Alarmins and Their Receptors as Modulators and Indicators of Alloimmune Responses.

Cell damage and death releases alarmins, self-derived immunomodulatory molecules that recruit and activate the immune system. Unfortunately, numerous processes critical to the transplantation of allogeneic materials result in the destruction of donor and recipient cells and may trigger alarmin release. Alarmins, often described as damage-associated molecular patterns, together with exogenous pathogen-associated molecular patterns, are potent orchestrators of immune responses; however, the precise role that alarmins play in alloimmune responses remains relatively undefined. We examined evolving concepts regarding how alarmins affect solid organ and allogeneic hematopoietic cell transplantation outcomes and the mechanisms by which self molecules are released. We describe how, once released, alarmins may act alone or in conjunction with nonself materials to contribute to cytokine networks controlling alloimmune responses and their intensity. It is becoming recognized that this class of molecules has pleotropic functions, and certain alarmins can promote both inflammatory and regulatory responses in transplant models. Emerging evidence indicates that alarmins and their receptors may be promising transplantation biomarkers. Developing the therapeutic ability to support alarmin regulatory mechanisms and the predictive value of alarmin pathway biomarkers for early intervention may provide opportunities to benefit graft recipients.

Effects of pneumoperitoneum and Trendelenburg position on intracranial pressure assessed using different non-invasive methods.

BACKGROUND: The laparoscopic approach is becoming increasingly frequent for many different surgical procedures. However, the combination of pneumoperitoneum and Trendelenburg positioning associated with this approach may increase the patient's risk for elevated intracranial pressure (ICP). Given that the gold standard for the measurement of ICP is invasive, little is known about the effect of these common procedures on ICP. METHODS: We prospectively studied 40 patients without any history of cerebral disease who were undergoing laparoscopic procedures. Three different methods were used for non-invasive estimation of ICP: ultrasonography of the optic nerve sheath diameter (ONSD); transcranial Doppler-based (TCD) pulsatility index (ICPPI); and a method based on the diastolic component of the TCD cerebral blood flow velocity (ICPFVd). The ONSD and TCD were measured immediately after induction of general anaesthesia, after pneumoperitoneum insufflation, after Trendelenburg positioning, and again at the end of the procedure. RESULTS: The ONSD, ICPFVd, and ICPPI increased significantly after the combination of pneumoperitoneum insufflation and Trendelenburg positioning. The ICPFVd showed an area under the curve of 0.80 [95% confidence interval (CI) 0.70-0.90] to distinguish the stage associated with the application of pneumoperitoneum and Trendelenburg position; ONSD and ICPPI showed an area under the curve of 0.75 (95% CI 0.65-0.86) and 0.70 (95% CI 0.58-0.81), respectively. CONCLUSIONS: The concomitance of pneumoperitoneum and the Trendelenburg position can increase ICP as estimated with non-invasive methods. In high-risk patients undergoing laparoscopic procedures, non-invasive ICP monitoring through a combination of ONSD ultrasonography and TCD-derived ICPFVd could be a valid option to assess the risk of increased ICP.

Acute Posterior Cranial Fossa Hemorrhage-Is Surgical Decompression Better than Expectant Medical Management?

BACKGROUND: To compare the in-hospital mortality and institutional morbidity from medical therapy (MT), external ventricular drainage (EVD) and suboccipital decompressive craniectomy (SDC) following an acute hemorrhagic posterior cranial fossa stroke (PCFH) in patients admitted to the neurosciences critical care unit (NCCU). Retrospective observational single-center cohort study in a tertiary care center. All consecutive patients (n = 104) admitted with PCFH from January 1st 2005-December 31st 2011 were included in the study. METHODS: All patients with a PCFH were identified and confirmed by reviewing computed tomography of the brain reported by a specialist neuroradiologist. Management decisions (MT, EVD, and SDC) were identified from operative notes and electronic patient records. RESULTS: Following a PCFH, 47.8 % (n = 11) patients died after EVD placement without decompression, 45.7 % (n = 16) died following MT alone, and 17.4 % (n = 8) died following SDC. SDC was associated with lower mortality compared to MT with or without EVD (χ 2 test p = 0.006, p = 0.008). Age, ICNARC score, brain stem involvement, and hematoma volume did not differ significantly between the groups. There was a statistically significant increase in hydrocephalus and intraventricular bleeds in patients treated with EVD placement and SDC (χ 2 test p = 0.02). Median admission Glasgow Coma Scale scores for the MT only, MT with EVD, and SDC groups were 8, 6, and 7, respectively (ranges 3-15, 3-11 and 3-13) and did not differ significantly (Friedman test: p = 0.89). SDC resulted in a longer NCCU stay (mean of 17.4 days, standard deviation = 15.4, p < 0.001) and increased incidence of tracheostomy (50 vs. 17.2 %, p = 0.0004) compared to MT with or without EVD. CONCLUSIONS: SDC following PCFH was associated with a reduction in mortality compared to expectant MT with or without EVD insertion. A high-quality multicenter randomized control trial is required to evaluate the superiority of SDC for PCFH.

Intraoperative non invasive intracranial pressure monitoring during pneumoperitoneum: a case report and a review of the published cases and case report series.

Non-invasive measurement of ICP (nICP) can be warranted in patients at risk for developing increased ICP during pneumoperitoneum (PP). Our aim was to assess available data on the application of nICP monitoring during these procedures and to present a patient assessed with an innovative combination of noninvasive tools. Literature review of nICP assessment during PP did not find any studies comparing different methods intraprocedurally and only few studies of any nICP monitoring were available: transcranial Doppler (TCD) studies used the pulsatility index (PI) as an estimator of ICP and failed to detect a significant ICP increase during PP, whereas two out of three optic nerve sheath diameter (ONSD) studies detected a statistically significant ICP increase. In the case study, we describe a 52 year old man with a high grade thalamic glioma who underwent urgent laparoscopic cholecystectomy. Considering the high intraoperative risk of developing intracranial hypertension, he was monitored through parallel ONSD ultrasound measurement and TCD derived formulae (flow velocity diastolic formula, FVdnICP, and PI). ONSD and FVdnICP methods indicated a significant ICP increase during PP, whereas PI was not significantly increased. Our experience, combined with the literature review, seems to suggest that PI might not detect ICP changes in this context, however we indicate a possible interest of nICP monitoring during PP by means of ONSD and of TCD derived FVdNICP, especially for patients at risk for increased ICP.

Longitudinal assessment of hepatitis C fibrosis progression by collagen and smooth muscle actin morphometry in comparison to serum markers.

BACKGROUND: Assessment of fibrosis progression in chronic liver disease relies upon non-invasive tools and changes in semi-quantitative histopathology scores that may not be reliable. AIM: To assess the diagnostic performance of the FibroSURE (FS) index and collagen/alpha smooth muscle actin (α-SMA) morphometry in relation to longitudinal changes in fibrosis on paired biopsies. METHODS: The study cohort included 201 chronic hepatitis C (CHC) nonresponders enrolled in a prior phase II anti-fibrotic study. Serum FS and paired biopsies, with both collagen and α-SMA morphometry, were evaluated at baseline and week 52. RESULTS: Study patients were mostly male (67%) and Caucasian (77%), with Ishak stages 2 (n = 79), 3 (n = 88) and 4 (n = 30), excluded (n = 4 stage 1 or 5). Mean biopsy length was 22.9 mm. For baseline Ishak 2/3 vs. 4, there were no significant differences in AUROCs for collagen (0.71), SMA (0.66) or FS (0.70). At week 52, 62% of patients had no change in Ishak stage, but collagen/α-SMA increased by 34-51% (P < 0.0001), and FS decreased by 5% (P = 0.008). Among the 33% of patients with +/-1 Ishak stage change, FS changes were not significant, but α-SMA increased 29-72%, and collagen increased by 12-38% (P = 0.01 for +1 only). CONCLUSIONS: Longitudinal changes in collagen and α-SMA morphometry are apparent prior to change in histological stage or FibroSURE in CHC nonresponders with intermediate fibrosis. This likely reflects quantitative morphological differences that are not detected by routine histological staging or serum markers such as FibroSURE.

DAP12 deficiency in liver allografts results in enhanced donor DC migration, augmented effector T cell responses and abrogation of transplant tolerance.

Liver interstitial dendritic cells (DC) have been implicated in immune regulation and tolerance induction. We found that the transmembrane immuno-adaptor DNAX-activating protein of 12 kDa (DAP12) negatively regulated conventional liver myeloid (m) DC maturation and their in vivo migratory and T cell allostimulatory ability. Livers were transplanted from C57BL/6(H2(b) ) (B6) WT or DAP12(-/-) mice into WT C3H (H2(k) ) recipients. Donor mDC (H2-K(b+) CD11c(+) ) were quantified in spleens by flow cytometry. Anti-donor T cell reactivity was evaluated by ex vivo carboxyfluorescein diacetate succinimidyl ester-mixed leukocyte reaction and delayed-type hypersensitivity responses, while T effector and regulatory T cells were determined by flow analysis. A threefold to fourfold increase in donor-derived DC was detected in spleens of DAP12(-/-) liver recipients compared with those given WT grafts. Moreover, pro-inflammatory cytokine gene expression in the graft, interferon gamma (IFNγ) production by graft-infiltrating CD8(+) T cells and systemic levels of IFNγ were all elevated significantly in DAP12(-/-) liver recipients. DAP12(-/-) grafts also exhibited reduced incidences of CD4(+) Foxp3(+) cells and enhanced CD8(+) T cell IFNγ secretion in response to donor antigen challenge. Unlike WT grafts, DAP12(-/-) livers failed to induce tolerance and were rejected acutely. Thus, DAP12 expression in liver grafts regulates donor mDC migration to host lymphoid tissue, alloreactive T cell responses and transplant tolerance.

Leg ulcers in patients with ß-thalassaemia intermedia: a single centre's experience.

BACKGROUND: Leg ulcers in ß-thalassaemia intermedia (TI) patients are a relatively common occurrence that have an 8% prevalence. Both the pathophysiology and treatment of this condition have not been well-elucidated. This is mainly because of the rarity of the disease and the lack of well-structured studies. The goal of this study was to better explore the risk factors for the development of this condition along with the treatment options available. METHODS: We present 11 such cases that have occurred in 6 ß-TI patients over the course of 19 years who are followed up at the Chronic Care Center of Lebanon. RESULTS: Our patient population comprised three men and three women aged between 25 and 58, most of whom had iron overload and with an average lifetime haemoglobin ranging between 49 g/L and 77 g/L. Most of the patients were treated with blood transfusions with varying degrees of success. Nonetheless, some received Hydroxyurea, granulocyte macrophage colony-stimulating factor (GM-CSF) or topical antibiotics. CONCLUSION: Our results show that chelation therapy, hydroxyurea use and blood transfusions are beneficial in the treatment of this condition. Whether foetal haemoglobin is directly related to the development of the ulcers is not clear based on our results. Larger studies are needed to better explore the risk factors that predispose patients to this condition.

Liver function test abnormalities after traumatic brain injury: is hepato-biliary ultrasound a sensitive diagnostic tool?

BACKGROUND: This study was to evaluate the usefulness of hepato-biliary ultrasound (HBUS) for the investigation of isolated liver function tests (LFTs) abnormalities. METHODS: We retrospectively reviewed HBUS reports in traumatic brain injury (TBI) patients admitted to our tertiary neuro-critical care unit (NCCU; January 2005-June 2011). We included patients receiving an HBUS for isolated LFTs derangement, excluding pre-existing hepato-biliary diseases or trauma. We assessed the temporal profile of alanine aminotransferase (ALT), bilirubin (Bil), and alkaline phosphatase (ALP). RESULTS: Of 511 patients, 58 received an HBUS. Of these, 47 were investigated for isolated LFTs derangement; HBUS always failed to identify a cause for these abnormalities. The HBUS was performed on day 18 (range 6-51) with the following mean values: 246 IU litre(-1) [ALT, 95% confidence interval (CI) 183-308], 24 µmol litre(-1) (Bil, 95% CI 8-40), and 329 IU litre(-1) (ALP, 95% CI 267-390); only ALT (72, 95% CI 36-107) and ALP (73, 95% CI 65-81) were deranged from admission values (both P<0.01). At NCCU discharge, both ALT (160, 95% CI 118-202) and ALP (300, 95% CI 240-360) were higher than at admission (P<0.01). Compared with HBUS-day value, only ALT improved by NCCU discharge (P<0.05), while both were recovering by hospital discharge (ALT 83, 95% CI 59-107; ALP 216, 95% CI 181-251; P<0.01). At hospital discharge, ALP remained higher than at admission (P<0.01). CONCLUSIONS: In TBI patients, HBUS did not appear sensitive in detecting causes for isolated LFT abnormalities. Both ALT and ALP worsened and gradually recovered. Their abnormalities did not prevent NCCU discharge. ALP recovered more slowly than ALT. TBI and its complications, critical illness, and pharmacological strategies may explain the LFTs derangement.

An interspecific QTL study of Drosophila wing size and shape variation to investigate the genetic basis of morphological differences.

The Drosophila wing has been used as a model in studies of morphogenesis and evolution; the use of such models can contribute to our understanding of mechanisms that promote morphological divergence among populations and species. We mapped quantitative trait loci (QTL) affecting wing size and shape traits using highly inbred introgression lines between D. simulans and D. sechellia, two sibling species of the melanogaster subgroup. Eighteen QTL peaks that are associated with 12 wing traits were identified, including two principal components. The wings of D. simulans and D. sechellia significantly diverged in size; two of the QTL peaks could account for part of this interspecific divergence. Both of these putative QTLs were mapped at the same cytological regions as other QTLs for intraspecific wing size variation identified in D. melanogaster studies. In these regions, one or more loci could account for intra- and interspecific variation in the size of Drosophila wings. Three other QTL peaks were related to a pattern of interspecific variation in wing size and shape traits that is summarized by one principal component. In addition, we observed that female wings are significantly larger and longer than male wings and the second, fourth and fifth longitudinal veins are closer together at the distal wing area. This pattern was summarized by another principal component, for which one QTL was mapped.

Investigation and management of an outbreak of multidrug-carbapenem-resistant Acinetobacter baumannii in Cambridge, UK.

Multidrug-resistant Acinetobacter baumannii resistant to carbapenems (MRAB-C) has become endemic in many hospitals in the UK. We describe an outbreak of MRAB-C that occurred on two intensive care units using ORION criteria (Outbreak Reports and Intervention studies Of Nosocomial infection). All patients colonised or infected with MRAB-C were included. Enhanced infection control precautions were introduced in Phase 1 of the outbreak. The adult neurosciences critical care unit (NCCU) was partially closed in Phase 2 and strict patient segregation, barrier nursing and screening thrice weekly was introduced. When control was achieved, NCCU was reopened (Phase 3) with post-discharge steam cleaning and monthly cleaning of extract and supply vents. There were 19 cases, 16 on NCCU and three on the general intensive care unit (ICU). Mean age was 52 years, with six cases being female. All patients were mechanically ventilated and ten had either an extraventricular drain or intracranial pressure monitoring device in place. Four patients developed a bacteraemia, with one further case of ventriculitis. Nine patients had no clinical evidence of infection and four were identified initially on screening. Ten patients were treated; there were eight deaths. Environmental samples showed heavy contamination throughout NCCU. MRAB-C affects critically ill patients and is associated with high mortality. This outbreak was controlled by early involvement of management, patient segregation, screening of patients and the environment, and increased hand hygiene environmental cleaning and clinical vigilance. A multidisciplinary approach to outbreak control is mandatory.

Cerebrovascular reactivity during hypothermia and rewarming.

BACKGROUND: Experimental evidence from a murine model of traumatic brain injury (TBI) suggests that hypothermia followed by fast rewarming may damage cerebral microcirculation. The effects of hypothermia and subsequent rewarming on cerebral vasoreactivity in human TBI are unknown. METHODS: This is a retrospective analysis of data acquired during a prospective, observational neuromonitoring and imaging data collection project. Brain temperature, intracranial pressure (ICP), and cerebrovascular pressure reactivity index (PRx) were continuously monitored. RESULTS: Twenty-four TBI patients with refractory intracranial hypertension were cooled from 36.0 (0.9) to 34.2 (0.5) degrees C [mean (sd), P < 0.0001] in 3.9 (3.7) h. Induction of hypothermia [average duration 40 (45) h] significantly reduced ICP from 23.1 (3.6) to 18.3 (4.8) mm Hg (P < 0.05). Hypothermia did not impair cerebral vasoreactivity as average PRx changed non-significantly from 0.00 (0.21) to -0.01 (0.21). Slow rewarming up to 37.0 degrees C [rate of rewarming, 0.2 (0.2) degrees C h(-1)] did not increase ICP [18.6 (6.2) mm Hg] or PRx [0.06 (0.18)]. However, in 17 (70.1%) out of 24 patients, rewarming exceeded the brain temperature threshold of 37 degrees C. In these patients, the average brain temperature was allowed to increase to 37.8 (0.3) degrees C (P < 0.0001), ICP remained stable at 18.3 (8.0) mm Hg (P = 0.74), but average PRx increased to 0.32 (0.24) (P < 0.0001), indicating significant derangement in cerebrovascular reactivity. After rewarming, PRx correlated independently with brain temperature (R = 0.53; P < 0.05) and brain tissue O2 (R = 0.66; P < 0.01). CONCLUSIONS: After moderate hypothermia, rewarming exceeding the 37 degrees C threshold is associated with a significant increase in average PRx, indicating temperature-dependent hyperaemic derangement of cerebrovascular reactivity.

Attitudes of anaesthetists to awareness and depth of anaesthesia monitoring in the UK.

BACKGROUND AND OBJECTIVE: Awareness with postoperative recall of intraoperative events is a rare but serious complication of general anaesthesia. This survey investigated the attitude of anaesthetists in the UK to awareness and depth of anaesthesia monitoring. METHODS: Questionnaires were sent to 4927 consultant anaesthetists in 285 hospitals in the UK in September 2004. The responses were recorded in an electronic database, summarized and compared with the results of studies performed in Australia and the USA. RESULTS: The response rate was 44%. When judged against published awareness rates, anaesthetists underestimated the incidence of awareness in their own practice (median 1: 5000). One-third of respondents have dealt with patients who have experienced intraoperative recall. The majority of anaesthetists perceived awareness as a minor problem on an 11-point scale (modal score 2, median score 3, IQR 2-5). Eighty-six percent of anaesthetists considered clinical signs unreliable but 91% felt that measurement of end-tidal anaesthetic agent concentration reduces the likelihood of awareness. The majority of anaesthetists would use a monitor at least some of the time if one was available to them. Overall, the attitudes of anaesthetists in the UK, USA and Australia are remarkably similar. CONCLUSIONS: Anaesthetists tend not to view awareness as a serious problem. Although most accept that clinical signs are unreliable indicators of awareness, few believe that monitors of anaesthetic depth should be used for routine cases.

Incidence of adrenal insufficiency after severe traumatic brain injury varies according to definition used: clinical implications.

BACKGROUND: Adrenal insufficiency impacts on the haemodynamic management of patients in intensive care. Very little is known about the incidence of adrenal insufficiency in the first 10 days after traumatic brain injury. METHODS: We retrospectively reviewed the charts of 113 traumatic brain injury patients within 10 days of their injury. They all had a high-dose corticotropin stimulation test performed because of haemodynamic instability. Blood cortisol concentrations were measured at baseline, 30 and 60 min after the administration of high-dose corticotropin. The incidence of adrenal insufficiency was determined according to various definitions used in the literature. RESULTS: The baseline cortisol concentration was <414 nmol litre(-1) (15 microg dl(-1)) in 78% of patients and <690 nmol litre(-1) (25 microg dl(-1)) in all patients. The cortisol concentration did not rise above 500 nmol litre(-1) (18 microg dl(-1)) at 30 and 60 min in 49 and 22% of patients, respectively. The cortisol concentration did not rise by 250 nmol litre(-1) (9 microg dl(-1)) at 30 and 60 min in 48 and 25% of patients respectively. Primary adrenal insufficiency defined by an abnormal baseline cortisol concentration and an abnormal response to the high-dose corticotropin stimulation test was present in 13-28% of patients according to the cut-off values used. CONCLUSIONS: The incidence of adrenal insufficiency varies from 25 to 100% in the first 10 days after traumatic brain injury. The range of incidences reported illustrates the need for standardization of the definition of adrenal insufficiency. This has a direct impact on treatment. Sampling at 60 min after the high-dose corticotropin stimulation test seems to correlate better with the maximum secreting capacity of the adrenal glands.

The health economics of blood use in cerebrovascular aneurysm surgery: the experience of a UK centre.

BACKGROUND AND OBJECTIVE: Surgical treatment of patients presenting with subarachnoid haemorrhage secondary to a leaking cerebrovascular aneurysm involves coiling or clipping. Traditionally all patients undergoing this procedure are cross-matched routinely. With ever-increasing strains on the health budget and transfusion services in particular, as well as the real, albeit low risk of transfusion transmitted disease, we propose that a simple 'group and save', coupled with a reliable 'fast-issue' blood transfusion service should replace this outdated concept. METHOD: To assess this assumption, we carried out a retrospective analysis of 103 patients who underwent clipping or coiling during January to December 2001 in our Neurosurgical Unit. RESULTS: All patients but one had been cross-matched (99%). However, only 33 patients (32%) eventually required a blood transfusion. In real terms, this meant a total of 294 units of blood that had been cross-matched routinely, in our series of 103 patients, were not used. Had these patients only been 'group and saved' and a system of 'fast-issue' been adopted, assuming that none of the patients had abnormal antibodies, the blood transfusion department would have made a saving of 4815.72 pounds sterling for this group of patients. CONCLUSION: We conclude that advances in surgical technique have made routine cross-matching of blood in cerebral aneurysm surgery unnecessary.

Acute and chronic pain following craniotomy: a review.

Postoperative pain is an important clinical problem that has received increasing attention in recent years. However, pain following craniotomy has been a comparatively neglected topic; this review seeks to redress this imbalance. A brief overview of the anatomy of the skull and its linings is given, with particular reference to innervation. The various approaches for craniotomies are classified, with their association with acute and long-term effects on analgesic requirements. A comprehensive search of the literature was undertaken to ascertain the incidence of acute pain post craniotomy and current thoughts on pharmacological management, touching briefly on pre-emptive treatment. Also discussed is the much neglected but nevertheless real incidence of chronic pain following craniotomy and its underlying pathogenesis, prevention and treatment.

Association between outcome, cerebral pressure reactivity and slow ICP waves following head injury.

OBJECTIVE: To investigate the relationships between slow vasogenic waves ('B waves') of intracranial pressure (ICP), pressure-reactivity and outcome after traumatic brain injury. MATERIAL AND METHOD: 193 head-injured patients (age 34 +/- 16.7 years; median GCS 6) were monitored from 1997 to 2002. ICP, arterial blood pressure (ABP) were continuously monitored. Pressure-reactivity index (PRx) and magnitude of ICP slow waves were evaluated using the bed-side computers. RESULTS: Distribution of PRx in different outcome groups indicated that pressure-reactivity was significantly worse in patients with fatal outcome. A magnitude of spontaneous slow waves of ICP was gradually decreasing in poorer outcome grades. Mortality indicated threshold rise from 20% to 70% when averaged PRx increased above 0.3 (p < 0.01). There was no threshold for mortality observed along distribution of magnitude of ICP slow waves. Mortality gradually increased when the magnitude of slow waves decreased (R = -0.26; p < 0.0001). CONCLUSION: Inadequate pressure-reactivity and low magnitude of slow vasogenic waves of ICP are associated with fatal outcome after head injury. Based on brain monitoring data, differentiation between favourable outcome and severe disability is more problematic than differentiation between survivors and non-survivors.

Cerebral blood flow augmentation in patients with severe subarachnoid haemorrhage.

Following aneurysmal subarachnoid haemorrhage (SAH), cerebral blood flow (CBF) may be reduced, resulting in poor outcome due to cerebral ischaemia and subsequent stroke. Hypertonic saline (HS) is known to be effective in reducing intracranial pressure (ICP). We have previously shown a 20-50% increase in CBF in ischaemic regions after intravenous infusion of HS. This study aims to determine the effect of HS on CBF augmentation, substrate delivery and metabolism. Continuous monitoring of arterial blood pressure (ABP), ICP, cerebral perfusion pressure (CPP), brain tissue oxygen (PbO2), middle cerebral artery flow velocity (FV), and microdialysis was performed in 14 poor grade SAH patients. Patients were given an infusion of 23.5% HS, and quantified xenon computerised tomography scanning (XeCT) was carried out before and after the infusion in 9 patients. The results showed a significant increase in ABP, CPP, FV and PbO2, and a significant decrease in ICP (p < 0.05). Nine patients showed a decrease in lactate-pyruvate ratio at 60 minutes following HS infusion. These results show that HS safely and effectively augments CBF in patients with poor grade SAH and significantly improves cerebral oxygenation. An improvement in cerebral metabolic status in terms of lactate-pyruvate ratio is also associated with HS infusion.

Genetic architecture of wing morphology in Drosophila simulans and an analysis of temperature effects on genetic parameter estimates.

The Drosophila wing has been used as a model to investigate the mechanisms responsible for size and shape changes in nature, since such changes might underlie morphological evolution. To improve the understanding of wing morphological variation and the interpretation of genetic parameters estimates, we have established 59 lines from a Drosophila simulans laboratory population through single pair random matings. The offspring of each line were reared at three different temperatures, and the wing morphology of 12 individuals was analyzed by adjusting an ellipse to the wings' contour. Temperature, sex and line significantly affected wing trait variation, which was mainly characterized by longer wings having the second, fourth and fifth longitudinal veins closer together at the wing tip. As for the genetic parameter estimates, while the cross-environment heritability of some traits, such as wing size (SI), decreased with an increasing difference between the temperatures at which parents and offspring were reared, wing shape (SH) heritability did not seem to change. Since we found indications that neither an increase in the phenotypic variation nor the occurrence of genotype-environment interactions could fully explain the low heritabilities of SI estimated by cross-environment regressions, we discuss the importance of other effects for explaining this discrepancy between the SI and SH heritability estimates. In addition, although the genetic matrix was not entirely represented in the phenotypic matrix, several correspondences were identified, suggesting that the observed patterns of wing morphology variation are genetically controlled.

Integrated approaches to academic anaesthesia - the Cambridge experience.

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.

Intracranial hypertension: what additional information can be derived from ICP waveform after head injury?

OBJECTIVE: Although intracranial hypertension is one of the important prognostic factors after head injury, increased intracranial pressure (ICP) may also be observed in patients with favourable outcome. We have studied whether the value of ICP monitoring can be augmented by indices describing cerebrovascular pressure-reactivity and pressure-volume compensatory reserve derived from ICP and arterial blood pressure (ABP) waveforms. METHOD: 96 patients with intracranial hypertension were studied retrospectively: 57 with fatal outcome and 39 with favourable outcome. ABP and ICP waveforms were recorded. Indices of cerebrovascular reactivity (PRx) and cerebrospinal compensatory reserve (RAP) were calculated as moving correlation coefficients between slow waves of ABP and ICP, and between slow waves of ICP pulse amplitude and mean ICP, respectively. The magnitude of 'slow waves' was derived using ICP low-pass spectral filtration. RESULTS: The most significant difference was found in the magnitude of slow waves that was persistently higher in patients with a favourable outcome (p<0.00004). In patients who died ICP was significantly higher (p<0.0001) and cerebrovascular pressure-reactivity (described by PRx) was compromised (p<0.024). In the same patients, pressure-volume compensatory reserve showed a gradual deterioration over time with a sudden drop of RAP when ICP started to rise, suggesting an overlapping disruption of the vasomotor response. CONCLUSION: Indices derived from ICP waveform analysis can be helpful for the interpretation of progressive intracranial hypertension in patients after brain trauma.