Military Anaesthesia in contingencies: what skill sets are required and how will we prepare our trainees?

The Defence Medical Services are now in an established period of contingency operations. In 2008, the Royal College of Anaesthetists approved a Military Anaesthesia Higher Training Module which could be easily achieved by deploying to the field hospital in Camp Bastion, Afghanistan, for two months under the supervision of a consultant anaesthetist. This opportunity no longer exists but the need to assure quality training and to demonstrate military skill sets is still essential. This article discusses the revised Military Higher Module and how it will be implemented in the future either during deployment or during times of peace.

Algorithm for the treatment of status epilepticus: an Australian perspective.

Convulsive status epilepticus (SE) is a medical emergency where successful treatment is associated with timely intervention and the use of a protocol has been recommended to provide the highest quality of care. Despite this, there is no nationally available protocol for the treatment of SE in adults in Australia. Treatment is therefore variable and often based on international guidelines or familiarity with certain medications. We have developed an Australian-based algorithm for the treatment of SE, focusing on simplifying management while delivering the safest possible care. We believe this algorithm is suitable for all health practitioners, regardless of training or experience.

Efficacies of spinosad and a combination of chlorpyrifos-methyl and deltamethrin against phosphine-resistant Rhyzopertha dominica (Coleoptera: Bostrichidae) and Tribolium castaneum (Coleoptera: Tenebrionidae) on wheat.

Highly phosphine-resistant populations of Rhyzopertha dominica (F.) (Coleoptera: Bostrichidae) and Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae) have recently been found in Oklahoma grain storage facilities. These findings necessitate development of a phosphine resistance management strategy to ensure continued effective use of phosphine. Therefore, we investigated the efficacies of two grain insecticides, namely, spinosad applied at label rate of 1 ppm and a mixture of chlorpyrifos-methyl and deltamethrin applied at label rates of 3 and 0.5 ppm, respectively, against highly phosphine-resistant R. dominica and T. castaneum. Adult mortality and progeny production suppression of spinosad- or chlorpyrifos-methyl + deltamethrin mixture-treated wheat that had been stored for 2, 84, 168, 252, and 336 d posttreatment were assessed. We found that both spinosad and chlorpyrifos-methyl + deltamethrin were effective against phosphine-resistant R. dominica and caused 83-100% mortality and also caused total progeny production suppression for all storage periods. Spinosad was not effective against phosphine-resistant T. castaneum; the highest mortality observed was only 3% for all the storage periods. Chlorpyrifos-methyl + deltamethrin was effective against phosphine-resistant T. castaneum only in treated wheat stored for 2 and 84 d, where it caused 93-99% mortality. However, chlorpyrifos-methyl + deltamethrin was effective and achieved total suppression of progeny production in T. castaneum for all the storage periods. Spinosad was not as effective as chlorpyrifos-methyl + deltamethrin mixture at suppressing progeny production of phosphine-resistant T. castaneum. These two insecticides can be used in a phosphine resistance management strategy for R. dominica and T. castaneum in the United States.

Allo-SCT for high-risk AML-CR1 in the molecular era: impact of FLT3/ITD outweighs the conventional markers.

Seventy-nine patients with AML in CR1 received allo-SCT between May 2006 and May 2011, and the prognostic impact of FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutation was evaluated in the context of other clinical prognostic factors. Patients with FLT3/ITD + AML had significantly inferior DFS (2-year DFS: 19% vs 64%, P = 0.0027), increased risk of relapse (1-year: 59% vs 19%, P = 0.01), and a trend towards decreased OS (P = 0.08) compared with patients without FLT3/ITD. Multivariate analysis confirmed FLT3/ITD + independently predicted a shorter DFS (HR, 3.0; 95% CI), 1.4-6.5; P = 0.01) and increased risk of relapse (HR, 4.9; 95% CI, 2.0-12.3, P = 0.01). Time to relapse in patients with FLT3/ITD + was short with 100-day cumulative risk of 45% (95% CI, 33-57). Our data suggest that the poor prognostic implication of FLT3/ITD positivity remains even after early allo-SCT in patients with FLT3/ITD + AML, and patients remain at high risk of early relapse. FLT3/ITD positivity also outweighs other conventional prognostic markers in predicting relapse.

Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project.

The promise of "personalized medicine" guided by an understanding of each individual's genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant information. We describe the operational implementation of prospective genotyping linked to an advanced clinical decision-support system to guide individualized health care in a large academic health center. This approach to personalized medicine entails engagement between patient and health-care provider, identification of relevant genetic variations for implementation, assay reliability, point-of-care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most of whom were scheduled for cardiac catheterization, were genotyped on a multiplexed platform that included genotyping for CYP2C19 variants that modulate response to the widely used antiplatelet drug clopidogrel. These data are deposited into the electronic medical record (EMR), and point-of-care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.

AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages.

The inflammasome is a signalling platform leading to caspase-1 activation. Caspase-1 causes pyroptosis, a necrotic-like cell death. AIM2 is an inflammasome sensor for cytosolic DNA. The adaptor molecule ASC mediates AIM2-dependent caspase-1 activation. To date, no function besides caspase-1 activation has been ascribed to the AIM2/ASC complex. Here, by comparing the effect of gene inactivation at different levels of the inflammasome pathway, we uncovered a novel cell death pathway activated in an AIM2/ASC-dependent manner. Francisella tularensis, the agent of tularaemia, triggers AIM2/ASC-dependent caspase-3-mediated apoptosis in caspase-1-deficient macrophages. We further show that AIM2 engagement leads to ASC-dependent, caspase-1-independent activation of caspase-8 and caspase-9 and that caspase-1-independent death is reverted upon caspase-8 inhibition. Caspase-8 interacts with ASC and active caspase-8 specifically colocalizes with the AIM2/ASC speck thus identifying the AIM2/ASC complex as a novel caspase-8 activation platform. Furthermore, we demonstrate that caspase-1-independent apoptosis requires the activation of caspase-9 and of the intrinsic pathway in a typical type II cell manner. Finally, we identify the AIM2/ASC-dependent caspase-1-independent pathway as an innate immune mechanism able to restrict bacterial replication in vitro and control IFN-γ levels in vivo in Casp1(KO) mice. This work underscores the crosstalk between inflammasome components and the apoptotic machinery and highlights the versatility of the pathway, which can switch from pyroptosis to apoptosis.

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1.

Constitutive and persistent activation of STAT3 has been implicated in the pathogenesis of many malignancies. Studies of CTCL cell lines have previously suggested that aberrant activation of STAT3 is mediated via silencing of the negative regulator SHP-1 by promoter methylation. In this study of ex vivo tumour cell populations from 18 Sézary syndrome (SS) patients, constitutive phosphorylation of STAT3, JAK1 and JAK2 was present in all patients, but was absent in comparative CD4+ T-cells from healthy controls. Furthermore, no loss or significant difference in SHP-1 expression was observed between patients and healthy control samples. Methylation-specific PCR analysis of the SHP-1 CpG island in 47 SS patients and 11 healthy controls did not detect any evidence of methylation. Moreover, small interfering RNA knockdown of SHP-1 had no effect on phosphorylation of STAT3. In contrast, treatment of SS tumour cells with the pan-JAK inhibitor pyridone 6 led to downregulation of phosphorylated STAT3 (pSTAT3), its target genes and induction of apoptosis. No evidence for common JAK1/JAK2-activating mutations was found. These data demonstrate that constitutive activation of STAT3 in SS is not due to the loss of SHP-1, but is mediated by constitutive aberrant activation of JAK family members.

The neural basis of illusory gustatory sensations: two rare cases of lexical-gustatory synaesthesia.

Lexical-gustatory synaesthesia is a rare phenomenon in which the individual experiences flavour sensations when they read, hear, or imagine words. In this study, we provide insight into the neural basis of this form of synaesthesia using functional neuroimaging. Words known to evoke pleasant, neutral, and unpleasant synaesthetic tastes and synaesthetically tasteless words were presented to two lexical-gustatory synaesthetes, during fMRI scanning. Ten non-synaesthetic participants were also scanned on the same list of words. The synaesthetic brain displayed a different pattern of activity to words when compared to the non-synaesthetes, with insula activation related to viewing words that elicited tastes that have an associated emotional valence (i.e., pleasant or unpleasant tastes). The subjective intensity of the synaesthesia was correlated with activity in the medial parietal lobes (precuneus/retrosplenial cortex), which are implicated in polymodal imagery and self-directed thought. This region has also previously been activated in studies of lexical-colour synaesthesia, suggesting its role may not be limited to the type of synaesthesia explored here.

Efficacy of heat treatment for disinfestation of concrete grain silos.

Field experiments were conducted in 2007 and 2008 to evaluate heat treatment for disinfestations of empty concrete elevator silos. A Mobile Heat Treatment Unit was used to introduce heat into silos to attain target conditions of 50 degrees C for at least 6 h. Ventilated plastic containers with a capacity of 100 g of wheat, Triticum aestivum L., held Rhyzopertha dominica (F.) (Coleoptera: Bostrichidae) and Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae). Polyvinyl chloride containers with a capacity of 300 g of wheat held adults of Liposcelis corrodens (Heymons) (Psocoptera: Liposcelididae) and Liposcelis decolor (Pearman), which were contained in 35-mm Petri dishes within the grain. Containers were fastened to a rope suspended from the top of the silo at depths of 0 m (just under the top manhole), 10 m, 20 m, and 30 m (silo floor). When the highest temperature achieved was approximately 50 degrees C for 6 h, parental mortality ofR. dominica and T. castaneum, and both psocid species was 98-100%. Progeny production of R. dominica occurred when there was parental survival, but in general R. dominica seemed less impacted by the heat treatment than T. castaneum. There was 100% mortality of L. corrodens at all depths in the heat treatments but only 92.5% mortality for L. decolor, with most survivors located in the bioassay containers at the top of the silo. Results show wheat kernels may have an insulating effect and heat treatment might be more effective when used in conjunction with sanitation and cleaning procedures.

Clinical development of 2NME-based oncology treatment regimens.

Over the past decade many signaling pathways have been identified and implicated in cancer development. This has lead to rational drug development of many new molecules that target specific nodes on one or more signaling pathways. It is now believed that targeting key parallel or compensatory pathways may require combining two or more new molecular entities (2NMEs). This approach to drug development differs from the classic case where a single component of a new combination regimen has yet to receive FDA approval. The approach presents numerous challenges to both regulatory authorities and industry sponsors. Of course, the key challenge is the usual demonstration of both safety and efficacy of the proposed combination. In addition, however, superiority of the 2NME-based regimen over both of the individual NME-based regimens and the standard of care (SOC) must be demonstrated. If the individual NME-based regimens are not very effective, then it is desirable to demonstrate the superiority of the 2NME-based regimen as early as possible in the clinical development program so that the number of patients exposed to an ineffective regimen is minimized. In this manuscript we present several strategies for clinical development programs for a 2NME-based oncology regimen. We make recommendations regarding settings where the proposed development strategies are most well suited.

Efficacy of ozone fumigation against the major grain pests in stored wheat.

Field experiments were conducted in steel bins containing 13,600 kg of hard red winter wheat, Triiticum aestivum L. One bin was treated with ozone and the second bin served as a control. Stored grain insects were placed in bins for 1-, 2-, 3-, and 4-d exposure periods in sampling tubes to test ozone concentrations of 0, 25, 50, and 70 parts per million by volume (ppmv). Ozone treatments on eggs and larvae of Plodia interpunctella (Hübner) were not effective, but pupae were more susceptible. Sitophilus oryzae (L.) adults were the most susceptible species with 100% mortality reached after 2 d in all ozone treatments. However, some progeny were produced at all concentrations and exposure periods. Tribolium castaneum (Herbst) adults had 100% mortality only after 4 d at 50 or 70 ppmv. No T. castaneum progeny were produced after 2-4 d at 70 ppmv. For Rhyzopertha dominica (F.), Cryptolestes ferrugineus (Stephens), and Oryzaephilus surinamensis (L.), 100% mortality was never achieved and progeny were produced at all ozone concentrations. Laboratory experiments, testing the effectiveness of ozone in controlling psocids, were conducted in two polyvinyl chloride cylinders each containing 55 kg of hard red winter wheat. Ozone treatment at a concentration of 70 ppmv was highly effective against adult female Liposcelis bostrychophila Badonnel and Liposcelis paeta Pearman after only 1 d of exposure. However, it was not effective against eggs of both species at all exposure periods. Ozonation has potential for the control of some stored grain insect pests on wheat.

T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension.

RATIONALE: Mounting data suggest that immune cell abnormalities participate in the pathogenesis of pulmonary arterial hypertension (PAH). OBJECTIVE: To determine whether the T lymphocyte subset composition in the systemic circulation and peripheral lung is altered in PAH. METHODS: Flow cytometric analyses were performed to determine the phenotypic profile of peripheral blood lymphocytes in idiopathic PAH (IPAH) patients (n=18) and healthy controls (n=17). Immunocytochemical analyses of lymphocytes and T cell subsets were used to examine lung tissue from PAH patients (n=11) and controls (n=11). MEASUREMENTS AND MAIN RESULTS: IPAH patients have abnormal CD8+ T lymphocyte subsets, with a significant increase in CD45RA+ CCR7- peripheral cytotoxic effector-memory cells (p=0.02) and reduction of CD45RA+ CCR7+ naive CD8+ cells versus controls (p=0.001). Further, IPAH patients have a higher proportion of circulating regulatory T cells (T(reg)) and 4-fold increases in the number of CD3+ and CD8+ cells in the peripheral lung compared with controls (p<0.01). CONCLUSIONS: Alterations in circulating T cell subsets, particularly CD8+ T lymphocytes and CD4+ T(reg), in patients with PAH suggest that a dysfunctional immune system contributes to disease pathogenesis. A preponderance of CD3+ and CD8+ T lymphocytes in the peripheral lung of PAH patients supports this concept.

The procurement of NHS dental services--a guide.

This paper gives an overview of the strategic background for procurement of NHS primary care dental services and an outline of the processes involved in procurement. The main aim is to bring procurement to the attention of a wider audience of dental practitioners and provide advice for potential primary care dental service providers. The move towards local procurement of healthcare services, including primary care dental services, has been shaped by a number of strategic Government publications and is supported by law. In line with other public bodies, the NHS is subject to the European Union and international rules regarding procurement and awarding contracts. Primary Care Trust (PCT) Dental Service Commissioners have to ensure that their procurement strategy is transparent and non-discriminatory so that all providers have an equal opportunity to compete for contracts. In order to successfully tender for future service provision contracts, dental practitioners not only need to be aware of the process of procurement and its associated legal requirements. It is also important that they have a grasp of the expectations of PCTs. Commissioning services via procurement is set to become more commonplace and it is likely, in time, that competition for some contracts will increase in intensity. The importance of researching proposals thoroughly and adopting a professional, businesslike approach to tendering cannot be understated as this maximises chance of success in the new commissioning environment.

Fatigue in patients with advanced cancer: a pilot study of an intervention with infliximab.

GOALS OF WORK: The objective of this study was to determine the effect of infliximab, an antitumor necrosis factor alpha (TNFalpha) antibody, on fatigue in patients with advanced cancer. MATERIALS AND METHODS: This was a pilot study undertaken in a specialist palliative care unit. Seventeen eligible outpatients were enrolled in this study. Infliximab 5 mg/kg was administered intravenously at baseline and if there was observable clinical benefit, every 4 weeks thereafter until clinical benefit was lost. The primary outcome measure assessing subjective functional improvement was the change in fatigue severity scale (FSS) score at 4 weeks following an infliximab infusion. Secondary outcome measures of subjective functional improvement that were assessed 4 weeks after each infliximab infusion included changes in Karnofsky performance status (KPS), hospital anxiety and depression scale (HADS) score, anxiety and depression subscores, and appetite visual analogue scale. Clinical laboratory assessments were C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), TNFalpha, interleukin-6, and leptin concentrations. MAIN RESULTS: At week 4, 9 of 14 patients improved in FSS, 3 of 15 improved in KPS, 7 of 15 improved in total HADS and the majority had modest improvements in serum CRP, ESR, or leptin concentrations. Case studies of six patients with overall improvement are described in detail. Five serious adverse events occurred; two were serious infections possibly related to treatment. CONCLUSIONS: A subgroup of patients in this small pilot study demonstrated uniform subjective/clinical benefit. We were not able to identify any predictors of this response; a larger, controlled study may reveal more information.

Comparison of yellow dent and NutriDense corn hybrids in swine diets.

Two experiments were conducted to verify the feeding value of NutriDense (ND) and Nutri-Dense Low-Phytate (NDLP) corn (Exseed Genetics LLC, BASF Plant Science, Research Triangle Park, NC) relative to that of yellow dent (YD) corn in swine diets. NutriDense corn is a high-protein, high-oil variety, and NDLP is a high-protein, high-oil, low-phytate variety. In Exp. 1, 315 nursery pigs that initially weighed 15.2 kg were used in a 21-d growth assay. Dietary treatments were arranged in a 3 x 3 factorial; main effects were corn source (YD, ND, and NDLP) and added fat (0, 3, or 6%, as-fed basis). Diets were formulated to contain 3.83 g of lysine/Mcal using calculated nutrient values. There were no corn source x fat interactions observed. Pigs fed YD, ND, and NDLP had ADG of 750, 734, and 738 g/d and G:F of 0.64, 0.66, and 0.65, respectively. No differences (P > 0.10) in ADG were observed among the three corn sources; however, pigs fed diets containing either ND or NDLP corn had decreased ADFI (P < 0.02) and improved G:F (P < 0.05) compared with pigs fed diets containing YD corn. Increasing dietary fat increased ADG (727, 746, and 748 g/d; linear, P < 0.04) and G:F (0.62, 0.66, and 0.68; linear, P < 0.01) and decreased ADFI (linear, P < 0.01). Using the NRC (1998) value for ME in YD corn, we calculated the energy value for ND and NDLP based on G:F differences compared with pigs fed YD corn. These data indicated the ME values for ND and NDLP corn are 4.5 and 2.5% greater (3,575 and 3,505 Kcal/kg), respectively, than for YD corn (3,420 Kcal/kg). In Exp. 2, 1,144 gilts (initial BW = 50.1 kg) were used in a commercial research facility to evaluate the effects of corn source (ND and YD) and added fat (0, 3, or 6%, as-fed basis) in a 2 x 3 factorial on pig performance and carcass traits. There was a corn source x fat interaction for ADFI and G:F. Increasing added fat resulted in greater changes in ADFI and G:F in pigs fed YD corn diets compared with those fed ND corn. Feeding ND corn increased ADG (main effect, P < 0.04), and greater percentages of added fat increased ADG (main effect; linear, P < 0.01). Results of Exp. 2 suggest that ND corn has 5.3% more ME than YD corn. The additional energy provided by ND corn improves G:F in both nursery and grow-finish pigs, and ND corn offers a means of formulating diets more concentrated in energy than YD corn.

Fragile X gene premutation in multiple system atrophy.

Previous reports have suggested that expansion of the CGG repeat located in the fragile X mental retardation 1 (FMR1) gene might be responsible for a significant number of patients with the multiple system atrophy (MSA) phenotype. Analysis of 65 MSA patients found only 4.6% displayed CGG expansions in the suspected range. This is similar to the frequency reported in the normal population, suggesting that this expansion does not play a major role in the MSA phenotype.

24-hour ambulatory blood pressure profile in patients with congenital adrenal hyperplasia--a preliminary report.

BACKGROUND: Blood pressure (BP) is maintained within normal limits by the interplay of various mechanisms including the action of cortisol and aldosterone. However, these hormones when exogenously administered are not under the regulatory feedback mechanisms that maintain BP homeostasis. Treatment of congenital adrenal hyperplasia (CAH) requires glucocorticoid replacement (with or without additional mineralocorticoid) at supra-physiological doses to normalize the pituitary adrenocortical axis. HYPOTHESIS: Long-term use of glucocorticoids at supra-physiological doses may result in high BP. OBJECTIVE: To document any changes in BP in patients with CAH following long-term conventional glucocorticoid replacement therapy. PATIENTS AND METHODS: 24-hour ambulatory BP (AmBP) monitoring was performed in 11 patients with CAH, all of whom were on glucocorticoid replacement at supra-physiological doses. In addition, a single random BP measurement was taken in each patient at enrolment. Mean systolic and diastolic pressure during awake and sleep periods, systolic and diastolic BP loads, and systolic and diastolic BP dips were calculated from the 24-hour AmBP profile of each patient, which was correlated with demographic and treatment details. AmBP readings were compared to Task Force references for casual BP and also to recently available AmBP specific reference values. RESULTS: None of the patients had significant BP loads at the 95th percentile (hypertensive BP range) using references for casual BP readings. However, in the subgroup of patients who had significant BP load at the 90' percentile (high normal BP range), higher mean systolic and diastolic pressures were noticed during the awake period. Seven patients did not have a systolic dip with or without a diastolic dip. There was no significant correlation between various BP parameters and demographic or treatment details in our sample. However, one patient had daytime systolic hypertension and six had nocturnal hypertension using AmBP specific reference values. CONCLUSIONS: In this preliminary study, longterm glucocorticoid replacement therapy at supra-physiological doses does not seem to be associated with hypertension in young people with CAH when using casual BP references. However, higher mean BP was noticed in the subgroup of patients with significant systolic or diastolic BP load at high normal BP range, and evidence of daytime and nocturnal hypertension was uncovered using AmBP specific reference values. Further large trials using appropriate BP references are necessary to clarify the significance of these findings.

Localization of MtuA, an LraI homologue in Streptococcus uberis.

AIMS: To determine the localization of MtuA, an LraI lipoprotein within Streptococcus uberis and assess whether the protein was able to induce an antibody response capable of growth inhibition. METHODS AND RESULTS: Immunoblots and ELISAs were performed on S. uberis cell fractions to localize the protein. The strongest reactivity was within the membrane-enriched fraction. Electron micrographs also showed labelling consistent with a location within the membrane. Specific antibodies from both rabbits and calves were unable to inhibit the growth of S. uberis in milk. In addition, MtuA was not detectable in a whole-cell ELISA and whole bacterial cells were unable to adsorb specific antibodies from antiserum raised against MtuA. CONCLUSIONS: The MtuA protein appears to be located within the cell membrane and is not on the bacterial surface and thus not available for interaction with potentially growth-inhibiting antibodies. SIGNIFICANCE AND IMPACT OF THE STUDY: Unlike PsaA of S. pneumoniae and MtsA of S. pyogenes, MtuA of S. uberis does not appear to be located at the cell surface. Therefore, in contrast to studies with other similar proteins, MtuA is unlikely to be a good vaccine candidate.