR safe’ medical implants are now being produced. New equipment is now available for use in MR. Out-of-hours availability of MR investigations has increased. Reports of allergic reactions to MR contrast media have increased. Gadolinium based contrast agents (Gd-CAs) are associated with a varying degree of risk of nephrogenic systemic fibrosis in patients with impaired renal function. Safety guidelines and legislation In 2007 the Medicines and Healthcare products Regulatory Agency (MHRA) updated safety guidance as a Device Bulletin [2]. Three terms are now to be used as standard in an attempt to remove any ambiguity caused by the old MR compatible system. These terms are MR conditional, MR safe and MR unsafe. MR conditional refers to an item that has been demonstrated to pose no known hazards in a specified MR environment with specified conditions of use. Many items in the MR environment will now be marked as MR conditional, and the conditions under which they can be safely used must accompany the device. This change of terminology has come about because of reports of injuries and problems with MR compatible equipment [3]. Conditions that define the specified MR environment include main magnetic field strength, spatial magnetic field gradient, dB/dt (time rate of change of the magnetic field), radio frequency (RF) field strength, and specific absorption rate. Additional conditions, including specific configurations of the item of equipment, may be required. Equipment is designated as MR safe if it presents no safety hazard to patients or personnel when it is taken into the MR examination room, provided that instructions concerning its use are correctly followed. This does not, however, guarantee that it will function normally and not interfere with the correct operation of the MR imaging equipment, with degradation of image quality. New equipment, such as infusion pumps [4], warming mattresses and temperature probes are now available. It is important to understand the manufacturers’ instructions of all equipment that is brought into the vicinity of the MR scanner. It should be recognised that the supervising MR radiographer is responsible operationally for MR safety within the controlled area and that anaesthetic staff should defer to him/her in relation to MR safety matters, in particular control of access of staff and equipment into the controlled area. Where staff are given access codes or swipe-card access to the controlled area, they should not be shared with others, nor should they provide access to others unless specifically authorised to do so. Inspired oxygen concentration The use of 100% O2 during anaesthesia should be reported to the reporting radiologist as this can produce an artefact in the form of an abnormally high signal in cerebrospinal fluid (CSF) spaces in the T2 weighted fluid attenuated inversion recovery (FLAIR) sequence.

This is a report of a questionnaire-based survey undertaken by the National Institute for the Mentally Handicapped, Secunderabad, India. The objective was to compile information about the existing educational facilities for children with mental handicaps in the country. The study revealed that the majority of the educational facilities were managed by voluntary organisations and were found in urban areas. It was observed that there were more facilities in the southern states, and fewer in most of the northern and the northeastern regions.

We used the Ilizarov circular external fixator to treat 16 patients with persistent nonunion of the diaphysis of the humerus despite surgical treatment. All patients had pain and severe functional impairment of the affected arm. In ten, nonunion followed intramedullary nailing. We successfully treated these by a closed technique. The nail was left in place and the fracture compressed over it. The fractures of the other six patients had previously been fixed by various methods. We explored these nonunions, removed the fixation devices and excised fibrous tissue and dead bone before stabilising with the Ilizarov fixator. In five patients union was achieved. Bone grafting was not required. In the single patient in whom treatment failed, there had been a severely comminuted open fracture. All except one patient had reduction of pain, and all reported an improvement in function.

Uncertainty remains as to the role of decompressive craniectomy (DC) for primary evacuation of acute subdural haematomas (ASDH). In 2011, a collaborative group was formed in the UK with the aim of answering the following question: "What is the clinical- and cost-effectiveness of decompressive craniectomy, in comparison with craniotomy for adult patients undergoing primary evacuation of an ASDH?" The proposed RESCUE-ASDH trial (Randomised Evaluation of Surgery with Craniectomy for patients Undergoing Evacuation of Acute Subdural Haematoma) is a multicentre, pragmatic, parallel group randomised trial of DC versus craniotomy for adult head-injured patients with an ASDH. In this study, we used an online questionnaire to assess the current practice patterns in the management of ASDH in the UK and the Republic of Ireland, and to gauge neurosurgical opinion regarding the proposed RESCUE-ASDH trial.A questionnaire survey of full members of the Society of British Neurological Surgeons and members of the British Neurosurgical Trainees Association was undertaken between the beginning of May and the end of July 2012.The online questionnaire was answered by 95 neurosurgeons representing 31 of the 32 neurosurgical units managing adult head-injured patients in the UK and the Republic of Ireland. Forty-five percent of the respondents use primary DC in at least 25% of patients with ASDH. In addition, of the 22 neurosurgical units with at least two Consultant respondents, only three units (14%) showed intradepartmental agreement regarding the proportion of their patients receiving a primary DC for ASDH.The survey results demonstrate that there is significant uncertainty as to the optimal surgical technique for primary evacuation of ASDH. The fact that the majority of the respondents are willing to become collaborators in the planned RESCUE-ASDH trial highlights the relevance of this important subject to the neurosurgical community in the UK and Ireland.

Changes in the magnitude of the mitochondrial membrane potential occur in a range of important pathologies. To assess changes in membrane potential in patients, we set out to develop an improved mitochondria-targeted positron emission tomography probe comprising a lipophilic triphenylphosphonium cation attached to a fluorine-18 radionuclide via an 11-carbon alkyl chain, which is well-established to effectively transport to and localise within mitochondria. Here, we describe the radiosynthesis of this probe, 11-[(18) F]fluoroundecyl-triphenylphosphonium (MitoF), from no-carrier-added [(18) F]fluoride and a fully automated synthetic protocol to prepare it in good radiochemical yields (2-3 GBq at end-of-synthesis) and radiochemical purity (97-99%).

Raised intracranial pressure (ICP) is frequent and associated with poor outcome after severe traumatic brain injury (TBI). Information obtained by ICP monitoring allows early detection of high ICP and goal-directed therapy. There is a large body of clinical evidence showing that protocol driven neurocritical care improves outcomes after TBI. A monitoring method cannot be separated from therapeutic implications, which may have beneficial or deleterious consequences. ICP monitoring and guided therapy are not risk-free. A rational use of ICP as a guide to therapy must take into account of the absolute threshold for treatment, but also of the risk/benefit balance of the used intervention.

The aim of this study was to evaluate the effect of ventriculostomy on intracranial pressure (ICP), and related parameters, including cerebrospinal compensation, cerebral oxygenation (PbtO2) and metabolism (microdialysis) in patients with traumatic brain injury (TBI).Twenty-four patients with parenchymal ICP sensors were prospectively included in the study. Ventriculostomy was performed after failure to control ICP with initial measures. Monitoring parameters were digitally recorded before and after ventriculostomy and compared using appropriate tests.In all patients ventriculostomy led to rapid reduction in ICP. Pooled mean daily values of ICP remained20mmHg for 72h after ventriculostomy and were lower than before (p0.001). In 11 out of 24 patients during the initial 24-h period following ventriculostomy an increase in ICP to values exceeding 20mmHg was observed. In the remaining 13 patients ICP remained stable, allowing reduction in the intensity of treatment. In this group ventriculostomy led to significant improvement in craniospinal compensation (RAP index), cerebral perfusion pressure and PbtO2. Improvement in lactate/pyruvate ratio, a marker of energy metabolism, was correlated with the increase in PbtO2.Ventriculostomy is a useful ICP-lowering manoeuvre, with sustained ICP reduction and related physiological improvements achieved in50% of patients.

In recent years there has been renewed interest in the use of steroids in sepsis and septic shock, focusing on lower doses and longer courses with the aim of supplementing a presumed under-activity of the hypothalamic-pituitary-adrenal (HPA) axis due to relative adrenal insufficiency or target tissue glucocorticoid resistance. An international task force of the American College of Critical Care Medicine recently published guidelines for the diagnosis and treatment of what they termed “critical illness-related corticosteroid insufficiency” [1]. This paper makes important recommendations regarding steroid therapy in sepsis and acute respiratory distress syndrome (ARDS). The authors also suggested biochemical definitions of relative adrenal insufficiency. A rational approach would be to use such definitions to make decisions regarding corticosteroid supplementation in critical illness. However, the authors concluded that the available literature provides no evidence to use such biochemical parameters as a basis for treating patients with supplemental steroids. This discordance, in large part, may arise from the fact that classical concepts of the HPA axis ignore many important nuances of glucocorticoid production, bioavailability and cellular action. The purpose of this chapter is to explore these nuances with particular focus on cellular and regional mechanisms of regulation of corticosteroid action, with specific reference to the context of critical illness.

This paper presents a rationale for working with families who have children with disabilities in India. The various types of parent and family involvement which have been developed at the National Institute for the Mentally Handicapped are described. These include: individual programmes; group activities; family cottages; parent training programmes; sibling groups; and, self-help groups. Finally, the difficulties encountered in working with such families in India are discussed.

The heterogeneity of the initial insult and subsequent pathophysiology has made both the study of human head injury and design of randomised controlled trials exceptionally difficult. The combination of multimodality bedside monitoring and functional brain imaging positron emission tomography (PET) and magnetic resonance (MR), incorporated within a Neurosciences Critical Care Unit, provides the resource required to study critically ill patients after brain injury from initial ictus through recovery from coma and rehabilitation to final outcome. Methods to define cerebral ischemia in the context of altered cerebral oxidative metabolism have been developed, traditional therapies for intracranial hypertension re-evaluated and bedside monitors cross-validated. New modelling and analytical approaches have been developed.

There is mounting concern about the pressures experienced by University Departments of Anaesthesia, which, if lost, could threaten undergraduate peri-operative medicine teaching, development of critical appraisal skills among anaesthetists, and the future of coherent research programs. We have addressed these problems by establishing a foundation course in scientific methods and research techniques (the Cambridge SMART Course), complemented by competitive, fully funded, 12-month academic trainee attachments. Research conducted during academic attachments has been published and used to underpin substantive grant applications allowing work towards higher degrees. Following the attachment, a flexible scheme ensures safe reintroduction to clinical training. Research at consultant level is facilitated by encouraging applications for Clinician Scientist Fellowships, and by ensuring that the University Department champions, legitimises and validates the allocation of research time within the new consultant contract. We believe that these are important steps in safeguarding research and teaching in anaesthesia, critical care and peri-operative medicine.

Today's students are generally computer literate and have high expectations of university information technology resources. Most United Kingdom medical schools now provide networked computers for learning, research, communication and accessing the worldwide web. We have exploited these advances to augment and improve the teaching of peri-operative medicine and anaesthesia to medical students in our university, who are taught in several hospitals over a wide geographical area. Course material such as departmental induction information, lecture notes and assessment sheets can be accessed online, contributing to the smooth running of the course. Streamed videos and simulations allow students to familiarise themselves with common practical procedures in advance. Development of a web-based end of course assessment has resulted in substantially less administration and bureaucracy for course organisers and proved to be a valuable research tool. Students' and teachers' opinions of the new course structure have been overwhelmingly positive.

There has long been an appreciation that cerebral blood flow is modulated to ensure adequate cerebral oxygen delivery in the face of systemic hypoxaemia. There is increasing appreciation of the modulatory role of hyperoxia in the cerebral circulation and a consideration of the effects of such modulation on the maintenance of cerebral tissue oxygen concentration. These newer findings are particularly important in view of the fact that cerebrovascular and tissue oxygen responses to hyperoxia may change in disease. Such alterations provide important insights into pathophysiological mechanisms and may provide novel targets for therapy. However, before the modulatory effects of hyperoxia can be used for diagnosis, to predict prognosis or to direct therapy, a more detailed analysis and understanding of the physiological concepts behind this modulation are required, as are the limitations of the measurement tools used to define the modulation. This overview summarizes the available information in this area and suggests some avenues for further research.

A reduction in the arterial partial pressure of CO2 (PaCO2) leads to a rapid reduction in cerebral blood flow (CBF). However, despite continuing hypocapnia there is secondary recovery of CBF over time as a result of increases in lactic acid production. Hyperoxia is thought to modulate the production of lactic acid. This study examined the kinetics of middle cerebral artery flow velocity (MCA FV) reduction during hyperventilation, and its modulation by hyperoxia.Cerebral blood flow was assessed using transcranial Doppler ultrasound in nine healthy, awake human volunteers. Subjects were ventilated, via a mouthpiece, to achieve a stable end-tidal CO2 (PETCO2). After a 20-min baseline period the minute volume on the ventilator was passively increased by approximately 20% to reduce PETCO2 by 0.75-1 kPa. After a 10-min stabilization period the new PETCO2 level was maintained at a constant level for 20 min, and MCA FV recovery was measured during this 20-min period. Subjects undertook the protocol breathing air and breathing 100% oxygen.The PETCO2 level was (mean +/- SD) 4.9 +/- 0.4 kPa (normoxia baseline), 4.0 +/- 0.3 kPa (normoxia hyperventilation), 4.6 +/- 0.4 kPa (hyperoxia baseline) and 3.9 +/- 0.4 kPa (hyperoxia hyperventilation). CO2 reactivity was significantly lower with normoxia than hyperoxia (16.5 +/- 3.8 vs. 21.2 +/- 4.6 % kPa-1; P0.05). Middle cerebral artery FV recovery was significantly more rapid with normoxia than hyperoxia (0.23 +/- 0.17 vs. 0.08 +/- 0.1 % baseline min-1; P0.01).Our results suggest that cerebral hemodynamic responses to moderate hyperventilation are different in normoxic and hyperoxic conditions. Clinical assessment of CO2 reactivity and CBF recovery during hyperventilation should take the degree of arterial oxygenation into account.

Intra-arterial measurement is considered the gold standard for continuous, beat-to-beat arterial blood pressure monitoring. However, arterial cannulation can be difficult and may cause complications such as thrombosis and ischaemia. Recently, a tonometric system, the Colin CBM-7000 has been developed for noninvasive beat-to-beat measurement of arterial blood pressure from the radial artery. We assessed the level of agreement between the CBM-7000 and invasive radial artery measurements in 15 patients on a neuro-intensive care unit. Agreement of systolic, diastolic and mean arterial pressure values was limited, with approximately 34% of mean arterial pressures differing by over 10 mmHg. In many cases, this was due to a downward drift of the noninvasive measurements over time. Furthermore, there was a tendency to underestimate low pressures and overestimate high pressures. In our opinion, the Colin CBM-7000 cannot be recommended for continuous blood pressure monitoring in the intensive care setting.

Deliberate release of biological agents is a growing threat, but clinical recognition of the resulting diseases is hampered by their rarity and similar presentation to more common illnesses. Despite substantial publicity, access to information may be difficult. Further, the available data are fragmented and not always relevant to critical care settings. We describe the clinical presentations of some important infections, highlighting the features that are relevant to critically ill patients. We provide an integrated set of guidelines for diagnosis, patient care and infection control and have attempted to list important print- and web-based resources for further information.

Demand for magnetic resonance investigations in critically ill patients is increasing. While these patients frequently need ventilatory support, not all of them require controlled ventilation and many may be treated with continuous positive airway pressure. Controlled ventilation, with the concurrent need for sedation, may be inappropriate when airway physiology is being studied and may retard weaning. No commercially available ventilator designed for the magnetic resonance environment can deliver high flow continuous positive airway pressure. We tested the Caradyne Whisperflow flow generator and five Whisperflow valves (2.5-15 cmH2O airway pressure) within a 3 Tesla environment for safety and possible dysfunction. All components had minimal ferromagnetic properties and tests showed no clinically relevant change in flow delivery or oxygen concentration in the magnetic field. In addition, the airway pressure generated by the valves was not affected by the magnetic field. We conclude that the tested system can be safely used in a 3 Tesla magnetic resonance environment.

Promising pre-clinical results from laboratory studies of neuro-protective drugs for the treatment of patients with stroke and head injury have not been translated into benefit during clinical trials. The objective of the study was to assess the feasibility of administrating a potential neuro-protective drug (chlormethiazole) in conjunction with multimodality monitoring (including microdialysis) to patients with severe head injury in order to determine the effect of the agent on surrogate endpoints and penetration into the brain.Multimodality monitoring including cerebral and peripheral microdialysis was applied to five head-injured patients on the neuro-intensive care unit. Chlormethiazole (0.8%) was administered as a rapid (10 ml min(-1)) intravenous loading infusion for 5 min followed by a slow (1 ml min(-1)) continuous infusion for 60 min. The following parameters were monitored: heart rate, mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, peripheral oxygen saturation, continuous arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial temperature, cerebral tissue oxygen pressure, cerebral tissue carbon dioxide pressure, cerebral pH, cerebral temperature, electroencephalograph (EEG), bi-spectral index, plasma glucose, plasma chlormethiazole, and cerebral and peripheral microdialysis assay for chlormethiazole, glucose, lactate, pyruvate and amino acids.Despite achieving adequate plasma concentrations, chlormethiazole was not detected in the peripheral or cerebral microdialysis samples. The drug was well tolerated and did not induce hypotension, hyperglycaemia or withdrawal seizures. The drug did not change the values of the physiological or chemical parameters including levels of GABA, lactate/pyruvate ratio and glutamate. The drug did, however, induce EEG changes, including burst suppression in two patients.Chlormethiazole can be safely given to ventilated patients with severe head injury. There was no evidence of hypotension or withdrawal seizures. Combining a pilot clinical study of a neuro-protective agent with multimodality monitoring is feasible and, despite the lack of effect on physiological and chemical parameters in this study, may be a useful adjunct to the development of neuro-protective drugs in the future. Further investigation of the capability of microdialysis in this setting is required. By investigating the effect of a drug on surrogate end-points, it may be possible to identify promising agents from small pilot clinical studies before embarking on large phase III clinical trials.

We have assessed the performance of a series of ventilators (modified versions of the ventiPAC, paraPAC and babyPAC ventilators; SIMS pneuPAC Ltd, Luton, UK) in a magnetic resonance imaging (MRI) scanning environment, with MR safety and compatibility issues being addressed. Following initial modifications to remove ferromagnetic components and replace them with MR-safe materials, all three ventilators performed well in a series of tests in static magnetic fields up to 2 T. Ventilator performance was unaffected by static fields, switching gradients or radio frequency fields within the MR suite. Furthermore, the devices produced no degradation of image quality when used during MR scanning. We discuss management strategies for the care of critically ill ventilated patients during MR procedures.

It is widely held that the frontal cortex plays a critical part in certain aspects of spatial and non-spatial working memory. One unresolved issue is whether there are functionally distinct subdivisions of the lateral frontal cortex that subserve different aspects of working memory. The present study used positron emission tomography (PET) to demonstrate that working memory processes within the human mid-dorsolateral and mid-ventrolateral frontal regions are organized according to the type of processing required rather than according to the nature (i.e. spatial or non-spatial), of the information being processed, as has been widely assumed. Two spatial working memory tasks were used which varied in the extent to which they required different executive processes. During a 'spatial span' task that required the subject to hold a sequence of five previously remembered locations in working memory a significant change in blood-flow was observed in the right mid-ventrolateral frontal cortex, but not in the anatomically and cytoarchitectonically distinct mid-dorsolateral frontal-lobe region. By contrast, during a '2-back' task that required the subject to continually update and manipulate an ongoing sequence of locations within working memory, significant blood flow increases were observed in both mid-ventrolateral and mid-dorsolateral frontal regions. When the two working memory tasks were compared directly, the one that emphasized manipulation of information within working memory yielded significantly greater activity in the right mid-dorsolateral frontal cortex only. This dissociation provides unambiguous evidence that the mid-dorsolateral and mid-ventrolateral frontal cortical areas make distinct functional contributions to spatial working memory and corresponds with a fractionation of working memory processes in psychological terms.

Isolated pig hearts, subsequently perfused with pig or human blood, were prepared for the cytochemical demonstration of sites of hydrogen peroxide generation and increased vascular permeability. Oxidant stress was associated with ultrastructural changes commonly seen following myocardial reperfusion. In addition, the precipitation of cerium perhydroxide following perfusion with physiological saline containing cerium chloride suggested the vascular endothelium and leukocytes as sources of oxidants. This was associated with rapid penetration of horseradish peroxidase through the intercellular clefts of the vascular endothelium into the interstitial space, suggesting increased vascular leakiness at these sites. The rapid penetration of horseradish peroxidase was observed at all monitored periods of reperfusion with pig or human blood. This indicates that the increased permeability occurred during the ischaemic period and continued during reperfusion. Morphological damage was greatest in pig hearts reperfused with whole human blood and this was attenuated if the blood was preabsorbed to remove antibodies prior to reperfusion. We conclude that oxidant stress was initiated during ischaemia and continued during reperfusion in this model.

BackgroundThis study explored the relation of level of socio-economic development to the course of non-affective psychosis, by extending the analysis of urban/rural differences in course in Chandigarh, India.MethodThe proportion of ‘best outcome cases between urban (n=110) and rural (n=50) catchment areas were compared at two-year follow-up, separately for CATEGO S+ and non-S+ schizophrenia.ResultsThe proportion of subjects with ‘best outcome’ ratings at the urban and rural sites, respectively, was similar for CATEGO S+ schizophrenia (29 v. 29%), but significantly different for non-S+ psychosis (26 v. 47%)ConclusionsThe fact that in rural Chandigarh, psychoses have a more favourable course than in the urban area may be explained in large part by psychoses distinct from ‘nuclear’ schizophrenia.

Sedative drugs are widely used in intensive care, primarily in ventilated patients. The common actions and side-effects of these agents are widely recognised. However, recent evidence suggests that opiates and other sedative agents that are used in this situation also have important, but not widely appreciated, effects on metabolism, physiological signalling and disease mechanisms. Some of these effects are an extension of their expected therapeutic actions; these are being elucidated as the biological consequences of stress, and its suppression is now being clarified. An example is the central effects of benzodiazepines and opioids on metabolism and immune function. In other instances these drugs have important peripheral actions, with immunomodulatory or metabolic roles. Furthermore, some drugs may modify disease processes--an example being the antioxidant effect of propofol. Finally, basic cellular mechanisms, such as immediate early gene expression and transcription factor activation, may involve processes that may be susceptible to modification by sedative agents. Such secondary effects of sedative agents need to be investigated for three reasons. First, they provide explanations for some phenomena observed during their use. Second, some of the undesirable side-effects may be avoided by judicious use of drugs in certain clinical situations. Finally, there is the prospect that we may be able to harness some actions for novel therapeutic purposes.

Coagulation and fibrinolytic activities were studied in 18 subjects with Behçet's disease and compared with results from 14 matched control patients suffering from sero-negative arthritis. Significantly higher plasma concentrations (median and range) were found in Behçet's patients for the following variables: fibrinogen 3.7 (1.7-6.9) vs 3.0 (2.0-5.1) g/l, p less than 0.05; von Willebrand factor antigen, 115 (72-344) vs 74 (60-119)%, p less than 0.002; plasminogen activator activity (10(6)/ECLT2) 219 (94-329) vs 137 (78-197) units, p less than 0.002; tissue plasminogen activator inhibitor (t-PA-I) activity, 9.1 (5.5-19.3) vs 5.1 (1.8-12.0) IU/ml, p less than 0.002; and PAI-1 antigen, 13.9 (4.5-20.9) vs 6.4 (2.4-11.1) ng/ml, p less than 0.002. Protein C antigen was significiantly lower: 97 (70-183) vs 126 (96-220)%, p less than 0.02. No differences were observed in antithrombin III activity or antigen, factor VIII coagulant activity, fibrinopeptides A and B beta 15-42, plasminogen, alpha-2-antiplasmin, functional and immunological tissue-plasminogen activator, thrombin-antithrombin complexes and D-dimer. Levels of tissue plasminogen activator inhibitor (activity and antigen) correlated with disease activity while fibrinogen and von Willebrand factor concentrations did not. Seven of the 18 subjects with Behçet's disease had suffered thrombotic events but it was not possible to distinguish these from the 11 patients without thrombosis using the assays performed. The results suggest the abnormal fibrinolytic activity in Behçet's disease is due to increased inhibition of tissue plasminogen activator. No abnormality of coagulation or fibrinolytic activity specific to Behçet's disease was detected.

A two-year follow-up was conducted of a subsample of the Chandigarh cohort of first-contact schizophrenic patients from the WHO Determinants of Outcome project. The patients were those living with family members who had been interviewed initially to determine their levels of expressed emotion (EE). The interview was repeated for 74% of the relatives at one-year follow-up. A dramatic reduction had occurred in each of the EE components and in the global index. No rural relative was rated as high EE at follow-up. Of the patients included in the one-year follow-up, 86% were followed for two years. In contrast to the one-year findings, the global EE index at initial interview did not predict relapse of schizophrenia over the subsequent two years. However, there was a significant association between initial hostility and subsequent relapse. The better outcome of this cohort of schizophrenic patients compared with samples from the West is partly attributable to tolerance and acceptance by family members.

We conducted a one-year follow-up of patients who had made a first contact with psychiatric services in Chandigarh, North India, and had been assigned a diagnosis of schizophrenia. The expressed emotion (EE) of the patients' relatives was assessed early on. We found the same associations between the individual components of EE and relapse of schizophrenia as in previous Anglo-American studies, but only the association between hostility and relapse was statistically significant. Applying the same criteria as in the Anglo American studies for ‘high EE’, we found a significant relationship between high EE and relapse. This relationship was not explained by other factors often associated with higher relapse rates. We conclude that the significantly better outcome of Chandigarh first-contact patients compared with a London sample is largely due to the significantly lower proportion of high-EE relatives in the North Indian sample.