The effect of a low-dose naloxone infusion on the incidence of respiratory depression after intrathecal morphine administration for major open hepatobiliary surgery: a randomised controlled trial.

Intrathecal morphine is an analgesic option for major hepatopancreaticobiliary procedures but is associated with a risk of respiratory depression. We hypothesised that a postoperative low-dose naloxone infusion would reduce the incidence of respiratory depression without an increase in pain scores. Patients scheduled for major open hepatopancreaticobiliary surgery and who were receiving 10 µg.kg-1 intrathecal morphine were eligible for inclusion. Patients were allocated randomly to receive a postoperative infusion of naloxone 5 µg.kg-1 .h-1 (naloxone group) or saline at an identical infusion rate (control group) until the morning after surgery. Clinicians, nursing staff and patients were blinded to group allocation. The primary outcome measure was the incidence of respiratory depression (respiratory rate < 10 breaths.min-1 and/or oxygen saturation < 90%). Secondary outcome measures included: arterial partial pressure of carbon dioxide; pain score; requirement for supplemental analgesic; and incidence of nausea and vomiting, pruritus and sedation. In total, data from 95 patients (48 in the naloxone group and 47 in the control group) were analysed. The incidence of respiratory depression was lower in the naloxone group compared with the control group (10/48 vs. 21/47 patients, respectively; p = 0.037, relative risk 0.47 (95%CI 0.25-0.87). Maximum pain scores were greater for patients allocated to the naloxone group compared with control (median 5 (95%CI 4-6) vs. 4 (95%CI 2-4), respectively; p < 0.001). A low-dose naloxone infusion decreases the incidence of respiratory depression following intrathecal morphine administration in patients having major hepatopancreaticobiliary surgery at the expense of a small increase in postoperative pain.

Novelty and anxiolytic drugs dissociate two components of hippocampal theta in behaving rats.

Hippocampal processing is strongly implicated in both spatial cognition and anxiety and is temporally organized by the theta rhythm. However, there has been little attempt to understand how each type of processing relates to the other in behaving animals, despite their common substrate. In freely moving rats, there is a broadly linear relationship between hippocampal theta frequency and running speed over the normal range of speeds used during foraging. A recent model predicts that spatial-translation-related and arousal/anxiety-related mechanisms of hippocampal theta generation underlie dissociable aspects of the theta frequency-running speed relationship (the slope and intercept, respectively). Here we provide the first confirmatory evidence: environmental novelty decreases slope, whereas anxiolytic drugs reduce intercept. Variation in slope predicted changes in spatial representation by CA1 place cells and novelty-responsive behavior. Variation in intercept predicted anxiety-like behavior. Our findings isolate and doubly dissociate two components of theta generation that operate in parallel in behaving animals and link them to anxiolytic drug action, novelty, and the metric for self-motion.

Systemic gene dysregulation in classical Galactosaemia: Is there a central mechanism?

Classical Galactosaemia is a rare disorder of carbohydrate metabolism caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT). The disease is life-threatening in the neonate, and the only treatment option is life-long dietary restriction of galactose. However, long-term complications persist in treated patients including cognitive impairments, speech and language abnormalities and premature ovarian insufficiency in females. Microarray analysis of T-lymphocytes from treated adult patients identified systemic dysregulation of numerous gene pathways, including the glycosylation, inflammatory and inositol pathways. Analysis of gene expression in patient-derived dermal fibroblasts of patients exposed to toxic levels of galactose, with immunostaining, has further identified the susceptibility of the glycosylation gene alpha-1,2-mannosyltransferase (ALG9) and the inflammatory gene annexin A1 (ANXA1) to increased galactose concentrations. These data suggest that Galactosaemia is a multi-system disorder affecting numerous signalling pathways.

Prognostic significance of neuroepithelial transforming gene 1 in adenocarcinoma of the oesophagogastric junction.

BACKGROUND: Neuroepithelial transforming gene 1 (NET1) mediates tumour invasion and metastasis in a number of cancers, including gastric adenocarcinoma. It is an indicator of poor prognosis in breast cancer and glioma. This study examined NET1 expression and its prognostic significance in patients with adenocarcinoma of the oesophagogastric junction (AOG). METHODS: NET1 expression was measured by immunohistochemistry in a tissue microarray, constructed from biobanked tissue collected over a 10-year interval, and linked to a prospectively maintained clinical database. RESULTS: Using the Siewert classification for AOG, type I tumours expressed significantly higher levels of NET1, with lowest expression in type III and intermediate levels in type II (P = 0.001). In patients with AOG type III, NET1-positive patients were more likely to be female (P = 0.043), have advanced stage cancer (P = 0.035), had a higher number of transmural cancers (P = 0.006) and had a significantly higher median number of positive lymph nodes (P = 0.029). In this subgroup, NET1-positive patients had worse median overall (15 versus 23 months; P = 0·025) and disease-free (11 versus 36 per cent; P = 0.025) survival compared with NET1-negative patients. CONCLUSION: Although existing data show differences in clinical and prognostic indices across AOG subtypes, there are no studies showing differences in tumour biology. These data suggest NET1, a known mediator of an aggressive tumour phenotype in a number of gastrointestinal cancers, is expressed differentially across AOG subtypes and may be of prognostic significance in the clinical management of this condition.

The COSPAR planetary protection policy for missions to Icy Worlds: A review of history, current scientific knowledge, and future directions.

Recent discoveries related to the habitability and astrobiological relevance of the outer Solar System have expanded our understanding of where and how life may have originated. As a result, the Icy Worlds of the outer Solar System have become among the highest priority targets for future spacecraft missions dedicated to astrobiology-focused and/or direct life detection objectives. This, in turn, has led to a renewed interest in planetary protection concerns and policies for the exploration of these worlds and has been a topic of discussion within the COSPAR (Committee on Space Research) Panel on Planetary Protection. This paper summarizes the results of those discussions, reviewing the current knowledge and the history of planetary protection considerations for Icy Worlds as well as suggesting ways forward. Based on those discussions, we therefore suggest to (1) Establish a new definition for Icy Worlds for Planetary Protection that captures the outer Solar System moons and dwarf planets like Pluto, but excludes more primitive bodies such as comets, centaurs, and asteroids: Icy Worlds in our Solar System are defined as all bodies with an outermost layer that is believed to be greater than 50 % water ice by volume and have enough mass to assume a nearly round shape. (2) Establish indices for the lower limits of Earth life with regards to water activity (LLAw) and temperature (LLT) and apply them into all areas of the COSPAR Planetary Protection Policy. These values are currently set at 0.5 and -28 °C and were originally established for defining Mars Special Regions; (3) Establish LLT as a parameter to assign categorization for Icy Worlds missions. The suggested categorization will have a 1000-year period of biological exploration, to be applied to all Icy Worlds and not just Europa and Enceladus as is currently the case. (4) Have all missions consider the possibility of impact. Transient thermal anomalies caused by impact would be acceptable so long as there is less than 10-4 probability of a single microbe reaching deeper environments where temperature is >LLT in the period of biological exploration. (5) Restructure or remove Category II* from the policy as it becomes largely redundant with this new approach, (6) Establish that any sample return from an Icy World should be Category V restricted Earth return.

Classical Galactosaemia in Ireland: incidence, complications and outcomes of treatment.

Newborn screening for the inborn error of metabolism, classical galactosaemia prevents life-threatening complications in the neonatal period. It does not however influence the development of long-term complications and the complex pathophysiology of this rare disease remains poorly understood. The objective of this study was to report the development of a healthcare database (using Distiller Version 2.1) to review the epidemiology of classical galactosaemia in Ireland since initiation of newborn screening in 1972 and the long-term clinical outcomes of all patients attending the National Centre for Inherited Metabolic Disorders (NCIMD). Since 1982, the average live birth incidence rate of classical galactosaemia in the total Irish population was approximately 1:16,476 births. This reflects a high incidence in the Irish 'Traveller' population, with an estimated birth incidence of 1:33,917 in the non-Traveller Irish population. Despite early initiation of treatment (dietary galactose restriction), the long-term outcomes of classical galactosaemia in the Irish patient population are poor; 30.6 % of patients ≥ 6 yrs have IQs <70, 49.6 % of patients ≥ 2.5 yrs have speech or language impairments and 91.2 % of females ≥ 13 yrs suffer from hypergonadotrophic hypogonadism (HH) possibly leading to decreased fertility. These findings are consistent with the international experience. This emphasizes the requirement for continued clinical research in this complex disorder.

Venous thromboembolism risk and prophylaxis in the acute hospital care setting: the Irish results of the ENDORSE study.

ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting), is a multinational, cross-sectional survey of venous thromboembolism (VTE) risk prevalence and effective prophylaxis in the acute hospital care setting. Three Irish hospitals enrolled in the study. The American College of Chest Physicians (ACCP) guidelines were employed to evaluate VTE risk and prophylaxis. Of 552 patients, 297 (53.8%) and 255 (46.2%) were categorised as surgical or medical, respectively, with 175 (59%) surgical and 109 (43%) medical patients deemed to be at risk for VTE. Of these, only 112 (64%) and 51 (47%) received recommended VTE prophylaxis, respectively. The results are consistent with those observed in other countries and demonstrate a high prevalence of risk for VTE and a low rate of prophylaxis use, particularly in medical patients. Awareness of VTE guidelines should be an integral component of health policy.

Direct effect of morphine on breast cancer cell function in vitro: role of the NET1 gene.

BACKGROUND: Experimental data suggest that postoperative analgesia in general and opioids in particular may affect the risk of metastases after primary cancer surgery. Perioperative single-gene activation may also spark metastatic disease. The NET1 gene promotes migration in adenocarcinoma cells. We investigated opioid receptor expression in both breast cancer cell lines and the direct effect of morphine and NET-1 on breast cancer cell migration in vitro. METHODS: Proliferation and migration of oestrogen receptor-negative MDA-MB-231 and oestrogen receptor-positive MCF7 breast cancer cells were studied after incubation with morphine 10-100 ng ml(-1) and control. NET1 gene expression was determined by polymerase chain reaction. The effect of NET1 on cell migration was determined using gene silencing with siRNA and stimulation with lysophosphatidic acid (LPA). The effect of morphine on NET1 expression and migration of cells with silenced NET1 was investigated. RESULTS: The NET1 gene was expressed in both cell lines and stimulated by LPA (2.9-fold in MCF7 and 78-fold in MDA-MB-231). NET1 expression was decreased by 96% after gene silencing in both cell lines with corresponding changes in migration. Despite the lack of opioid receptor expression, morphine increased the expression of NET1 (by 94% in MCF7 and by 263% in MDA-MB-231 cells). Morphine also increased migration by 17-27% and 7-53% in MCF7 and MDA-MB-231, respectively. Silencing the NET1 gene reversed the effect of morphine on migration. CONCLUSIONS: The NET1 gene, but not opioid receptors, is expressed in breast adenocarcinoma cells and may facilitate their migration. Morphine increased both expression of NET1 and cell migration but not when NET1 was silenced, implying that NET1 contributes to mediating the direct effect of morphine on breast cancer cell migration.

Perennial Antarctic lake ice: an oasis for life in a polar desert.

The permanent ice covers of Antarctic lakes in the McMurdo Dry Valleys develop liquid water inclusions in response to solar heating of internal aeolian-derived sediments. The ice sediment particles serve as nutrient (inorganic and organic)-enriched microzones for the establishment of a physiologically and ecologically complex microbial consortium capable of contemporaneous photosynthesis, nitrogen fixation, and decomposition. The consortium is capable of physically and chemically establishing and modifying a relatively nutrient- and organic matter-enriched microbial "oasis" embedded in the lake ice cover.

Effect of anaesthetic technique on oestrogen receptor-negative breast cancer cell function in vitro.

BACKGROUND: Metastatic recurrence is the main cause of breast cancer-related deaths. Tumour cell proliferation and migration are crucial steps in the metastatic process. Several perioperative factors, including general anaesthesia and opioid analgesia, adversely affect immune function, potentially increasing metastatic recurrence. Regional anaesthesia-analgesia has been consistently shown to attenuate the stress response to surgery, and also reduce opioid and general anaesthesia requirements, thereby attenuating this perioperative immunosuppression. We investigated the effect of serum from breast cancer surgery patients who received different anaesthetic techniques on breast cancer cell function in vitro. METHODS: Patients were randomized to receive propofol/paravertebral anaesthesia-analgesia (propofol/paravertebral, n=11) or sevoflurane general anaesthesia with opioid analgesia (sevoflurane/opioid, n=11). The ER-negative MDA-MB-231 cell line was treated with patient serum from both groups. The effects on proliferation and migration were measured. RESULTS: Treatment groups were well balanced for age, weight, surgical procedure, and cancer pathology. Pain scores were lower at 1 and 2 h in the propofol/paravertebral analgesia group. Compared with preoperative values, proliferation of MDA-MB-231 cells treated with postoperative patient serum at 10% concentration from the propofol/paravertebral group was significantly reduced compared with the sevoflurane/opioid group (-24% vs 73%, P=0.01). There was no significant change in MDA-MB-231 cell migration after treatment with patient serum between the two groups. CONCLUSIONS: Serum from patients receiving propofol/paravertebral anaesthesia for breast cancer surgery inhibited proliferation, but not migration, of ER-MDA-MB-231 cells in vitro, to a greater extent than that from patients receiving sevoflurane/opioid anaesthesia-analgesia. This implies that anaesthetic technique alters the serum molecular milieu in ways that may affect breast cancer cell function, possibly by altering anaesthetic and opioid drug administration and resultant pain scores.

An outbreak of tuberculosis affecting cattle and people on an Irish dairy farm, following the consumption of raw milk.

UNLABELLED: Bovine tuberculosis is an ongoing problem in Ireland, and herd incidence has remained at approximately 5% for some years. Spillover of infection from cattle to people remains an ever-present possibility, given the ongoing pool of infection in the Irish cattle population. This paper describes an outbreak of tuberculosis affecting cattle and people on a dairy farm in southeastern Ireland following the consumption of milk from a seven-year-old cow with tuberculous mastitis. Twenty-five of 28 calves born during autumn 2004 and spring 2005 were subsequently identified as TB reactors, and five of six family members were positive on the Mantoux test. During 2005, milk from this cow had mainly been used to feed calves, and was added only occasionally to the bulk tank. Therefore, the calves each received infected milk on an almost continuous basis between birth and weaning. The family collected milk from the bulk milk tank, and consumed it without pasteurisation. This case highlights the risks associated with the consumption of raw milk. In this family, TB has had a very significant impact on the health of two young children. These risks are well recognised, and relevant information for farmers is available. It is of concern, therefore, that raw milk consumption remains prevalent on Irish farms. New strategies are needed, in partnership with industry, to address this important issue. KEYWORDS: bovine tuberculosis, Ireland, mastitis, milk, Mycobacterium bovis, pasteurisation, TB, zoonosis.

NET1-mediated RhoA activation facilitates lysophosphatidic acid-induced cell migration and invasion in gastric cancer.

The most lethal aspects of gastric adenocarcinoma (GA) are its invasive and metastatic properties. This aggressive phenotype remains poorly understood. We have recently identified neuroepithelial cell transforming gene 1 (NET1), a guanine exchange factor (GEF), as a novel GA-associated gene. Neuroepithelial cell transforming gene 1 expression is enhanced in GA and it is of functional importance in cell invasion. In this study, we demonstrate the activity of NET1 in driving cytoskeletal rearrangement, a key pathological mechanism in gastric tumour cell migration and invasion. Neuroepithelial cell transforming gene 1 expression was increased 10-fold in response to treatment with lysophosphatidic acid (LPA), resulting in an increase in active levels of RhoA and a 2-fold increase in cell invasion. Lysophosphatidic acid-induced cell invasion and migration were significantly inhibited using either NET1 siRNA or a RhoA inhibitor (C3 exoenzyme), thus indicating the activity of both NET1 and RhoA in gastric cancer progression. Furthermore, LPA-induced invasion and migration were also significantly reduced in the presence of cytochalasin D, an inhibitor of cytoskeletal rearrangements. Neuroepithelial cell transforming gene 1 knockdown resulted in AGS cell rounding and a loss of actin filament organisation, demonstrating the function of NET1 in actin organisation. These data highlight the importance of NET1 as a driver of tumour cell invasion, an activity mediated by RhoA activation and cytoskeletal reorganisation.

Drivers of solar radiation variability in the McMurdo Dry Valleys, Antarctica.

Annually averaged solar radiation in the McMurdo Dry Valleys, Antarctica has varied by over 20 W m-2 during the past three decades; however, the drivers of this variability are unknown. Because small differences in radiation are important to water availability and ecosystem functioning in polar deserts, determining the causes are important to predictions of future desert processes. We examine the potential drivers of solar variability and systematically eliminate all but stratospheric sulfur dioxide. We argue that increases in stratospheric sulfur dioxide increase stratospheric aerosol optical depth and decrease solar intensity. Because of the polar location of the McMurdo Dry Valleys (77-78°S) and relatively long solar ray path through the stratosphere, terrestrial solar intensity is sensitive to small differences in stratospheric transmissivity. Important sources of sulfur dioxide include natural (wildfires and volcanic eruptions) and anthropogenic emission.

Proteomic analysis identifies alterations in cellular morphology and cell death pathways in mouse brain after chronic corticosterone treatment.

Some patients with Major Depression and other neurological afflictions display hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. HPA hyperactivity may be due to impaired feedback inhibition and manifested as increased levels of circulating cortisol. Subcutaneous implants of corticosterone pellets were used to mimic this situation in mice to gain insight into any effects on brain function by comparative proteomic analysis using two-dimensional Differential In-Gel Electrophoresis. A total of 150 different protein spots were altered by corticosterone treatment in the hypothalamus, hippocampus and cerebral cortex. Of these, 117 spots were identified by matrix-assisted laser desorption/ionization-time of flight mass fingerprinting equating to 51 different proteins. Association of these corticosterone-modulated proteins with biological functions using the Ingenuity Pathways Analysis tool showed that cell morphology was significantly altered in the hippocampus and cerebral cortex, whereas the hypothalamus showed significant changes in cell death. Ingenuity Pathways Analysis of the canonical signaling pathways showed that glycolysis and gluconeogenesis were altered in the hypothalamus and the hippocampus and all three brain regions showed changes in phenylalanine, glutamate and nitrogen metabolism. Further elucidation of these pathways could lead to identification of biomarkers for the development of pharmacological therapies targeted at neuropsychiatric disorders.

Foreign protein production in plant tissue cultures.

Foreign proteins synthesised by plants are now in the marketplace, and clinical trials for plant-derived therapeutic proteins are underway. Economic analysis of plant production systems has helped identify the types of protein that would be most suitable for manufacture using tissue culture methods. The major advantages associated with in vitro plant systems include the ability to manipulate environmental conditions for better control over protein levels and quality, the rapidity of production compared with agriculture, and the use of simpler and cheaper downstream processing schemes for product recovery from the culture medium.

Biogeological Raman spectroscopic studies of Antarctic lacustrine sediments.

Analysis of lacustrine sediments is an accepted method for deciphering the palaeoenvironment of a lake's catchment area, as each strata of the sediment gives information about the rock type it was eroded from and also the state of the lake, i.e. oxic or anoxic. Antarctica has long been accepted as a putative analogue for Mars, so the analysis of Antarctic material may give results that can be compared to sediments on Mars. Raman spectroscopy has been selected as the method of analysis as it does not destroy the sample, can be used in situ and requires very little sample preparation. It is a suitable method for analysing both inorganic and organic matter and a miniature spectrometer is currently being developed for use in the field. The results from the spectrometers can serve as a guide for analysing sediments on Mars. It has been shown that Raman spectroscopy can detect and differentiate between oxic and anoxic sediments. Both 1064 and 785 nm wavelengths are suitable for laser excitation of organic and inorganic matter.

Deep groundwater and potential subsurface habitats beneath an Antarctic dry valley.

The occurrence of groundwater in Antarctica, particularly in the ice-free regions and along the coastal margins is poorly understood. Here we use an airborne transient electromagnetic (AEM) sensor to produce extensive imagery of resistivity beneath Taylor Valley. Regional-scale zones of low subsurface resistivity were detected that are inconsistent with the high resistivity of glacier ice or dry permafrost in this region. We interpret these results as an indication that liquid, with sufficiently high solute content, exists at temperatures well below freezing and considered within the range suitable for microbial life. These inferred brines are widespread within permafrost and extend below glaciers and lakes. One system emanates from below Taylor Glacier into Lake Bonney and a second system connects the ocean with the eastern 18 km of the valley. A connection between these two basins was not detected to the depth limitation of the AEM survey (∼350 m).

A goal direction signal in the human entorhinal/subicular region.

Navigating to a safe place, such as a home or nest, is a fundamental behavior for all complex animals. Determining the direction to such goals is a crucial first step in navigation. Surprisingly, little is known about how or where in the brain this "goal direction signal" is represented. In mammals, "head-direction cells" are thought to support this process, but despite 30 years of research, no evidence for a goal direction representation has been reported. Here, we used fMRI to record neural activity while participants made goal direction judgments based on a previously learned virtual environment. We applied multivoxel pattern analysis to these data and found that the human entorhinal/subicular region contains a neural representation of intended goal direction. Furthermore, the neural pattern expressed for a given goal direction matched the pattern expressed when simply facing that same direction. This suggests the existence of a shared neural representation of both goal and facing direction. We argue that this reflects a mechanism based on head-direction populations that simulate future goal directions during route planning. Our data further revealed that the strength of direction information predicts performance. Finally, we found a dissociation between this geocentric information in the entorhinal/subicular region and egocentric direction information in the precuneus.

Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men.

Several lines of evidence implicate estrogen deficiency as a cause of bone loss in elderly men. Thus, in 50 elderly men (mean age +/- SD, 69.1 +/- 6.0 years), we performed a randomized blinded study to assess the effect of 6 months of treatment with 60 mg/day of raloxifene (a selective estrogen receptor modulator [SERM] that has an agonist effect on bone but is not feminizing) versus placebo on bone turnover markers. The mean changes in bone turnover markers, serum sex steroid, or lipid levels with treatment did not differ between groups. However, changes in urinary cross-linked N-telopeptide of type I collagen (NTX) excretion were related directly to the baseline serum estradiol level in the raloxifene (r = 0.57; p = 0.004) but not in the placebo-treated (r = 0.15; p = 0.485) men (p = 0.015 for the difference between groups). Moreover, the men in whom NTX excretion decreased after raloxifene treatment had significantly lower baseline estradiol levels (mean +/- SEM, 22 +/- 2 pg/ml) than the men in whom urinary NTX excretion didn't change or increased after raloxifene therapy (30 +/- 3 pg/ml; p = 0.03), and no such difference was found in the placebo group. Thus, raloxifene has no significant effect on bone turnover markers or lipid levels in elderly men. However, the association noted between baseline estradiol levels and the change in urine NTX excretion in the raloxifene-treated men suggests that a subset of men with low estradiol levels may respond to raloxifene or other SERMs, and further studies are needed to directly test this possibility.

Retinal pigment epithelial correlates of avian retinal degeneration: electron microscopic analysis.

The delayed amelanotic (DAM) strain of domestic chicken is characterized by an early, developmental onset of choroidal inflammation and destruction of both feather and choroidal melanocytes. Secondarily, retinal pigment epithelial (RPE) cells in the peripapillary region develop abnormalities, and a series of progressive histopathological changes ensues which includes reduction and ultimate loss of RPE-melanin granules and RPE-cell atrophy. The earliest sign of RPE-cell abnormality is a dramatic alteration in the distribution of intracellular melanin granules. Apical processes also show a lessening of contact with photoreceptor outer segments, leading in more advanced stages to their retraction and development of retinal detachments. Other progressive alterations in RPE cells include disorganization and loss of basal infoldings; size reductions and density increases in both mitochondria and myeloid bodies from early to advanced stages; appearance of large macrophages in the subretinal space; Loss of intercellular junctional complexes; and progressive reduction in the density of melanin granules. These abnormalities appear to spread in a cell-by-cell, radial pattern, until widespread areas of the retina become severely pathologic and atrophic. The DAM chorioretinal disorder appears to show many of the histopathologic features which characterize experimentally induced uveitis and other ocular diseases which may result from hypersensitivity to, or autoimmune reaction against, pigments of the uveal tract.