Quantum Quenches in Isolated Quantum Glasses out of Equilibrium.

In this work, we address the question of how a closed quantum system thermalizes in the presence of a random external potential. By investigating the quench dynamics of the isolated quantum spherical p-spin model, a paradigmatic model of a mean-field glass, we aim to shed new light on this complex problem. Employing a closed-time Schwinger-Keldysh path integral formalism, we first initialize the system in a random, infinite-temperature configuration and allow it to equilibrate in contact with a thermal bath before switching off the bath and performing a quench. We find evidence that increasing the strength of either the interactions or the quantum fluctuations can act to lower the effective temperature of the isolated system and stabilize glassy behavior.

Neuro-Oncology and Radiogenomics: Time to Integrate?

Radiogenomics aims to predict genetic markers based on imaging features. The critical importance of molecular markers in the diagnosis and management of intracranial gliomas has led to a rapid growth in radiogenomics research, with progressively increasing complexity. Despite the advances in the techniques being examined, there has been little translation into the clinical domain. This has resulted in a growing disconnect between cutting-edge research and assimilation into clinical practice, though the fundamental goal is for these techniques to improve patient care. The goal of this review, therefore, is to discuss possible clinical scenarios in which the addition of radiogenomics may aid patient management. This includes facilitating patient counseling, determining optimal patient management when complete molecular characterization is not possible, reclassifying tumors, and overcoming some of the limitations of histologic assessment. The review also discusses considerations for selecting relevant radiogenomic features based on the clinical setting.

Collective vibrations of a hydrodynamic active lattice.

Recent experiments show that quasi-one-dimensional lattices of self-propelled droplets exhibit collective instabilities in the form of out-of-phase oscillations and solitary-like waves. This hydrodynamic lattice is driven by the external forcing of a vertically vibrating fluid bath, which invokes a field of subcritical Faraday waves on the bath surface, mediating the spatio-temporal droplet coupling. By modelling the droplet lattice as a memory-endowed system with spatially non-local coupling, we herein rationalize the form and onset of instability in this new class of dynamical oscillator. We identify the memory-driven instability of the lattice as a function of the number of droplets, and determine equispaced lattice configurations precluded by geometrical constraints. Each memory-driven instability is then classified as either a super- or subcritical Hopf bifurcation via a systematic weakly nonlinear analysis, rationalizing experimental observations. We further discover a previously unreported symmetry-breaking instability, manifest as an oscillatory-rotary motion of the lattice. Numerical simulations support our findings and prompt further investigations of this nonlinear dynamical system.

Assessment of CXC ligand 12-mediated calcium signalling and its regulators in basal-like breast cancer cells.

CXC ligand (L)12 is a chemokine implicated in the migration, invasion and metastasis of cancer cells via interaction with its receptors CXC chemokine receptor (CXCR)4 and CXCR7. In the present study, CXCL12-mediated Ca2+ signalling was compared with two basal-like breast cancer cell lines, MDA-MB-231 and MDA-MB-468, which demonstrate distinct metastatic potential. CXCL12 treatment induced Ca2+ responses in the more metastatic MDA-MB-231 cells but not in the less metastatic MDA-MB-468 cells. Assessment of mRNA levels of CXCL12 receptors and their potential modulators in both cell lines revealed that CXCR4 and CXCR7 levels were increased in MDA-MB-231 cells compared with MDA-MB-468 cells. Cluster of differentiation (CD)24, the negative regulator of CXCL12 responses, demonstrated increased expression in MDA-MB-468 cells compared with MDA-MB-231 cells, and the two cell lines expressed comparable levels of hypoxia-inducible factor (HIF)2α, a CXCR4 regulator. Induction of epithelial-mesenchymal transition (EMT) by epidermal growth factor exhibited opposite effects on CXCR4 mRNA levels compared with hypoxia-induced EMT. Neither EMT inducer exhibited an effect on CXCR7 expression, however hypoxia increased HIF2α expression levels in MDA-MB-468 cells. Analysis of the gene expression profiles of breast tumours revealed that the highest expression levels of CXCR4 and CXCR7 were in the Claudin-Low molecular subtype, which is markedly associated with EMT features.

Oncosis and apoptosis induction by activation of an overexpressed ion channel in breast cancer cells.

The critical role of calcium signalling in processes related to cancer cell proliferation and invasion has seen a focus on pharmacological inhibition of overexpressed ion channels in specific cancer subtypes as a potential therapeutic approach. However, despite the critical role of calcium in cell death pathways, pharmacological activation of overexpressed ion channels has not been extensively evaluated in breast cancer. Here we define the overexpression of transient receptor potential vanilloid 4 (TRPV4) in a subgroup of breast cancers of the basal molecular subtype. We also report that pharmacological activation of TRPV4 with GSK1016790A reduced viability of two basal breast cancer cell lines with pronounced endogenous overexpression of TRPV4, MDA-MB-468 and HCC1569. Pharmacological activation of TRPV4 produced pronounced cell death through two mechanisms: apoptosis and oncosis in MDA-MB-468 cells. Apoptosis was associated with PARP-1 cleavage and oncosis was associated with a rapid decline in intracellular ATP levels, which was a consequence of, rather than the cause of, the intracellular ion increase. TRPV4 activation also resulted in reduced tumour growth in vivo. These studies define a novel therapeutic strategy for breast cancers that overexpress specific calcium permeable plasmalemmal ion channels with available selective pharmacological activators.

A Case of Fulminant Hepatitis due to Echovirus 9 in a Patient on Maintenance Rituximab Therapy for Follicular Lymphoma.

Rituximab is a CD20 monoclonal antibody commonly used in the treatment of haematological malignancies. It causes lymphopenia with subsequent compromised humoral immunity resulting in an increased risk of infection. A number of infections and viral reactivations have been described as complicating Rituximab therapy. We report an apparently unique case of echovirus 9 (an enterovirus) infection causing an acute hepatitis and significant morbidity in an adult patient on maintenance treatment of Rituximab for follicular lymphoma. We also describe potential missed opportunities to employ more robust screening for viral infections which may have prevented delays in the appropriate treatment and thus may have altered the patient's clinical course. We also make suggestions for lowering the threshold of viral testing in similar patients in the future.

Calcium influx pathways in breast cancer: opportunities for pharmacological intervention.

Ca(2+) influx through Ca(2+) permeable ion channels is a key trigger and regulator of a diverse set of cellular events, such as neurotransmitter release and muscle contraction. Ca(2+) influx is also a regulator of processes relevant to cancer, including cellular proliferation and migration. This review focuses on calcium influx in breast cancer cells as well as the potential for pharmacological modulators of specific Ca(2+) influx channels to represent future agents for breast cancer therapy. Altered expression of specific calcium permeable ion channels is present in some breast cancers. In some cases, such changes can be related to breast cancer subtype and even prognosis. In vitro and in vivo models have now helped identify specific Ca(2+) channels that play important roles in the proliferation and invasiveness of breast cancer cells. However, some aspects of our understanding of Ca(2+) influx in breast cancer still require further study. These include identifying the mechanisms responsible for altered expression and the most effective therapeutic strategy to target breast cancer cells through specific Ca(2+) channels. The role of Ca(2+) influx in processes beyond breast cancer cell proliferation and migration should become the focus of studies in the next decade.

Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent.

Signals from the tumor microenvironment trigger cancer cells to adopt an invasive phenotype through epithelial-mesenchymal transition (EMT). Relatively little is known regarding key signal transduction pathways that serve as cytosolic bridges between cell surface receptors and nuclear transcription factors to induce EMT. A better understanding of these early EMT events may identify potential targets for the control of metastasis. One rapid intracellular signaling pathway that has not yet been explored during EMT induction is calcium. Here we show that stimuli used to induce EMT produce a transient increase in cytosolic calcium levels in human breast cancer cells. Attenuation of the calcium signal by intracellular calcium chelation significantly reduced epidermal growth factor (EGF)- and hypoxia-induced EMT. Intracellular calcium chelation also inhibited EGF-induced activation of signal transducer and activator of transcription 3 (STAT3), while preserving other signal transduction pathways such as Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. To identify calcium-permeable channels that may regulate EMT induction in breast cancer cells, we performed a targeted siRNA-based screen. We found that transient receptor potential-melastatin-like 7 (TRPM7) channel expression regulated EGF-induced STAT3 phosphorylation and expression of the EMT marker vimentin. Although intracellular calcium chelation almost completely blocked the induction of many EMT markers, including vimentin, Twist and N-cadherin, the effect of TRPM7 silencing was specific for vimentin protein expression and STAT3 phosphorylation. These results indicate that TRPM7 is a partial regulator of EMT in breast cancer cells, and that other calcium-permeable ion channels are also involved in calcium-dependent EMT induction. In summary, this work establishes an important role for the intracellular calcium signal in the induction of EMT in human breast cancer cells. Manipulation of calcium-signaling pathways controlling EMT induction in cancer cells may therefore be an important therapeutic strategy for preventing metastases.

The patient presenting with decompensated cirrhosis.

The rates of liver disease in the UK are rising and hence more patients than ever are presenting to acute medical units with potentially life threatening sequelae. Early recognition and treatment of sepsis, kidney injury, bleeding and alcoholic hepatitis can significantly improve outcomes, but requires a comprehensive approach to assessment. This patient cohort often suffers from a perceived uniform poor prognosis, especially in alcohol related disease, but evidence for this is changing and reassessment of prognosis after 48 hours of organ support may be more accurate than that made 'at the front door'. This article summarises the most important complications of decompensated cirrhosis, their early management, and presents a targeted system of care: 'RING Liver'--Renal failure, Infection, Nutrition, Gastrointestinal bleeding and transit, Liver dysfunction/transplantation. Factors favouring transfer to tertiary units are also explored.

Review article: towards a considered and ethical approach to organ support in critically-ill patients with cirrhosis.

BACKGROUND: Increasing numbers of patients are being admitted to hospital with decompensated chronic liver disease in the UK. A significant proportion will develop complicating extra-hepatic organ dysfunction, but the selection of those who should be admitted to intensive care is complex and challenging. Alcohol-related liver disease also presents complex ethical dilemmas. AIM: To review recent survival analyses and explore differences in secondary and tertiary care; to highlight strengths and weaknesses of prognostic models, therapeutic advances and shifts in prognostic expectation. We also aim to explore the ethical challenges presented by addiction and self-injury in an area of limited resource. METHODS: We searched PubMed for articles discussing 'cirrhosis', 'prognosis', 'critical illness', 'organ failure', 'renal failure', 'alcohol', 'ethics' and 'addiction'. We also explored particular ethical dilemmas encountered by the authors and colleagues. RESULTS: Prognosis has improved in many cirrhotic complications and historically poor outcomes in tertiary care may reflect a more complex patient cohort. Previously 'untreatable' complications are now being managed successfully. Estimates of survival are more accurate after a 48-h period of supportive care. Physicians are not best placed to make judgments with regard to deservingness, moral responsibility, rationing and access to organ support in cases of acute deterioration related to alcoholism, and the case for denying support must be made on purely medical grounds. CONCLUSIONS: An early, aggressive approach to organ support is justified. Further discussions between hepatologists and critical care physicians are required to determine acceptable burden-to-benefit ratios for prolonged intensive care support in young alcoholic patients.

Clostridium difficile-associated disease acquired in the neurocritical care unit.

BACKGROUND: Clostridium difficile is an important cause of nosocomial infection on the intensive care unit. Little is known about infection rates on the neurocritical care unit (NICU). The purpose of this study was to determine the prevalence, severity, and outcome associated with Clostridium difficile-associated disease (CDAD) acquired on the NICU. METHODS: Patients on NICU with a positive stool Clostridium difficile toxin assay, from August 2004 to February 2008, were identified by the Department of Microbiology. Each patient's medical notes and charts were reviewed in turn. Patients with a positive assay within 48 h of NICU admission were excluded. RESULTS: Twenty-one (0.6%) NICU patients developed CDAD. All were emergency admissions, 18 (86.0%) were neurosurgical. Subarachnoid hemorrhage was the most common diagnosis, 5 (23.8%) patients. Median age and APACHE II score on admission were 55 (IQR 40-66) and 21 (IQR 16-24), respectively. Thirteen (61.9%) patients were female. Median interval between NICU admission and diarrhea onset and CDAD diagnosis were 5 (3-8) days and 7 (4-12) days, respectively. At the time of diagnosis most, 11 (52.4%) patients, had moderate CDAD. Previously identified risk factors for ICU-acquired CDAD comprised: age > 65 (6), antibiotics (21), and medical device requirements (21). Five (23.8%) patients deteriorated clinically as a result of CDAD. The overall in-hospital mortality for those with NICU acquired CDAD was 19%. CONCLUSIONS: Although CDAD is rarely acquired on the NICU, up to one quarter of affected patients may experience complications. Prospective validation of severity definitions and treatment guidelines may help to reduce the complication rates.

Outcomes of critically ill patients with cirrhosis admitted to intensive care: an important perspective from the non-transplant setting.

BACKGROUND: Hospital admissions for cirrhosis have been increasing in the United Kingdom, leading to increased pressure on intensive care (ICU) services. Outcome data for patients admitted to ICU are currently limited to transplant centre reports, with mortality rates exceeding 70%. These tertiary reports could fuel a negative bias when patients with cirrhosis are reviewed for ICU admission in secondary care. AIMS: To determine whether disease severity and mortality rates in non-transplant general ICU are less severe than those reported by tertiary datasets. METHODS: A prospective dual-centre non-transplant ICU study. Admissions were screened for cirrhosis and physiological and biochemical data were collected. Disease-specific and critical illness scoring systems were evaluated. RESULTS: Cirrhosis was present in 137/4198 (3.3%) of ICU admissions. ICU and hospital mortality were 38% and 47%, respectively; median age 50 [43-59] years, 68% men, 72% alcoholic cirrhosis, median Child Pugh Score (CPS) 10 [8-11], Model for End-Stage Liver Disease (MELD) 18 [12-24], Acute Physiology and Chronic Health Evaluation II score (APACHE II) 16 [13-22]. CONCLUSIONS: Mortality rates and disease staging were notably lower than in the published literature, suggesting that patients have a more favourable outlook than previously considered. Transplant centre data should therefore be interpreted with caution when evaluating the merits of intensive care admission for patients in general secondary care ICUs.

The increasing hospital disease burden of haemochromatosis in England.

BACKGROUND: Hereditary haemochromatosis is a preventable cause of liver disease with an increasing disease burden. AIMS: To investigate time trends for hospital admission ascribed to haemochromatosis in England during the period from 1989/1990 to 2002/2003 and mortality from 1979 to 2005. METHODS: Hospital admission data, relating to both in-patients and day-cases, were obtained from the Hospital Episodes Statistics service. Mortality rates for England and Wales were provided by the Office for National Statistics. RESULTS: Haemochromatosis is an uncommon cause for hospital admission. Age-standardized in-patient admission rates increased over the study period by 269% in men and by 290% in women: (from 0.64 to 2.36 and from 0.21 to 0.81 per year per 100 000). The increase in age-standardized day-case admission rates was even higher (men: from 2.78 to 34.9 per year per 100 000, 1155%; women: from 0.58 to 11.67 per year per 100 000, 1924%). Haemochromatosis was recorded as an uncommon cause of death. CONCLUSIONS: Hospital in-patient and day case admissions for haemochromatosis increased markedly over the study period while mortality remained low. Both admission rates and mortality were higher in men than in women. The increase in admission rate may reflect improved recognition and diagnosis of iron overload disorders following identification of the HFE gene.

'Liver function tests' on the intensive care unit: a prospective, observational study.

AIMS: To evaluate the prevalence, patterns and significance of deranged liver function tests (LFT) in critically ill patients. METHODS: A prospective, observational data collection of the LFT [bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (AKP), gamma glutaryl transferase (gammaGT)] and critical care parameters in all admissions to the general intensive care unit (ICU) of our institution. Prevalence of abnormal LFT on the day of ITU admission is described and the relationship of abnormal LFT to clinical events and 30-day mortality analysed. RESULTS: Of 263 first admissions without hepatobiliary disease, 61% demonstrated an abnormal LFT at the point of admission. The majority of abnormalities were less than twice the upper limit of normal. Episodes of ventilation, haemofiltration and hypotension during the first 48 h were associated with an abnormal ALT on day 3. The presence of an abnormal ALT [odds ratio 2.7 (1.2-6.0)], AKP [OR 2.8 (1.1-7.3)] or gammaGT [OR 3.9 (1.9-8.3)] was associated with an increased risk of death within 30 days of admission. When adjusted for APACHE II score, LFTs were not independent predictors of mortality. DISCUSSION: Low-grade abnormalities of LFT are a significant entity in critically ill patients and show an association with mortality outcomes and clinical events on ICU. They are likely to represent part of a spectrum of liver injury associated with critical illness and should not be disregarded.

United States Department of Agriculture-Agricultural Research Service research in application technology for pest management.

A research summary is presented that emphasizes ARS achievements in application technology over the past 2-3 years. Research focused on the improvement of agricultural pesticide application is important from the standpoint of crop protection as well as environmental safety. Application technology research is being actively pursued within the ARS, with a primary focus on application system development, drift management, efficacy enhancement and remote sensing. Research on application systems has included sensor-controlled hooded sprayers, new approaches to direct chemical injection, and aerial electrostatic sprayers. For aerial application, great improvements in on-board flow controllers permit accurate field application of chemicals. Aircraft parameters such as boom position and spray release height are being altered to determine their effect on drift. Other drift management research has focused on testing of low-drift nozzles, evaluation of pulsed spray technologies and evaluation of drift control adjuvants. Research on the use of air curtain sprayers in orchards, air-assist sprayers for row crops and vegetables, and air deflectors on aircraft has documented improvements in application efficacy. Research has shown that the fate of applied chemicals is influenced by soil properties, and this has implications for herbicide efficacy and dissipation in the environment. Remote sensing systems are being used to target areas in the field where pests are present so that spray can be directed to only those areas. Soil and crop conditions influence propensity for weeds and insects to proliferate in any given field area. Research has indicated distinct field patterns favorable for weed growth and insect concentration, which can provide further assistance for targeted spraying.

Optimisation of polystyrene resin-supported Pt catalysts in room temperature, solvent-less, oct-l-ene hydrosilylation using methyldichlorosilane.

Six precursor resins with systematic variation of porous parameters were prepared by suspension polymerisation using specific compositions of divinylbenzene, styrene vinylbenzyl chloride (VBC) and 2-ethylhexan-l-ol (a porogen). Surface areas from N(2) sorption and BET analysis were approximately 2-170 m(2)g-(1). The VBC content in each case was 38 mol% and these groups were aminated using the sodium salt of trimethylethylene diamine. Pt was introduced onto each resin at three different loadings (approximately 0.03, approximately 0.2 and approximately 0.4 mmol g-(1)) by appropriate manipulation of K(2)PtCl(6). The matrix of 18 resin-supported Pt complexes was then assessed for catalytic activity in the room temperature, solvent-less, hydrosilylation of oct-l-ene using methyldichlorosilane such that alkene: silane: Pt ratio was fixed at 2:1:1x10(-3). Though all the catalysts showed activity lower than that of homogeneous Speier s catalyst, most were sufficiently active to be potentially valuable heterogeneous catalysts in the laboratory, and indeed the plant. The most lightly loaded resins proved to be the least active. The remainder were recycled 5 times, and the best performers, the most highly loaded species, a further 5 times making 10 consecutive uses in all. A strong dependence on the porous structure of the resins was demonstrated with the activity rising systemically with the surface area. The two highest surface area highest loaded species displayed good activity even when used for the tenth time. The level of concurrent alkene isomerisation observed was very low throughout (<1%) making these heterogeneous species very selective as well as highly active. Overall the derived catalysts are excellent candidates for use in the research laboratory, and with further development could also be valuable in continuous processes.

Activation of the peroxisome proliferator-activated receptor-alpha enhances cell death in cultured cerebellar granule cells.

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a member of the steroid hormone receptor superfamily. In rodents, PPARalpha alters genes involved in cell cycle regulation in hepatocytes. Some of these genes are implicated in neuronal cell death. Therefore, in this study, we examined the toxicological consequence of PPARalpha activation in rat primary cultures of cerebellar granule neurons. Our studies demonstrated the presence of PPARalpha mRNA in cultures by reverse transcriptase-polymerase chain reaction. After 10 days in vitro, cerebellar granule neuron cultures were incubated with the selective PPARalpha activator 4-chloro-6-(2,3-xylidino)2-pyrimidinylthioacetic acid (Wy-14,643). The inherent toxicity of Wy-14,643 and the effect of PPARalpha activation following toxic stimuli were assessed. In these studies, neurotoxicity was induced through reduction of extracellular [KCl] from 25 mM to 5.36 mM. We observed no inherent toxicity of Wy-14,643 (24 hr) in cultured cerebellar granule cells. However, after reduction of [KCl], cerebellar granule cell cultures incubated with Wy-14,643 showed significantly greater toxicity than controls. These results suggest a possible role for PPARalpha in augmentation of cerebellar granule neuronal death after toxic stimuli.

PMCA1 mRNA expression in rat aortic myocytes: a real-time RT-PCR study.

The plasmalemmal Ca(2+) adenosine triphosphatase (PMCA) is a key regulator of Ca(2+) efflux in vascular smooth muscle. In these studies we developed a real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR) assay for assessing PMCA1 mRNA levels in rat primary cultured aortic myocytes. This assay detected fetal bovine serum-induced increases in PMCA1 mRNA (relative to 18S rRNA) 4, 8, and 24 h after stimulation. Early fetal bovine serum-induced increases in PMCA1 mRNA were insensitive to the Ca(2+) channel blockers nifedipine, flunarizine, and SKF-96365. These studies demonstrate the feasibility of real-time RT-PCR to assess mRNA levels of PMCA1 and illustrate dynamic regulation of this Ca(2+) pump isoform in rat primary cultured aortic myocytes.